[Title 21 CFR ]
[Code of Federal Regulations (annual edition) - April 1, 2024 Edition]
[From the U.S. Government Publishing Office]



[[Page i]]

          

          Title 21

Food and Drugs


________________________

Parts 200 to 299

                         Revised as of April 1, 2024

          Containing a codification of documents of general 
          applicability and future effect

          As of April 1, 2024
                    Published by the Office of the Federal Register 
                    National Archives and Records Administration as a 
                    Special Edition of the Federal Register

[[Page ii]]

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                            Table of Contents



                                                                    Page
  Explanation.................................................       v

  Title 21:
          Chapter I--Food and Drug Administration, Department 
          of Health and Human Services (Continued)                   3
  Finding Aids:
      Table of CFR Titles and Chapters........................     241
      Alphabetical List of Agencies Appearing in the CFR......     261
      List of CFR Sections Affected...........................     271

[[Page iv]]





                     ----------------------------

                     Cite this Code: CFR
                     To cite the regulations in 
                       this volume use title, 
                       part and section number. 
                       Thus, 21 CFR 200.5 refers 
                       to title 21, part 200, 
                       section 5.

                     ----------------------------

[[Page v]]



                               EXPLANATION

    The Code of Federal Regulations is a codification of the general and 
permanent rules published in the Federal Register by the Executive 
departments and agencies of the Federal Government. The Code is divided 
into 50 titles which represent broad areas subject to Federal 
regulation. Each title is divided into chapters which usually bear the 
name of the issuing agency. Each chapter is further subdivided into 
parts covering specific regulatory areas.
    Each volume of the Code is revised at least once each calendar year 
and issued on a quarterly basis approximately as follows:

Title 1 through Title 16.................................as of January 1
Title 17 through Title 27..................................as of April 1
Title 28 through Title 41...................................as of July 1
Title 42 through Title 50................................as of October 1

    The appropriate revision date is printed on the cover of each 
volume.

LEGAL STATUS

    The contents of the Federal Register are required to be judicially 
noticed (44 U.S.C. 1507). The Code of Federal Regulations is prima facie 
evidence of the text of the original documents (44 U.S.C. 1510).

HOW TO USE THE CODE OF FEDERAL REGULATIONS

    The Code of Federal Regulations is kept up to date by the individual 
issues of the Federal Register. These two publications must be used 
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    To determine whether a Code volume has been amended since its 
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Register page number of the latest amendment of any given rule.

EFFECTIVE AND EXPIRATION DATES

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inserted following the text.

OMB CONTROL NUMBERS

    The Paperwork Reduction Act of 1980 (Pub. L. 96-511) requires 
Federal agencies to display an OMB control number with their information 
collection request.

[[Page vi]]

Many agencies have begun publishing numerous OMB control numbers as 
amendments to existing regulations in the CFR. These OMB numbers are 
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requirements.

PAST PROVISIONS OF THE CODE

    Provisions of the Code that are no longer in force and effect as of 
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the Code prior to the LSA listings at the end of the volume, consult 
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2001, consult the List of CFR Sections Affected compilations, published 
for 1949-1963, 1964-1972, 1973-1985, and 1986-2000.

``[RESERVED]'' TERMINOLOGY

    The term ``[Reserved]'' is used as a place holder within the Code of 
Federal Regulations. An agency may add regulatory information at a 
``[Reserved]'' location at any time. Occasionally ``[Reserved]'' is used 
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INCORPORATION BY REFERENCE

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This material, like any other properly issued regulation, has the force 
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Federal Register will approve an incorporation by reference only when 
the requirements of 1 CFR part 51 are met. Some of the elements on which 
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    (a) The incorporation will substantially reduce the volume of 
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    (b) The matter incorporated is in fact available to the extent 
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    An index to the text of ``Title 3--The President'' is carried within 
that volume.

[[Page vii]]

    The Federal Register Index is issued monthly in cumulative form. 
This index is based on a consolidation of the ``Contents'' entries in 
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the revision dates of the 50 CFR titles.

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    Oliver A. Potts,
    Director,
    Office of the Federal Register
    April 1, 2024.







[[Page ix]]



                               THIS TITLE

    Title 21--Food and Drugs is composed of nine volumes. The parts in 
these volumes are arranged in the following order: Parts 1-99, 100-169, 
170-199, 200-299, 300-499, 500-599, 600-799, 800-1299 and 1300 to end. 
The first eight volumes, containing parts 1-1299, comprise Chapter I--
Food and Drug Administration, Department of Health and Human Services. 
The ninth volume, containing part 1300 to end, includes Chapter II--Drug 
Enforcement Administration, Department of Justice, and Chapter III--
Office of National Drug Control Policy. The contents of these volumes 
represent all current regulations codified under this title of the CFR 
as of April 1, 2024.

    For this volume, Susannah C. Hurley was Chief Editor. The Code of 
Federal Regulations publication program is under the direction of John 
Hyrum Martinez, assisted by Stephen J. Frattini.

[[Page 1]]



                        TITLE 21--FOOD AND DRUGS




                  (This book contains parts 200 to 299)

  --------------------------------------------------------------------
                                                                    Part

chapter i--Food and Drug Administration, Department of 
  Health and Human Services (Continued).....................         200

[[Page 3]]



CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN 
                          SERVICES (CONTINUED)




  --------------------------------------------------------------------


  Editorial Note: Nomenclature changes to chapter I appear at 59 FR 
14366, Mar. 28, 1994, and 66 FR 56035, Nov. 6, 2001.

                      SUBCHAPTER C--DRUGS: GENERAL
Part                                                                Page
200             General.....................................           5
201             Labeling....................................           8
202             Prescription drug advertising...............         106
203             Prescription drug marketing.................         116
205             Guidelines for State licensing of wholesale 
                    prescription drug distributors..........         128
206             Imprinting of solid oral dosage form drug 
                    products for human use..................         133
207             Requirements for foreign and domestic 
                    establishment registration and listing 
                    for human drugs, including drugs that 
                    are regulated under a biologics license 
                    application, and animal drugs, and the 
                    national drug code......................         134
208             Medication Guides for prescription drug 
                    products................................         150
209             Requirement for authorized dispensers and 
                    pharmacies to distribute a side effects 
                    statement...............................         154
210             Current good manufacturing practice in 
                    manufacturing, processing, packing, or 
                    holding of drugs; general...............         155
211             Current good manufacturing practice for 
                    finished pharmaceuticals................         157
212             Current good manufacturing practice for 
                    positron emission tomography drugs......         178
216             Human drug compounding......................         187
225             Current good manufacturing practice for 
                    medicated feeds.........................         190
226             Current good manufacturing practice for Type 
                    A medicated articles....................         197
250             Special requirements for specific human 
                    drugs...................................         202

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251             Section 804 importation program.............         210
290             Controlled drugs............................         234
299             Drugs; official names and established names.         235

[[Page 5]]



                       SUBCHAPTER C_DRUGS: GENERAL





PART 200_GENERAL--Table of Contents



                      Subpart A_General Provisions

Sec.
200.5 Mailing of important information about drugs.
200.7 Supplying pharmacists with indications and dosage information.
200.10 Contract facilities (including consulting laboratories) utilized 
          as extramural facilities by pharmaceutical manufacturers.
200.11 Use of octadecylamine in steam lines of drug establishments.
200.15 Definition of term ``insulin''.

Subpart B [Reserved]

          Subpart C_Requirements for Specific Classes of Drugs

200.50 Ophthalmic preparations and dispensers.
200.51 Aqueous-based drug products for oral inhalation.

Subpart D [Reserved]

           Subpart E_Prescription Drug Consumer Price Listing

200.200 Prescription drugs; reminder advertisements and reminder 
          labeling to provide price information to consumers.

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360e, 371, 
374, 375.

    Source: 40 FR 13996, Mar. 27, 1975, unless otherwise noted.



                      Subpart A_General Provisions



Sec.  200.5  Mailing of important information about drugs.

    Manufacturers and distributors of drugs and the Food and Drug 
Administration occasionally are required to mail important information 
about drugs to physicians and others responsible for patient care. In 
the public interest, such mail should be distinctive in appearance so 
that it will be promptly recognized and read. The Food and Drug 
Administration will make such mailings in accordance with the 
specifications set forth in this section. Manufacturers and distributors 
of drugs are asked to make such mailings as prescribed by this section 
and not to use the distinctive envelopes for ordinary mail.
    (a) Use first class mail and No. 10 white envelopes.
    (b) The name and address of the agency or the drug manufacturer or 
distributor is to appear in the upper left corner of the envelope.
    (c) The following statements are to appear in the far left third of 
the envelope front, in the type and size indicated, centered in a 
rectangular space approximately 3 inches wide and 2\1/4\ inches high 
with an approximately \3/8\ inch-wide border in the color indicated:
    (1) When the information concerns a significant hazard to health, 
the statement:

                                IMPORTANT

                                  DRUG

                                 WARNING


The statement shall be in three lines, all capitals, and centered. 
``Important'' shall be in 36 point Gothic Bold type. ``Drug'' and 
``Warning'' shall be in 36 point Gothic Condensed type. The rectangle's 
border and the statement therein shall be red.
    (2) When the information concerns important changes in drug package 
labeling, the statement:

                                IMPORTANT

                               PRESCRIBING

                               INFORMATION


The statement shall be in three lines, all capitals, and centered. 
``Important'' shall be in 36 point Gothic Bold type. ``Prescribing'' and 
``Information'' shall be in 36 point Gothic Condensed type. The 
rectangle's border and the statement therein shall be blue.
    (3) When the information concerns a correction of prescription drug 
advertising or labeling, the statement:


[[Page 6]]



                                IMPORTANT

                               CORRECTION

                                 OF DRUG

                               INFORMATION


The statement shall be in four lines, all capitals, and centered. 
``Important'' shall be in 36 point Gothic Bold type. ``Correction,'' 
``Of Drug,'' and ``Information'' shall be in 36 point Gothic Condensed 
type. The rectangle's border and the statement therein shall be brown.



Sec.  200.7  Supplying pharmacists with indications and dosage information.

    There are presently no regulations under the Federal Food, Drug, and 
Cosmetic Act that prevent a manufacturer of prescription drugs from 
sending the pharmacist data he needs on indications and dosage in 
exercising his important professional function of checking against 
possible mistakes in a prescription. The Food and Drug Administration 
believes manufacturers should be encouraged to supply such printed 
matter to the pharmacist for his professional information. Obviously, 
such printed matter should not be displayed to prospective purchasers to 
promote over-the-counter sale of prescription drugs.



Sec.  200.10  Contract facilities (including consulting laboratories)
utilized as extramural facilities by pharmaceutical manufacturers.

    (a) Section 704(a) of the Federal Food, Drug, and Cosmetic Act 
specifically authorizes inspection of consulting laboratories as well as 
any factory, warehouse, or establishment in which prescription drugs are 
manufactured, processed, packed, or held.
    (b) The Food and Drug Administration is aware that many 
manufacturers of pharmaceutical products utilize extramural independent 
contract facilities, such as testing laboratories, contract packers or 
labelers, and custom grinders, and regards extramural facilities as an 
extension of the manufacturer's own facility.
    (c) The Food and Drug Administration reserves the right to disclose 
to the pharmaceutical manufacturer, or to the applicant of a new drug 
application (NDA) or to the sponsor of an Investigational New Drug (IND) 
Application, any information obtained during the inspection of an 
extramural facility having a specific bearing on the compliance of the 
manufacturer's, applicant's, or sponsor's product with the Federal Food, 
Drug, and Cosmetic Act. The Food and Drug Administration's position is 
that by the acceptance of such contract work, the extramural facility 
authorizes such disclosures.
    (d) The Food and Drug Administration does not consider results of 
validation studies of analytical and assay methods and control 
procedures to be trade secrets that may be withheld from the drug 
manufacturer by the contracted extramural facility.

[40 FR 13996, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990]



Sec.  200.11  Use of octadecylamine in steam lines of drug establishments.

    The Food and Drug Administration will not object to the use of 
octadecylamine in steam lines where the steam may be used for 
autoclaving surgical instruments and gauze if the octadecylamine in the 
steam is not more than 2.4 parts per million.



Sec.  200.15  Definition of term ``insulin.''

    For purposes of sections 801 and 802 of the act and this title, the 
term insulin means the active principle of the pancreas that affects the 
metabolism of carbohydrates in the animal body and which is of value in 
the treatment of diabetes mellitus. The term includes synthetic and 
biotechnologically derived products that are the same as, or similar to, 
naturally occurring insulins in structure, use, and intended effect and 
are of value in the treatment of diabetes mellitus.

[63 FR 26698, May 13, 1998]

Subpart B [Reserved]



          Subpart C_Requirements for Specific Classes of Drugs



Sec.  200.50  Ophthalmic preparations and dispensers.

    (a)(1) Informed medical opinion is in agreement that all 
preparations offered

[[Page 7]]

or intended for ophthalmic use, including preparations for cleansing the 
eyes, should be sterile. It is further evident that such preparations 
purport to be of such purity and quality as to be suitable for safe use 
in the eye.
    (2) The Food and Drug Administration concludes that all such 
preparations, if they are not sterile, fall below their professed 
standard of purity or quality and may be unsafe. In a statement of 
policy issued on September 1, 1964, the Food and Drug Administration 
ruled that liquid preparations offered or intended for ophthalmic use 
that are not sterile may be regarded as adulterated within the meaning 
of section 501(c) of the Federal Food, Drug, and Cosmetic Act (the act), 
and, further, may be deemed misbranded within the meaning of section 
502(j) of the act. This ruling is extended to affect all preparations 
for ophthalmic use. By this regulation, this ruling is applicable to 
ophthalmic preparations that are regulated as drugs. By the regulation 
in Sec.  800.10 of this chapter, this ruling is applicable to ophthalmic 
preparations that are regulated as medical devices.
    (3) The containers of ophthalmic preparations shall be sterile at 
the time of filling and closing, and the container or individual carton 
shall be so sealed that the contents cannot be used without destroying 
the seal. The packaging and labeling of ophthalmic preparations that are 
over-the-counter drugs shall also comply with Sec.  211.132 of this 
chapter on tamper-resistant packaging requirements.
    (b) Liquid ophthalmic preparations packed in multiple-dose 
containers should:
    (1) Contain one or more suitable and harmless substances that will 
inhibit the growth of microorganisms; or
    (2) Be so packaged as to volume and type of container and so labeled 
as to duration of use and with such necessary warnings as to afford 
adequate protection and minimize the hazard of injury resulting from 
contamination during use.
    (c) Eye cups, eye droppers, and other dispensers intended for 
ophthalmic use should be sterile, and may be regarded as falling below 
their professed standard of purity or quality if they are not sterile. 
These articles, which are regulated as drugs if packaged with the drugs 
with which they are to be used, should be packaged so as to maintain 
sterility until the package is opened and be labeled, on or within the 
retail package, so as to afford adequate directions and necessary 
warnings to minimize the hazard of injury resulting from contamination 
during use.

[40 FR 13996, Mar. 27, 1975, as amended at 47 FR 50455, Nov. 5, 1982]



Sec.  200.51  Aqueous-based drug products for oral inhalation.

    (a) All aqueous-based drug products for oral inhalation must be 
manufactured to be sterile.
    (b) Manufacturers must also comply with the requirements in Sec.  
211.113(b) of this chapter.

[65 FR 34089, May 26, 2000]

Subpart D [Reserved]



           Subpart E_Prescription Drug Consumer Price Listing



Sec.  200.200  Prescription drugs; reminder advertisements and reminder
labeling to provide price information to consumers.

    (a) Prescription drug reminder advertisements and reminder labeling 
intended to provide price information to consumers are exempt from the 
requirements of Sec. Sec.  201 .100 and 202.1 of this chapter if all of 
the following conditions are met:
    (1) The only purpose of the reminder advertisement or reminder 
labeling is to provide consumers with information concerning the price 
charged for a prescription for a particular drug product, and the 
reminder advertisement or reminder labeling contains no representation 
or suggestion concerning the drug product's safety, effectiveness, or 
indications for use.
    (2) The reminder advertisement or reminder labeling contains the 
proprietary name of the drug product, if any; the established (generic) 
name of the drug product, if any; the drug product's strength if the 
product contains a single active ingredient or if the product contains 
more than one active ingredient and a relevant strength can be

[[Page 8]]

associated with the product without indicating each active ingredient 
(the established name and quantity of each active ingredient are not 
required); the dosage form; and the price charged for a prescription for 
a specific quantity of the drug product.
    (3) The reminder advertisement or reminder labeling may also include 
other written, printed, or graphic matter, e.g., identification of 
professional or convenience services provided by the pharmacy: Provided, 
That such information is neither false nor misleading and contains no 
representation or suggestion concerning the drug product's safety, 
effectiveness, or indications for use.
    (4) The price stated in the reminder advertisement or reminder 
labeling as that charged for a prescription shall include all charges to 
the consumer including, but not limited to, the cost of the drug 
product, professional fees, and handling fees, if any. Mailing fees and 
delivery fees, if any, may be stated separately and without repetition.
    (b) This exemption from Sec. Sec.  201.100 and 202.1 of this chapter 
is applicable to all prescription drug reminder labeling and reminder 
advertisements solely intended to provide consumers with information 
regarding the price charged for prescriptions including price lists, 
catalogs, and other promotional material, whether mailed, posted in a 
pharmacy, placed in a newspaper, or aired on radio or television.
    (c) Any reminder advertisement or reminder labeling intended to 
provide consumers with prescription price information which is not in 
compliance with this section shall be the subject of appropriate 
regulatory action. Such action may be taken against the product and/or 
the responsible person.

[40 FR 58799, Dec. 18, 1975]



PART 201_LABELING--Table of Contents



                  Subpart A_General Labeling Provisions

Sec.
201.1 Drugs; name and place of business of manufacturer, packer, or 
          distributor.
201.2 Drugs and devices; National Drug Code numbers.
201.5 Drugs; adequate directions for use.
201.6 Drugs; misleading statements.
201.10 Drugs; statement of ingredients.
201.15 Drugs; prominence of required label statements.
201.16 Drugs; Spanish-language version of certain required statements.
201.17 Drugs; location of expiration date.
201.18 Drugs; significance of control numbers.
201.19 Drugs; use of term ``infant''.
201.20 Declaration of presence of FD&C Yellow No. 5 and/or FD&C Yellow 
          No. 6 in certain drugs for human use.
201.21 Declaration of presence of phenylalanine as a component of 
          aspartame in over-the-counter and prescription drugs for human 
          use.
201.22 Prescription drugs containing sulfites; required warning 
          statements.
201.23 Required pediatric studies.
201.24 Labeling for systemic antibacterial drug products.
201.25 Bar code label requirements.
201.26 Exceptions or alternatives to labeling requirements for human 
          drug products held by the Strategic National Stockpile.

  Subpart B_Labeling Requirements for Prescription Drugs and/or Insulin

201.50 Statement of identity.
201.51 Declaration of net quantity of contents.
201.55 Statement of dosage.
201.56 Requirements on content and format of labeling for human 
          prescription drug and biological products.
201.57 Specific requirements on content and format of labeling for human 
          prescription drug and biological products described in Sec.  
          201.56(b)(1).
201.58 Waiver of labeling requirements.

       Subpart C_Labeling Requirements for Over-the-Counter Drugs

201.60 Principal display panel.
201.61 Statement of identity.
201.62 Declaration of net quantity of contents.
201.63 Pregnancy/breast-feeding warning.
201.64 Sodium labeling.
201.66 Format and content requirements for over-the-counter (OTC) drug 
          product labeling.
201.70 Calcium labeling.
201.71 Magnesium labeling.
201.72 Potassium labeling.
201.80 Specific requirements on content and format of labeling for human 
          prescription drug and biological products; older drugs not 
          described in Sec.  201.56(b)(1).

          Subpart D_Exemptions From Adequate Directions for Use

201.100 Prescription drugs for human use.
201.105 Veterinary drugs.
201.115 New drugs or new animal drugs.

[[Page 9]]

201.116 Drugs having commonly known directions.
201.117 Inactive ingredients.
201.119 In vitro diagnostic products.
201.120 Prescription chemicals and other prescription components.
201.122 Drugs for processing, repacking, or manufacturing.
201.125 Drugs for use in teaching, law enforcement, research, and 
          analysis.
201.127 Drugs; expiration of exemptions.
201.128 Meaning of ``intended uses''.
201.129 Drugs; exemption for radioactive drugs for research use.

                       Subpart E_Other Exemptions

201.150 Drugs; processing, labeling, or repacking.
201.161 Medical gases.

       Subpart F_Labeling Claims for Drugs in Drug Efficacy Study

201.200 Disclosure of drug efficacy study evaluations in labeling and 
          advertising.

   Subpart G_Specific Labeling Requirements for Specific Drug Products

201.300 Notice to manufacturers, packers, and distributors of glandular 
          preparations.
201.301 Notice to manufacturers, packers, and distributors of estrogenic 
          hormone preparations.
201.302 Notice to manufacturers, packers, and distributors of drugs for 
          internal use which contain mineral oil.
201.303 Labeling of drug preparations containing significant proportions 
          of wintergreen oil.
201.304 Tannic acid and barium enema preparations.
201.305 Isoproterenol inhalation preparations (pressurized aerosols, 
          nebulizers, powders) for human use; warnings.
201.306 Potassium salt preparations intended for oral ingestion by man.
201.307 Sodium phosphates; package size limitation, warnings, and 
          directions for over-the-counter sale.
201.308 Ipecac syrup; warnings and directions for use for over-the-
          counter sale.
201.309 Acetophenetidin (phenacetin)-containing preparations; necessary 
          warning statement.
201.310 Phenindione; labeling of drug preparations intended for use by 
          man.
201.311 [Reserved]
201.312 Magnesium sulfate heptahydrate; label declaration on drug 
          products.
201.313 Estradiol labeling.
201.314 Labeling of drug preparations containing salicylates.
201.315 Over-the-counter drugs for minor sore throats; suggested 
          warning.
201.316 Drugs with thyroid hormone activity for human use; required 
          warning.
201.317 Digitalis and related cardiotonic drugs for human use in oral 
          dosage forms; required warning.
201.319 Water-soluble gums, hydrophilic gums, and hydrophilic mucilloids 
          (including, but not limited to agar, alginic acid, calcium 
          polycarbophil, carboxymethylcellulose sodium, carrageenan, 
          chondrus, glucomannan ((B-1,4 linked) polymannose acetate), 
          guar gum, karaya gum, kelp, methylcellulose, plantago seed 
          (psyllium), polycarbophil tragacanth, and xanthan gum) as 
          active ingredients; required warnings and directions.
201.320 Warning statements for drug products containing or manufactured 
          with chlorofluorocarbons or other ozone-depleting substances.
201.323 Aluminum in large and small volume parenterals used in total 
          parenteral nutrition.
201.325 Over-the-counter drugs for vaginal contraceptive and spermicide 
          use containing nonoxynol 9 as the active ingredient; required 
          warnings and labeling information.
201.326 Over-the-counter drug products containing internal analgesic/
          antipyretic active ingredients; required warnings and other 
          labeling.
201.327 Over-the-counter sunscreen drug products; required labeling 
          based on effectiveness testing.
201.328 Labeling of medical gas containers.

Appendix A to Part 201--Examples of Graphic Enhancements Used by FDA

    Authority: 21 U.S.C. 321, 331, 343, 351, 352, 353, 355, 358, 360, 
360b, 360ccc, 360ccc-1, 360ee, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 
216, 241, 262, 264.

    Source: 40 FR 13998, Mar. 27, 1975, unless otherwise noted.

    Editorial Note: Nomenclature changes to part 201 appear at 69 FR 
13717, Mar. 24, 2004.



                  Subpart A_General Labeling Provisions



Sec.  201.1  Drugs; name and place of business of manufacturer, packer,
or distributor.

    (a) A drug or drug product (as defined in Sec.  320.1 of this 
chapter) in finished package form is misbranded under section 502 (a) 
and (b)(1) of the act if its label does not bear conspicuously the name 
and place of business of the manufacturer, packer, or distributor. This 
paragraph does not apply to any drug

[[Page 10]]

or drug product dispensed in accordance with section 503(b)(1) of the 
act.
    (b) As used in this section, and for purposes of section 502 (a) and 
(b)(1) of the act, the manufacturer of a drug product is the person who 
performs all of the following operations that are required to produce 
the product: (1) Mixing, (2) granulating, (3) milling, (4) molding, (5) 
lyophilizing, (6) tableting, (7) encapsulating, (8) coating, (9) 
sterilizing, and (10) filling sterile, aerosol, or gaseous drugs into 
dispensing containers.
    (c) If no person performs all of the applicable operations listed in 
paragraph (b) of this section, no person may be represented as 
manufacturer except as follows:
    (1) If the person performs more than one half of the applicable 
operations listed in paragraph (b) of this section and acknowledges the 
contribution of other persons who have performed the remaining 
applicable operations by stating on the product label that ``Certain 
manufacturing operations have been performed by other firms.''; or
    (2) If the person performs at least one applicable operation listed 
in paragraph (b) of this section and identifies by appropriate 
designation all other persons who have performed the remaining 
applicable operations, e.g., ``Made by (Person A), Filled by (Person B), 
Sterilized by (Person C)''; or
    (3) If the person performs at least one applicable operation listed 
in paragraph (b) of this section and the person is listed along with all 
other persons who have performed the remaining applicable operations as 
``joint manufacturers.'' A list of joint manufacturers shall be 
qualified by the phrase ``Jointly Manufactured By ______,'' and the 
names of all of the manufacturers shall be printed together in the same 
type size and style; or
    (4) If the person performs all applicable operations listed in 
paragraph (b) of this section except for those operations listed in 
paragraph (d) of this section. For purposes of this paragraph, person, 
when it identifies a corporation, includes a parent, subsidiary, or 
affiliate company where the related companies are under common ownership 
and control.
    (d) The Food and Drug Administration finds that it is the common 
practice in the drug industry to contract out the performance of certain 
manufacturing operations listed in paragraph (b) of this section. These 
operations include: (1) Soft-gelatin encapsulating, (2) aerosol filling, 
(3) sterilizing by irradiation, (4) lyophilizing, and (5) ethylene oxide 
sterilization.
    (e) A person performs an operation listed in paragraph (b) of this 
section only if the operation is performed, including the performance of 
the appropriate in-process quality control operations, except laboratory 
testing of samples taken during processing, as follows:
    (1) By individuals, a majority of whom are employees of the person 
and, throughout the performance of the operation, are subject to the 
person's direction and control;
    (2) On premises that are continuously owned or leased by the person 
and subject to the person's direction and control; and
    (3) On equipment that is continuously owned or leased by the person. 
As used in this paragraph, person, when it identifies a corporation, 
includes a parent, subsidiary, or affiliate company where the related 
companies are under common ownership and control.
    (f) The name of the person represented as manufacturer under 
paragraph (b) or (c) of this section must be the same as either (1) the 
name of the establishment (as defined in Sec.  207.1 of this chapter) 
under which that person is registered at the time the labeled product is 
produced or (2) the registered establishment name of a parent, 
subsidiary, or affiliate company where the related companies are under 
common ownership and control. In addition, the name shall meet the 
requirements of paragraph (g) of this section.
    (g) The requirement for declaration of the name of the manufacturer, 
packer, or distributor shall be deemed to be satisfied, in the case of a 
corporate person, only by the actual corporate name, except that the 
corporate name may be the name of a parent, subsidiary, or affiliate 
company where the related companies are under common ownership and 
control. The corporate

[[Page 11]]

name may be preceded or followed by the name of the particular division 
of the corporation. ``Company,'' ``Incorporated,'' etc., may be 
abbreviated or omitted and ``The'' may be omitted. In the case of an 
individual, partnership, or association, the name under which the 
business is conducted shall be used.
    (h)(1) Except as provided in this section, no person other than the 
manufacturer, packer, or distributor may be identified on the label of a 
drug or drug product.
    (2) The appearance on a drug product label of a person's name 
without qualification is a representation that the named person is the 
sole manufacturer of the product. That representation is false and 
misleading, and the drug product is misbranded under section 502(a) of 
the act, if the person is not the manufacturer of the product in 
accordance with this section.
    (3) If the names of two or more persons appear on the label of a 
drug or drug product, the label may identify which of the persons is to 
be contacted for further information about the product.
    (4) If a trademark appears on the drug or drug product label or 
appears as a mark directly on the drug product (e.g., tablet or 
capsule), the label may identify the holder or licensee of the 
trademark. The label may also state whether the person identified holds 
the trademark or is licensee of the trademark.
    (5) If the distributor is named on the label, the name shall be 
qualified by one of the following phrases: ``Manufactured for ______'', 
``Distributed by ______'', ``Manufactured by ______ for ______'', 
``Manufactured for _____by _____'', ``Distributor: ______'', ``Marketed 
by ______''. The qualifying phrases may be abbreviated.
    (6) If the packer is identified on the label, the name shall be 
qualified by the phrase ``Packed by ______'' or ``Packaged by ______''. 
The qualifying phrases may be abbreviated.
    (i) The statement of the place of business shall include the street 
address, city, State, and ZIP Code. For a foreign manufacturer, the 
statement of the place of business shall include the street address, 
city, country, and any applicable mailing code. The street address may 
be omitted if it is shown in a current city directory or telephone 
directory. The requirement for inclusion of the ZIP Code shall apply to 
consumer commodity labels developed or revised after July 1, 1969. In 
the case of nonconsumer packages, the ZIP Code shall appear either on 
the label or the labeling (including the invoice).
    (j) If a person manufactures, packs, or distributes a drug or drug 
product at a place other than the person's principal place of business, 
the label may state the principal place of business in lieu of the 
actual place where such drug or drug product was manufactured or packed 
or is to be distributed, unless such statement would be misleading.
    (k) Paragraphs (b), (c), (d), (e), and (f) of this section, do not 
apply to the labeling of drug components.
    (l) A drug product is misbranded under section 502(a) of the act if 
its labeling identifies a person as manufacturer, packer, or 
distributor, and that identification does not meet the requirements of 
this section.
    (m) This section does not apply to biological drug products that are 
subject to the requirements of section 351 of the Public Health Service 
Act, 42 U.S.C. 262.

[45 FR 25775, Apr. 15, 1980; 45 FR 72118, Oct. 31, 1980, as amended at 
48 FR 37620, Aug. 19, 1983; 81 FR 60212, Aug. 31, 2016]



Sec.  201.2  Drugs and devices; National Drug Code numbers.

    The National Drug Code (NDC) number is requested but not required to 
appear on all drug labels and in all drug labeling, including the label 
of any prescription drug container furnished to a consumer.

[40 FR 52002, Nov. 7, 1975, as amended at 81 FR 60212, Aug. 31, 2016]



Sec.  201.5  Drugs; adequate directions for use.

    Adequate directions for use means directions under which the layman 
can use a drug safely and for the purposes for which it is intended. 
(Section 201.128 defines ``intended use.'') Directions for use may be 
inadequate because, among other reasons, of omission, in whole or in 
part, or incorrect specification of:

[[Page 12]]

    (a) Statements of all conditions, purposes, or uses for which such 
drug is intended, including conditions, purposes, or uses for which it 
is prescribed, recommended, or suggested in its oral, written, printed, 
or graphic advertising, and conditions, purposes, or uses for which the 
drug is commonly used; except that such statements shall not refer to 
conditions, uses, or purposes for which the drug can be safely used only 
under the supervision of a practitioner licensed by law and for which it 
is advertised solely to such practitioner.
    (b) Quantity of dose, including usual quantities for each of the 
uses for which it is intended and usual quantities for persons of 
different ages and different physical conditions.
    (c) Frequency of administration or application.
    (d) Duration of administration or application.
    (e) Time of administration or application (in relation to time of 
meals, time of onset of symptoms, or other time factors).
    (f) Route or method of administration or application.
    (g) Preparation for use, i.e., shaking, dilution, adjustment of 
temperature, or, other manipulation or process.

[41 FR 6908, Feb. 13, 1976]



Sec.  201.6  Drugs; misleading statements.

    (a) Among representations in the labeling of a drug which render 
such drug misbranded is a false or misleading representation with 
respect to another drug or a device or a food or cosmetic.
    (b) The labeling of a drug which contains two or more ingredients 
may be misleading by reason, among other reasons, of the designation of 
such drug in such labeling by a name which includes or suggests the name 
of one or more but not all such ingredients, even though the names of 
all such ingredients are stated elsewhere in the labeling.

[41 FR 6908, Feb. 13, 1976]



Sec.  201.10  Drugs; statement of ingredients.

    (a) The ingredient information required by section 502(e) of the 
Federal Food, Drug, and Cosmetic Act shall appear together, without any 
intervening written, printed, or graphic matter, except the proprietary 
names of ingredients, which may be included with the listing of 
established names, and such statements that are specifically required 
for certain ingredients by the act or regulations in this chapter.
    (b) The term ingredient applies to any substance in the drug, 
whether added to the formulation as a single substance or in admixture 
with other substances.
    (c) The labeling of a drug may be misleading by reason (among other 
reasons) of:
    (1) The order in which the names of the ingredients present in the 
drug appear in the labeling, or the relative prominence otherwise given 
such names.
    (2) Failure to reveal the proportion of, or other fact with respect 
to, an ingredient present in such drug, when such proportion or other 
fact is material in the light of the representation that such ingredient 
is present in such drug.
    (3) The employment of a fanciful proprietary name for a drug or 
ingredient in such a manner as to imply that the drug or ingredient has 
some unique effectiveness or composition when, in fact, the drug or 
ingredient is a common substance, the limitations of which are readily 
recognized when the drug or ingredient is listed by its established 
name.
    (4) The featuring in the labeling of inert or inactive ingredients 
in a manner that creates an impression of value greater than their true 
functional role in the formulation.
    (5) Designation of a drug or ingredient by a proprietary name that, 
because of similarity in spelling or pronunciation, may be confused with 
the proprietary name or the established name of a different drug or 
ingredient.
    (d)(1) If the drug is in tablet or capsule form or other unit dosage 
form, any statement of the quantity of an ingredient contained therein 
shall express the quantity of such ingredient in each such unit. If the 
drug is not in unit dosage form, any statement of the quantity of an 
ingredient contained therein shall express the amount of such ingredient 
in a specified unit of

[[Page 13]]

weight or measure of the drug, or the percentage of such ingredient in 
such drug. Such statements shall be in terms that are informative to 
licensed practitioners, in the case of a prescription drug, and to the 
layman, in the case of a nonprescription drug.
    (2) A statement of the percentage of an ingredient in a drug shall, 
if the term percent is used without qualification, mean percent weight-
in-weight, if the ingredient and the drug are both solids, or if the 
ingredient is a liquid and the drug is a solid; percent weight in volume 
at 68 [deg]F. (20 [deg]C.), if the ingredient is a solid and the drug is 
a liquid; and percent volume in volume at 68 [deg]F. (20 [deg]C.), if 
both the ingredient and the drug are liquids, except that alcohol shall 
be stated in terms of percent volume of absolute alcohol at 60 [deg]F. 
(15.56 [deg]C.).
    (e) A derivative or preparation of a substance named in section 
502(e) of the act is an article derived or prepared from such substance 
by any method, including actual or theoretical chemical action.
    (f) If an ingredient is a derivative or preparation of a substance 
specifically named in section 502(e) of the act and the established name 
of such ingredient does not indicate that it is a derivative or 
preparation of the parent substance named in section 502(e) of the act, 
the labeling shall, in conjunction with the listing of the established 
name of such ingredient, declare that such article is a derivative or 
preparation of such parent substance.
    (g)(1) If the label or labeling of a prescription drug bears a 
proprietary name or designation for the drug or any ingredient thereof, 
the established name, if such there be, corresponding to such 
proprietary name or designation shall accompany such proprietary name or 
designation each time it is featured on the label or in the labeling for 
the drug; but, except as provided in this subparagraph, the established 
name need not be used with the proprietary name or designation in the 
running text of the label or labeling. On any label or page of labeling 
in which the proprietary name or designation is not featured but is used 
in the running text, the established name shall be used at least once in 
the running text in association with such proprietary name or 
designation and in the same type size used in such running text: 
Provided, however, That if the proprietary name or designation is used 
in the running text in larger size type, the established name shall be 
used at least once in association with, and in type at least half as 
large as the type used for, the most prominent presentation of the 
proprietary name or designation in such running text. If any labeling 
includes a column with running text containing detailed information as 
to composition, prescribing, side effects, or contraindications and the 
proprietary name or designation is used in such column but is not 
featured above or below the column, the established name shall be used 
at least once in such column of running text in association with such 
proprietary name or designation and in the same type size used in such 
column of running text: Provided, however, That if the proprietary name 
or designation is used in such column of running text in larger size 
type, the established name shall be used at least once in association 
with, and in type at least half as large as the type used for, the most 
prominent presentation of the proprietary name or designation in such 
column of running text. Where the established name is required to 
accompany or to be used in association with the proprietary name or 
designation, the established name shall be placed in direct conjunction 
with the proprietary name or designation, and the relationship between 
the proprietary name or designation and the established name shall be 
made clear by use of a phrase such as ``brand of'' preceding the 
established name, by brackets surrounding the established name, or by 
other suitable means.
    (2) The established name shall be printed in letters that are at 
least half as large as the letters comprising the proprietary name or 
designation with which it is joined, and the established name shall have 
a prominence commensurate with the prominence with which such 
proprietary name or designation appears, taking into account all 
pertinent factors, including typography, layout, contrast, and other 
printing features.

[[Page 14]]

    (h)(1) In the case of a prescription drug containing two or more 
active ingredients, if the label bears a proprietary name or designation 
for such mixture and there is no established name corresponding to such 
proprietary name or designation, the quantitative ingredient information 
required on the label by section 502(e) of the act shall be placed in 
direct conjunction with the most prominent display of the proprietary 
name or designation. The prominence of the quantitative ingredient 
information shall bear a reasonable relationship to the prominence of 
the proprietary name.
    (2) If the drug is packaged in a container too small to bear the 
quantitative ingredient information on the main display panel, the 
quantitative ingredient information required by section 502(e) of the 
act may appear elsewhere on the label, even though the proprietary name 
or designation appears on the main display panel of the label; but side- 
or back-panel placement shall in this case be so arranged and printed as 
to provide size and prominence of display reasonably related to the size 
and prominence of the front-panel display.
    (i) A drug packaged in a container too small or otherwise unable to 
accommodate a label with sufficient space to bear the information 
required for compliance with section 502(e)(1) (A)(ii) and (B) of the 
act shall be exempt from compliance with those clauses: Provided, That:
    (1) The label bears:
    (i) The proprietary name of the drug;
    (ii) The established name, if such there be, of the drug;
    (iii) An identifying lot or control number; and
    (iv) The name of the manufacturer, packer, or distributor of the 
drug; and
    (2) All the information required to appear on the label by the act 
and the regulations in this chapter appears on the carton or other outer 
container or wrapper if such carton, outer container, or wrapper has 
sufficient space to bear such information, or such complete label 
information appears on a leaflet with the package.

[40 FR 13998, Mar. 27, 1975, as amended at 67 FR 4906, Feb. 1, 2002]



Sec.  201.15  Drugs; prominence of required label statements.

    (a) A word, statement, or other information required by or under 
authority of the act to appear on the label may lack that prominence and 
conspicuousness required by section 502(c) of the act by reason, among 
other reasons, of:
    (1) The failure of such word, statement, or information to appear on 
the part or panel of the label which is presented or displayed under 
customary conditions of purchase;
    (2) The failure of such word, statement, or information to appear on 
two or more parts or panels of the label, each of which has sufficient 
space therefor, and each of which is so designed as to render it likely 
to be, under customary conditions of purchase, the part or panel 
displayed;
    (3) The failure of the label to extend over the area of the 
container or package available for such extension, so as to provide 
sufficient label space for the prominent placing of such word, 
statement, or information;
    (4) Insufficiency of label space for the prominent placing of such 
word, statement, or information, resulting from the use of label space 
for any word, statement, design, or device which is not required by or 
under authority of the act to appear on the label;
    (5) Insufficiency of label space for the prominent placing of such 
word, statement, or information, resulting from the use of label space 
to give materially greater conspicuousness to any other word, statement, 
or information, or to any design or device; or
    (6) Smallness or style of type in which such word, statement, or 
information appears, insufficient background contrast, obscuring designs 
or vignettes, or crowding with other written, printed, or graphic 
matter.
    (b) No exemption depending on insufficiency of label space, as 
prescribed in regulations promulgated under section 502 (b) or (e) of 
the act, shall apply if such insufficiency is caused by:
    (1) The use of label space for any word, statement, design, or 
device which is not required by or under authority of the act to appear 
on the label;
    (2) The use of label space to give greater conspicuousness to any 
word,

[[Page 15]]

statement, or other information than is required by section 502(c) of 
the act; or
    (3) The use of label space for any representation in a foreign 
language.
    (c)(1) All words, statements, and other information required by or 
under authority of the act to appear on the label or labeling shall 
appear thereon in the English language: Provided, however, That in the 
case of articles distributed solely in the Commonwealth of Puerto Rico 
or in a Territory where the predominant language is one other than 
English, the predominant language may be substituted for English.
    (2) If the label contains any representation in a foreign language, 
all words, statements, and other information required by or under 
authority of the act to appear on the label shall appear thereon in the 
foreign language.
    (3) If the labeling contains any representation in a foreign 
language, all words, statements, and other information required by or 
under authority of the act to appear on the label or labeling shall 
appear on the labeling in the foreign language.

[41 FR 6908, Feb. 13, 1976]



Sec.  201.16  Drugs; Spanish-language version of certain required
statements.

    An increasing number of medications restricted to prescription use 
only are being labeled solely in Spanish for distribution in the 
Commonwealth of Puerto Rico where Spanish is the predominant language. 
Such labeling is authorized under Sec.  201.15(c). One required warning, 
the wording of which is fixed by law in the English language, could be 
translated in various ways, from literal translation to loose 
interpretation. The statutory nature of this warning requires that the 
translation convey the meaning properly to avoid confusion and dilution 
of the purpose of the warning. Section 503(b)(4) of the Federal Food, 
Drug, and Cosmetic Act requires, at a minimum, that the label bear the 
statement ``Rx only.'' The Spanish-language version of this must be 
``Solamente Rx''.

[67 FR 4906, Feb. 1, 2002]



Sec.  201.17  Drugs; location of expiration date.

    When an expiration date of a drug is required, e.g., expiration 
dating of drug products required by Sec.  211.137 of this chapter, it 
shall appear on the immediate container and also the outer package, if 
any, unless it is easily legible through such outer package. However, 
when single-dose containers are packed in individual cartons, the 
expiration date may properly appear on the individual carton instead of 
the immediate product container.

[43 FR 45076, Sept. 29, 1978]



Sec.  201.18  Drugs; significance of control numbers.

    The lot number on the label of a drug should be capable of yielding 
the complete manufacturing history of the package. An incorrect lot 
number may be regarded as causing the article to be misbranded.



Sec.  201.19  Drugs; use of term ``infant''.

    The regulations affecting special dietary foods (Sec.  105.3(e) of 
this chapter) define an infant as a child not more than 12 months old. 
Apart from this, the Food and Drug Administration has not established 
any definition of the term infant. Some question has arisen whether, for 
the purposes of drug labeling, an infant means a child up to 1 year of 
age or a child up to 2 years of age. Until the term is more precisely 
defined by legislation or formal regulation, where the exact meaning of 
the term is significant, manufacturers should qualify any reference to 
``infant'' to indicate whether it refers to a child who is not more than 
1 year of age, or a child not more than 2 years of age.

[40 FR 13998, Mar. 27, 1975, as amended at 42 FR 14091, Mar. 15, 1977; 
44 FR 16006, Mar. 16, 1979]



Sec.  201.20  Declaration of presence of FD&C Yellow No. 5 and/or
FD&C Yellow No. 6 in certain drugs for human use.

    (a) The label for over-the-counter and prescription drug products 
intended for human use administered orally, nasally, rectally, or 
vaginally, or for use in the area of the eye, containing

[[Page 16]]

FD&C Yellow No. 5 as a color additive using the names FD&C Yellow No. 5 
and tartrazine. The labeling for over-the-counter and prescription drug 
products shall bear a statement such as ``Contains FD&C Yellow No. 5 
(tartrazine) as a color additive'' or ``Contains color additives 
including FD&C Yellow No. 5 (tartrazine)''. The labels of certain drug 
products subject to this labeling requirement that are also cosmetics, 
such as antibacterial mouthwashes and fluoride toothpastes, need not 
comply with this requirement provided they comply with the requirements 
of Sec.  701.3 of this chapter.
    (b) For prescription drugs for human use containing FD&C Yellow No. 
5 that are administered orally, nasally, vaginally, or rectally, or for 
use in the area of the eye, the labeling required by Sec.  201.100(d) 
shall bear the warning statement ``This product contains FD&C Yellow No. 
5 (tartrazine) which may cause allergic-type reactions (including 
bronchial asthma) in certain susceptible persons. Although the overall 
incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general 
population is low, it is frequently seen in patients who also have 
aspirin hypersensitivity.'' This warning statement shall appear in the 
``Precautions'' section of the labeling.
    (c) The label for over-the-counter drug products intended for human 
use administered orally, nasally, rectally, or vaginally containing FD&C 
Yellow No. 6 shall specifically declare the presence of FD&C Yellow No. 
6 by listing the color additive using the name FD&C Yellow No. 6. The 
labeling for over-the-counter and prescription drug products containing 
FD&C Yellow No. 6 shall declare the presence of FD&C Yellow No. 6. The 
labels of certain drug products subject to this labeling requirement 
that are also cosmetics, such as antibacterial mouthwashes and fluoride 
toothpastes, need not comply with this requirement provided they comply 
with the requirements of Sec.  701.3 of this chapter.

[45 FR 60422, Sept. 12, 1980, as amended at 51 FR 41783, Nov. 19, 1986; 
52 FR 21509, June 8, 1987; 59 FR 60898, Nov. 29, 1994]

    Effective Date Note: At 53 FR 49138, Dec. 6, 1988, Sec.  201.20(c) 
was suspended pending further agency action.



Sec.  201.21  Declaration of presence of phenylalanine as a component
of aspartame in over-the-counter and prescription drugs for human use.

    (a) Aspartame is the methylester of a dipeptide composed of two 
amino acids, phenylalanine and aspartic acid. When these two amino acids 
are so combined to form aspartame (1-methyl N-L-[alpha]-aspartyl-L-
phenylalanine), they produce an intensely sweet-tasting substance, 
approximately 180 times as sweet as sucrose. The Food and Drug 
Administration has determined that aspartame when used at a level no 
higher than reasonably required to perform its intended technical 
function is safe for use as an inactive ingredient in human drug 
products, provided persons with phenylketonuria, who must restrict 
carefully their phenylalanine intake, are alerted to the presence of 
phenylalanine in the drug product and the amount of the ingredient in 
each dosage unit.
    (b) The label and labeling of all over-the-counter human drug 
products containing aspartame as an inactive ingredient shall bear a 
statement to the following effect: Phenylketonurics: Contains 
Phenylalanine (_)mg Per (Dosage Unit).
    (c) The package labeling and other labeling providing professional 
use information concerning prescription drugs for human use containing 
aspartame as an inactive ingredient shall bear a statement to the 
following effect under the ``Precautions'' section of the labeling, as 
required in Sec.  201.57(f)(2): Phenylketonurics: Contains Phenylalanine 
(_)mg Per (Dosage Unit).
    (d) Holders of approved new drug applications who reformulate their 
drug products under the provisions of this section shall submit 
supplements under Sec.  314.70 of this chapter to provide for the new 
composition and the labeling changes.

(Approved by the Office of Management and Budget under control number 
0910-0242)

[52 FR 2111, Jan. 20, 1987; 52 FR 12152, Apr. 15, 1987; 53 FR 4135, Feb. 
12, 1988]



Sec.  201.22  Prescription drugs containing sulfites; required warning
statements.

    (a) Sulfites are chemical substances that are added to certain drug 
products

[[Page 17]]

to inhibit the oxidation of the active drug ingredient. Oxidation of the 
active drug ingredient may result in instability and a loss of potency 
of the drug product. Examples of specific sulfites used to inhibit this 
oxidation process include sodium bisulfite, sodium metabisulfite, sodium 
sulfite, potassium bisulfite, and potassium metabisulfite. Recent 
studies have demonstrated that sulfites may cause allergic-type 
reactions in certain susceptible persons, especially asthmatics. The 
labeling for any prescription drug product to which sulfites have been 
added as an inactive ingredient, regardless of the amount added, must 
bear the warning specified in paragraph (b) or (c) of this section.
    (b) The labeling required by Sec. Sec.  201.57 and 201.100(d) for 
prescription drugs for human use containing a sulfite, except 
epinephrine for injection when intended for use in allergic or other 
emergency situations, shall bear the warning statement ``Contains 
(insert the name of the sulfite, e.g., sodium metabisulfite), a sulfite 
that may cause allergic-type reactions including anaphylactic symptoms 
and life-threatening or less severe asthmatic episodes in certain 
susceptible people. The overall prevalence of sulfite sensitivity in the 
general population is unknown and probably low. Sulfite sensitivity is 
seen more frequently in asthmatic than in nonasthmatic people.'' This 
statement shall appear in the ``Warnings'' section of the labeling.
    (c) The labeling required by Sec. Sec.  201.57 and 201.100(d) for 
sulfite-containing epinephrine for injection for use in allergic 
emergency situations shall bear the warning statement ``Epinephrine is 
the preferred treatment for serious allergic or other emergency 
situations even though this product contains (insert the name of the 
sulfite, e.g., sodium metabisulfite), a sulfite that may in other 
products cause allergic-type reactions including anaphylactic symptoms 
or life-threatening or less severe asthmatic episodes in certain 
susceptible persons. The alternatives to using epinephrine in a life-
threatening situation may not be satisfactory. The presence of a 
sulfite(s) in this product should not deter administration of the drug 
for treatment of serious allergic or other emergency situations.'' This 
statement shall appear in the ``Warnings'' section of the labeling.

[51 FR 43904, Dec. 5, 1986]



Sec.  201.23  Required pediatric studies.

    (a) A manufacturer of a marketed drug product, including a 
biological drug product, that is used in a substantial number of 
pediatric patients, or that provides a meaningful therapeutic benefit 
over existing treatments for pediatric patients, as defined in 
Sec. Sec.  314.55(c)(5) and 601.27(c)(5) of this chapter, but whose 
label does not provide adequate information to support its safe and 
effective use in pediatric populations for the approved indications may 
be required to submit an application containing data adequate to assess 
whether the drug product is safe and effective in pediatric populations. 
The application may be required to contain adequate evidence to support 
dosage and administration in some or all pediatric subpopulations, 
including neonates, infants, children, and adolescents, depending upon 
the known or appropriate use of the drug product in such subpopulations. 
The applicant may also be required to develop a pediatric formulation 
for a drug product that represents a meaningful therapeutic benefit over 
existing therapies for pediatric populations for whom a pediatric 
formulation is necessary, unless the manufacturer demonstrates that 
reasonable attempts to produce a pediatric formulation have failed.
    (b) The Food and Drug Administration (FDA) may by order, in the form 
of a letter, after notifying the manufacturer of its intent to require 
an assessment of pediatric safety and effectiveness of a pediatric 
formulation, and after offering an opportunity for a written response 
and a meeting, which may include an advisory committee meeting, require 
a manufacturer to submit an application containing the information or 
request for approval of a pediatric formulation described in paragraph 
(a) of this section within a time specified in the order, if FDA finds 
that:
    (1) The drug product is used in a substantial number of pediatric 
patients for the labeled indications and the absence of adequate 
labeling could pose

[[Page 18]]

significant risks to pediatric patients; or
    (2) There is reason to believe that the drug product would represent 
a meaningful therapeutic benefit over existing treatments for pediatric 
patients for one or more of the claimed indications, and the absence of 
adequate labeling could pose significant risks to pediatric patients.
    (c)(1) An applicant may request a full waiver of the requirements of 
paragraph (a) of this section if the applicant certifies that:
    (i) Necessary studies are impossible or highly impractical because, 
e.g., the number of such patients is so small or geographically 
dispersed, or
    (ii) There is evidence strongly suggesting that the product would be 
ineffective or unsafe in all pediatric age groups.
    (2) An applicant may request a partial waiver of the requirements of 
paragraph (a) of this section with respect to a specified pediatric age 
group, if the applicant certifies that:
    (i) The product:
    (A) Does not represent a meaningful therapeutic benefit over 
existing therapies for pediatric patients in that age group, and
    (B) Is not likely to be used in a substantial number of patients in 
that age group, and
    (C) The absence of adequate labeling could not pose significant 
risks to pediatric patients; or
    (ii) Necessary studies are impossible or highly impractical because, 
e.g., the number of patients in that age group is so small or 
geographically dispersed, or
    (iii) There is evidence strongly suggesting that the product would 
be ineffective or unsafe in that age group, or
    (iv) The applicant can demonstrate that reasonable attempts to 
produce a pediatric formulation necessary for that age group have 
failed.
    (3) FDA shall grant a full or partial waiver, as appropriate, if the 
agency finds that there is a reasonable basis on which to conclude that 
one or more of the grounds for waiver specified in paragraphs (c)(2) or 
(c)(3) of this section have been met. If a waiver is granted on the 
ground that it is not possible to develop a pediatric formulation, the 
waiver will cover only those pediatric age groups requiring that 
formulation. If a waiver is granted because there is evidence that the 
product would be ineffective or unsafe in pediatric populations, this 
information will be included in the product's labeling.
    (d) If a manufacturer fails to submit a supplemental application 
containing the information or request for approval of a pediatric 
formulation described in paragraph (a) of this section within the time 
specified by FDA, the drug product may be considered misbranded or an 
unapproved new drug or unlicensed biologic.

[63 FR 66668, Dec. 2, 1998]



Sec.  201.24  Labeling for systemic antibacterial drug products.

    The labeling of all systemic drug products intended for human use 
indicated to treat a bacterial infection, except a mycobacterial 
infection, must bear the following statements:
    (a) At the beginning of the label, under the product name, the 
labeling must state:

    To reduce the development of drug-resistant bacteria and maintain 
the effectiveness of (insert name of antibacterial drug product) and 
other antibacterial drugs, (insert name of antibacterial drug product) 
should be used only to treat or prevent infections that are proven or 
strongly suspected to be caused by bacteria.

    (b) In the ``Indications and Usage'' section, the labeling must 
state:

    To reduce the development of drug-resistant bacteria and maintain 
the effectiveness of (insert name of antibacterial drug product) and 
other antibacterial drugs, (insert name of antibacterial drug product) 
should be used only to treat or prevent infections that are proven or 
strongly suspected to be caused by susceptible bacteria. When culture 
and susceptibility information are available, they should be considered 
in selecting or modifying antibacterial therapy. In the absence of such 
data, local epidemiology and susceptibility patterns may contribute to 
the empiric selection of therapy.

    (c) In the ``Precautions'' section, under the ``General'' 
subsection, the labeling must state:

    Prescribing (insert name of antibacterial drug product) in the 
absence of a proven or strongly suspected bacterial infection or a

[[Page 19]]

prophylactic indication is unlikely to provide benefit to the patient 
and increases the risk of the development of drug-resistant bacteria.

    (d) In the ``Precautions'' section, under the ``Information for 
Patients'' subsection, the labeling must state:

    Patients should be counseled that antibacterial drugs including 
(insert name of antibacterial drug product) should only be used to treat 
bacterial infections. They do not treat viral infections (e.g., the 
common cold). When (insert name of antibacterial drug product) is 
prescribed to treat a bacterial infection, patients should be told that 
although it is common to feel better early in the course of therapy, the 
medication should be taken exactly as directed. Skipping doses or not 
completing the full course of therapy may (1) decrease the effectiveness 
of the immediate treatment and (2) increase the likelihood that bacteria 
will develop resistance and will not be treatable by (insert name of 
antibacterial drug product) or other antibacterial drugs in the future.

[68 FR 6081, Feb. 6, 2003]



Sec.  201.25  Bar code label requirements.

    (a) Who is subject to these bar code requirements? Manufacturers, 
repackers, relabelers, and private label distributors of a human 
prescription drug product or an over-the-counter (OTC) drug product that 
is regulated under the Federal Food, Drug, and Cosmetic Act or the 
Public Health Service Act are subject to these bar code requirements 
unless they are exempt from the registration and drug listing 
requirements in section 510 of the Federal Food, Drug, and Cosmetic Act.
    (b) What drugs are subject to these bar code requirements? The 
following drug products are subject to the bar code label requirements:
    (1) Prescription drug products, however:
    (i) The bar code requirement does not apply to the following 
entities:
    (A) Prescription drug samples;
    (B) Allergenic extracts;
    (C) Intrauterine contraceptive devices regulated as drugs;
    (D) Medical gases;
    (E) Radiopharmaceuticals; and
    (F) Low-density polyethylene form fill and seal containers that are 
not packaged with an overwrap.
    (ii) The bar code requirement does not apply to prescription drugs 
sold by a manufacturer, repacker, relabeler, or private label 
distributor directly to patients, but versions of the same drug product 
that are sold to or used in hospitals are subject to the bar code 
requirements.
    (2) Biological products; and
    (3) OTC drug products that are dispensed pursuant to an order and 
are commonly used in hospitals. For purposes of this section, an OTC 
drug product is ``commonly used in hospitals'' if it is packaged for 
hospital use, labeled for hospital use (or uses similar terms), or 
marketed, promoted, or sold to hospitals.
    (c) What does the bar code look like? Where does the bar code go? 
(1) Each drug product described in paragraph (b) of this section must 
have a bar code that contains, at a minimum, the appropriate National 
Drug Code (NDC) number in a linear bar code that meets European Article 
Number/Uniform Code Council (EAN/UCC) or Health Industry Business 
Communications Council (HIBCC) standards or another standard or format 
that has been approved by the relevant Food and Drug Administration 
Center Director. Additionally, the bar code must:
    (i) Be surrounded by sufficient blank space so that the bar code can 
be scanned correctly; and
    (ii) Remain intact under normal conditions of use.
    (2) The bar code must appear on the drug's label as defined by 
section 201(k) of the Federal Food, Drug, and Cosmetic Act.
    (d) Can a drug be exempted from the bar code requirement? (1) On our 
own initiative, or in response to a written request from a manufacturer, 
repacker, relabeler or private label distributor, we may exempt a drug 
product from the bar code label requirements set forth in this section. 
The exemption request must document why:
    (i) compliance with the bar code requirement would adversely affect 
the safety, effectiveness, purity or potency of the drug or not be 
technologically feasible, and the concerns underlying the request could 
not reasonably be addressed by measures such as package redesign or use 
of overwraps; or
    (ii) an alternative regulatory program or method of product use 
renders

[[Page 20]]

the bar code unnecessary for patient safety.
    (2) Requests for an exemption should be sent to the Office of 
Compliance, Center for Drug Evaluation and Research, Food and Drug 
Administration, 10903 New Hampshire Ave., Bldg. 51, Silver Spring, MD 
20993-0002 (requests involving a drug product or biological product 
regulated by the Center for Drug Evaluation and Research) or to the Food 
and Drug Administration, Center for Biologics Evaluation and Research, 
Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, 
Silver Spring, MD 20993-0002 (requests involving a biological product 
regulated by the Center for Biologics Evaluation and Research).

[69 FR 9170, Feb. 26, 2004, as amended at 76 FR 12847, Mar. 9, 2011; 80 
FR 18090, Apr. 3, 2015; 81 FR 60212, Aug. 31, 2016]



Sec.  201.26  Exceptions or alternatives to labeling requirements for
human drug products held by the Strategic National Stockpile.

    (a) The appropriate FDA Center Director may grant an exception or 
alternative to any provision listed in paragraph (f) of this section and 
not explicitly required by statute, for specified lots, batches, or 
other units of a human drug product, if the Center Director determines 
that compliance with such labeling requirement could adversely affect 
the safety, effectiveness, or availability of such product that is or 
will be included in the Strategic National Stockpile.
    (b)(1)(i) A Strategic National Stockpile official or any entity that 
manufactures (including labeling, packing, relabeling, or repackaging), 
distributes, or stores a human drug product that is or will be included 
in the Strategic National Stockpile may submit, with written concurrence 
from a Strategic National Stockpile official, a written request for an 
exception or alternative described in paragraph (a) of this section to 
the Center Director.
    (ii) The Center Director may grant an exception or alternative 
described in paragraph (a) of this section on his or her own initiative.
    (2) A written request for an exception or alternative described in 
paragraph (a) of this section must:
    (i) Identify the specified lots, batches, or other units of the 
human drug product that would be subject to the exception or 
alternative;
    (ii) Identify the labeling provision(s) listed in paragraph (f) of 
this section that are the subject of the exception or alternative 
request;
    (iii) Explain why compliance with such labeling provision(s) could 
adversely affect the safety, effectiveness, or availability of the 
specified lots, batches, or other units of a human drug product that are 
or will be held in the Strategic National Stockpile;
    (iv) Describe any proposed safeguards or conditions that will be 
implemented so that the labeling of the product includes appropriate 
information necessary for the safe and effective use of the product, 
given the anticipated circumstances of use of the product;
    (v) Provide a draft of the proposed labeling of the specified lots, 
batches, or other units of the human drug product subject to the 
exception or alternative; and
    (vi) Provide any other information requested by the Center Director 
in support of the request.
    (c) The Center Director must respond in writing to all requests 
under this section.
    (d) A grant of an exception or alternative under this section will 
include any safeguards or conditions deemed appropriate by the Center 
Director so that the labeling of product subject to the exception or 
alternative includes the information necessary for the safe and 
effective use of the product, given the anticipated circumstances of 
use.
    (e) If you are a sponsor receiving a grant of a request for an 
exception or alternative to the labeling requirements under this 
section:
    (1) You need not submit a supplement under Sec.  314.70(a) through 
(c) or Sec.  601.12(f)(1) through (f)(2) of this chapter; however,
    (2) You must report any grant of a request for an exception or 
alternative under this section as part of your annual report under 
Sec. Sec.  314.70(d) or 601.12(f)(3) of this chapter.
    (f) The Center Director may grant an exception or alternative under 
this section to the following provisions of this

[[Page 21]]

chapter, to the extent that the requirements in these provisions are not 
explicitly required by statute:
    (1) Sec.  201.1(h)(1) through (h)(2), (h)(5) through (h)(6), and 
(i);
    (2) Sec.  201.10(a), (d)(2), (f), (g)(1), and (h)(1);
    (3) Sec.  201.17;
    (4) Sec.  201.18;
    (5) Sec.  201.19;
    (6) Sec.  201.20;
    (7) Sec.  201.21;
    (8) Sec.  201.22;
    (9) Sec.  201.24; and
    (10) Sec.  312.6.

[72 FR 73599, Dec. 28, 2007]



  Subpart B_Labeling Requirements for Prescription Drugs and/or Insulin



Sec.  201.50  Statement of identity.

    (a) The label of prescription and insulin-containing drugs in 
package form shall bear as one of its principal features a statement of 
the identity of the drug.
    (b) Such statement of identity shall be in terms of the established 
name of the drug. In the case of a prescription drug that is a mixture 
and that has no established name, the requirement for statement of 
identity shall be deemed to be satisfied by a listing of the 
quantitative ingredient information as prescribed by Sec.  201.10.
    (c) The statement of identity of a prescription drug shall also 
comply with the placement, size and prominence requirements of Sec.  
201.10.

[40 FR 13998, Mar. 27, 1975, as amended at 63 FR 26698, May 13, 1998]



Sec.  201.51  Declaration of net quantity of contents.

    (a) The label of a prescription or insulin-containing drug in 
package form shall bear a declaration of the net quantity of contents. 
This shall be expressed in the terms of weight, measure, numerical 
count, or a combination of numerical count and weight or measure. The 
statement of quantity of drugs in tablet, capsule, ampule, or other unit 
dosage form shall be expressed in terms of numerical count; the 
statement of quantity for drugs in other dosage forms shall be in terms 
of weight if the drug is solid, semi-solid, or viscous, or in terms of 
fluid measure if the drug is liquid. When the drug quantity statement is 
in terms of the numerical count of the drug units, it shall be augmented 
to give the weight or measure of the drug units or the quantity of each 
active ingredient in each drug unit or, when quantity does not 
accurately reflect drug potency, a statement of the drug potency.
    (b) Statements of weight of the contents shall in the case of 
prescription drugs be expressed in terms of avoirdupois pound, ounce, 
and grain or of kilogram, gram, and subdivisions thereof. A statement of 
liquid measure of the contents shall in the case of prescription drugs 
be expressed in terms of the U.S. gallon of 231 cubic inches and quart, 
pint, fluid-ounce, and fluid-dram subdivisions thereof, or of the liter 
and milliliter, or cubic centimeter, and shall express the volume at 68 
[deg]F. (20 [deg]C.). A statement of the liquid measure of the contents 
in the case of insulin-containing drugs shall be expressed in terms of 
the liter and milliliter, or cubic centimeter, and shall express the 
volume at 68 [deg]F. (20 [deg]C.).
    (c) The declaration shall contain only such fractions as are 
generally used in expressing the quantity of the drug. A common fraction 
shall be reduced to its lowest terms; a decimal fraction shall not be 
carried out to more than three places, except in the case of a statement 
of the quantity of an active ingredient in a unit of a drug.
    (d) The declaration shall appear as a distinct item on the label 
and, in the case of large volume parenterals, may be embossed on the 
glass.
    (e) The declaration shall accurately reveal the quantity of drug in 
the package exclusive of wrappers and other material packed therewith.
    (f) A statement of the quantity of a prescription or insulin-
containing drug in terms of weight or measure applicable to such drug, 
under the provisions of paragraph (a) of this section, shall express 
with prominence and conspicuousness the number of the largest whole 
unit, as specified in paragraph (b) of this section, that are contained 
in the package. Any remainder shall be expressed in terms of common or 
decimal fractions of such unit or in terms

[[Page 22]]

of the next smaller whole unit and common or decimal fractions thereof.
    (g) The declaration of net quantity of contents shall express an 
accurate statement of the quantity of contents of the package. 
Reasonable variations caused by loss or gain of moisture during the 
course of good distribution practice or by unavoidable deviations in 
good manufacturing practice will be recognized. Variations from stated 
quantity of contents shall not be unreasonably large. In the case of a 
liquid drug in ampules or vials, intended for injection, the declaration 
shall be considered to express the minimum quantity and the variation 
above the stated measure shall comply with the excess volume prescribed 
by the National Formulary or the U.S. Pharmacopeia for filling of 
ampules. In the case of a solid drug in ampules or vials, the 
declaration shall be considered to express the accurate net weight. 
Variations shall comply with the limitations provided in the U.S. 
Pharmacopeia or the National Formulary.
    (h) A drug shall be exempt from compliance with the net quantity 
declaration required by this section if it is an ointment labeled 
``sample'', ``physician's sample'', or a substantially similar statement 
and the contents of the package do not exceed 8 grams.



Sec.  201.55  Statement of dosage.

    Section 201.100(b)(2) requires that labels for prescription drugs 
bear a statement of the recommended or usual dosage. Since the dosage 
for some prescription drugs varies within extremely wide limits, 
depending upon the conditions being treated, it may not be possible in 
all cases to present an informative or useful statement of the 
recommended or usual dosage in the space available on the label or 
carton of the package. It is the view of the Food and Drug 
Administration that when such a situation prevails, compliance with this 
requirement would be met by a statement such as ``See package insert for 
dosage information'', where the detailed information is contained in 
such insert. However, if an informative, realistic, recommended or usual 
dosage can readily be set forth on the label, it should appear thereon.



Sec.  201.56  Requirements on content and format of labeling for human
prescription drug and biological products.

    (a) General requirements. Prescription drug labeling described in 
Sec.  201.100(d) must meet the following general requirements:
    (1) The labeling must contain a summary of the essential scientific 
information needed for the safe and effective use of the drug.
    (2) The labeling must be informative and accurate and neither 
promotional in tone nor false or misleading in any particular. In 
accordance with Sec. Sec.  314.70 and 601.12 of this chapter, the 
labeling must be updated when new information becomes available that 
causes the labeling to become inaccurate, false, or misleading.
    (3) The labeling must be based whenever possible on data derived 
from human experience. No implied claims or suggestions of drug use may 
be made if there is inadequate evidence of safety or a lack of 
substantial evidence of effectiveness. Conclusions based on animal data 
but necessary for safe and effective use of the drug in humans must be 
identified as such and included with human data in the appropriate 
section of the labeling.
    (b) Categories of prescription drugs subject to the labeling content 
and format requirements in Sec. Sec.  201.56(d) and 201.57. (1) The 
following categories of prescription drug products are subject to the 
labeling requirements in paragraph (d) of this section and Sec.  201.57 
in accordance with the implementation schedule in paragraph (c) of this 
section:
    (i) Prescription drug products for which a new drug application 
(NDA), biologics license application (BLA), or efficacy supplement was 
approved by the Food and Drug Administration (FDA) between June 30, 2001 
and June 30, 2006;
    (ii) Prescription drug products for which an NDA, BLA, or efficacy 
supplement is pending on June 30, 2006; or
    (iii) Prescription drug products for which an NDA, BLA, or efficacy 
supplement is submitted anytime on or after June 30, 2006.

[[Page 23]]

    (2) Prescription drug products not described in paragraph (b)(1) of 
this section are subject to the labeling requirements in paragraph (e) 
of this section and Sec.  201.80.
    (c) Schedule for implementing the labeling content and format 
requirements in Sec. Sec.  201.56(d) and 201.57. For products described 
in paragraph (b)(1) of this section, labeling conforming to the 
requirements in paragraph (d) of this section and Sec.  201.57 must be 
submitted according to the following schedule:
    (1) For products for which an NDA, BLA, or efficacy supplement is 
submitted for approval on or after June 30, 2006, proposed conforming 
labeling must be submitted as part of the application.
    (2) For products for which an NDA, BLA, or efficacy supplement is 
pending on June 30, 2006, or that has been approved any time from June 
30, 2005, up to and including June 30, 2006, a supplement with proposed 
conforming labeling must be submitted no later than June 30, 2009.
    (3) For products for which an NDA, BLA, or efficacy supplement has 
been approved anytime from June 30, 2004, up to and including June 29, 
2005, a supplement with proposed conforming labeling must be submitted 
no later than June 30, 2010.
    (4) For products for which an NDA, BLA, or efficacy supplement has 
been approved anytime from June 30, 2003, up to and including June 29, 
2004, a supplement with proposed conforming labeling must be submitted 
no later than June 30, 2011.
    (5) For products for which an NDA, BLA, or efficacy supplement has 
been approved anytime from June 30, 2002, up to and including June 29, 
2003, a supplement with proposed conforming labeling must be submitted 
no later than June 30, 2012.
    (6) For products for which an NDA, BLA, or efficacy supplement has 
been approved anytime from June 30, 2001, up to and including June 29, 
2002, a supplement with proposed conforming labeling must be submitted 
no later than June 30, 2013.
    (d) Labeling requirements for new and more recently approved 
prescription drug products. This paragraph applies only to prescription 
drug products described in paragraph (b)(1) of this section and must be 
implemented according to the schedule specified in paragraph (c) of this 
section.
    (1) Prescription drug labeling described in Sec.  201.100(d) must 
contain the specific information required under Sec.  201.57(a), (b), 
and (c) under the following headings and subheadings and in the 
following order:

Highlights of Prescribing Information
    Product Names, Other Required Information
    Boxed Warning
    Recent Major Changes
    Indications and Usage
    Dosage and Administration
    Dosage Forms and Strengths
    Contraindications
    Warnings and Precautions
    Adverse Reactions
    Drug Interactions
    Use in Specific Populations
Full Prescribing Information: Contents
Full Prescribing Information
    Boxed Warning
    1 Indications and Usage
    2 Dosage and Administration
    3 Dosage Forms and Strengths
    4 Contraindications
    5 Warnings and Precautions
    6 Adverse Reactions
    7 Drug Interactions
    8 Use in Specific Populations
     8.1 Pregnancy
     8.2 Lactation
     8.3 Females and Males of Reproductive Potential
     8.4 Pediatric use
     8.5 Geriatric use
    9 Drug Abuse and Dependence
     9.1 Controlled substance
     9.2 Abuse
     9.3 Dependence
    10 Overdosage
    11 Description
    12 Clinical Pharmacology
     12.1 Mechanism of action
     12.2 Pharmacodynamics
     12.3 Pharmacokinetics
    13 Nonclinical Toxicology
     13.1 Carcinogenesis, mutagenesis, impairment of fertility
     13.2 Animal toxicology and/or pharmacology
    14 Clinical Studies
    15 References
    16 How Supplied/Storage and Handling
    17 Patient Counseling Information

    (2) Additional nonstandard subheadings that are used to enhance 
labeling organization, presentation, or ease of use (e.g., for 
individual warnings or precautions, or for each drug

[[Page 24]]

interaction) must be assigned a decimal number that corresponds to their 
placement in labeling. The decimal numbers must be consistent with the 
standardized identifying numbers listed in paragraph (d)(1) of this 
section (e.g., subheadings added to the ``Warnings and Precautions'' 
section must be numbered 5.1, 5.2, and so on).
    (3) Any reference in Highlights to information appearing in the full 
prescribing information must be accompanied by the identifying number 
(in parentheses) corresponding to the location of the information in the 
full prescribing information.
    (4) Omit clearly inapplicable sections, subsections, or specific 
information. If sections or subsections required under paragraph (d)(1) 
of this section are omitted from the full prescribing information, the 
heading ``Full Prescribing Information: Contents'' must be followed by 
an asterisk and the following statement must appear at the end of 
Contents: ``* Sections or subsections omitted from the full prescribing 
information are not listed.''
    (5) Any risk information that is required under Sec.  
201.57(c)(9)(iv) is considered ``appropriate pediatric 
contraindications, warnings, or precautions'' within the meaning of 
section 505A(l)(2) of the Federal Food, Drug, and Cosmetic Act (the act) 
(21 U.S.C. 355A(l)(2)), whether such information appears in the 
``Contraindications,'' ``Warnings and Precautions,'' or ``Use in 
Specific Populations'' section of labeling.
    (e) Labeling requirements for older prescription drug products. This 
paragraph applies only to approved prescription drug products not 
described in paragraph (b)(1) of this section.
    (1) Prescription drug labeling described in Sec.  201.100(d) must 
contain the specific information required under Sec.  201.80 under the 
following section headings and in the following order:

    Description
    Clinical Pharmacology
    Indications and Usage
    Contraindications
    Warnings
    Precautions
    Adverse Reactions
    Drug Abuse and Dependence
    Overdosage
    Dosage and Administration
    How Supplied

    (2) The labeling may contain the following additional section 
headings if appropriate and if in compliance with Sec.  201.80(l) and 
(m):

    Animal Pharmacology and/or Animal Toxicology
    Clinical Studies
    References

    (3) Omit clearly inapplicable sections, subsections, or specific 
information.
    (4) The labeling may contain a ``Product Title'' section preceding 
the ``Description'' section and containing only the information required 
by Sec.  201.80(a)(1)(i), (a)(1)(ii), (a)(1)(iii), and (a)(1)(iv) and 
Sec.  201.100(e). The information required by Sec.  201.80(a)(1)(i) 
through (a)(1)(iv) must appear in the ``Description'' section of the 
labeling, whether or not it also appears in a ``Product Title.''
    (5) The labeling must contain the date of the most recent revision 
of the labeling, identified as such, placed prominently immediately 
after the last section of the labeling.
    (6) The requirement in Sec.  201.80(f)(2) to reprint any FDA-
approved patient labeling at the end of prescription drug labeling or 
accompany the prescription drug labeling must be implemented no later 
than June 30, 2007.

[71 FR 3986, Jan. 24, 2006, as amended at 79 FR 72101, Dec. 4, 2014]



Sec.  201.57  Specific requirements on content and format of labeling
for human prescription drug and biological products described in 
Sec. 201.56(b)(1).

    The requirements in this section apply only to prescription drug 
products described in Sec.  201.56(b)(1) and must be implemented 
according to the schedule specified in Sec.  201.56(c), except for the 
requirement in paragraph (c)(18) of this section to reprint any FDA-
approved patient labeling at the end of prescription drug labeling or 
accompany the prescription drug labeling, which must be implemented no 
later than June 30, 2007.
    (a) Highlights of prescribing information. The following information 
must appear in all prescription drug labeling:

[[Page 25]]

    (1) Highlights limitation statement. The verbatim statement ``These 
highlights do not include all the information needed to use (insert name 
of drug product) safely and effectively. See full prescribing 
information for (insert name of drug product).''
    (2) Drug names, dosage form, route of administration, and controlled 
substance symbol. The proprietary name and the established name of the 
drug, if any, as defined in section 502(e)(3) of the Federal Food, Drug, 
and Cosmetic Act (the act) or, for biological products, the proper name 
(as defined in Sec.  600.3 of this chapter) including any appropriate 
descriptors. This information must be followed by the drug's dosage form 
and route of administration. For controlled substances, the controlled 
substance symbol designating the schedule in which the controlled 
substance is listed must be included as required by Sec.  1302.04 of 
this chapter.
    (3) Initial U.S. approval. The verbatim statement ``Initial U.S. 
Approval'' followed by the four-digit year in which FDA initially 
approved a new molecular entity, new biological product, or new 
combination of active ingredients. The statement must be placed on the 
line immediately beneath the established name or, for biological 
products, proper name of the product.
    (4) Boxed warning. A concise summary of any boxed warning required 
by paragraph (c)(1) of this section, not to exceed a length of 20 lines. 
The summary must be preceded by a heading, in upper-case letters, 
containing the word ``WARNING'' and other words that are appropriate to 
identify the subject of the warning. The heading and the summary must be 
contained within a box and bolded. The following verbatim statement must 
be placed immediately following the heading of the boxed warning: ``See 
full prescribing information for complete boxed warning.''
    (5) Recent major changes. A list of the section(s) of the full 
prescribing information, limited to the labeling sections described in 
paragraphs (c)(1), (c)(2), (c)(3), (c)(5), and (c)(6) of this section, 
that contain(s) substantive labeling changes that have been approved by 
FDA or authorized under Sec.  314.70(c)(6) or (d)(2), or Sec.  
601.12(f)(1) through (f)(3) of this chapter. The heading(s) and, if 
appropriate, the subheading(s) of the labeling section(s) affected by 
the change must be listed together with each section's identifying 
number and the date (month/year) on which the change was incorporated in 
labeling. These labeling sections must be listed in the order in which 
they appear in the full prescribing information. A changed section must 
be listed under this heading in Highlights for at least 1 year after the 
date of the labeling change and must be removed at the first printing 
subsequent to the 1 year period.
    (6) Indications and usage. A concise statement of each of the 
product's indications, as required under paragraph (c)(2) of this 
section, with any appropriate subheadings. Major limitations of use 
(e.g., lack of effect in particular subsets of the population, or second 
line therapy status) must be briefly noted. If the product is a member 
of an established pharmacologic class, the concise statement under this 
heading in Highlights must identify the class in the following manner: 
``(Drug) is a (name of class) indicated for (indication(s)).''
    (7) Dosage and administration. A concise summary of the information 
required under paragraph (c)(3) of this section, with any appropriate 
subheadings, including the recommended dosage regimen, starting dose, 
dose range, critical differences among population subsets, monitoring 
recommendations, and other clinically significant clinical pharmacologic 
information.
    (8) Dosage forms and strengths. A concise summary of the information 
required under paragraph (c)(4) of this section, with any appropriate 
subheadings (e.g., tablets, capsules, injectable, suspension), including 
the strength or potency of the dosage form in metric system (e.g., 10-
milligram tablets) and whether the product is scored.
    (9) Contraindications. A concise statement of each of the product's 
contraindications, as required under paragraph (c)(5) of this section, 
with any appropriate subheadings.
    (10) Warnings and precautions. A concise summary of the most 
clinically significant information required under

[[Page 26]]

paragraph (c)(6) of this section, with any appropriate subheadings, 
including information that would affect decisions about whether to 
prescribe a drug, recommendations for patient monitoring that are 
critical to safe use of the drug, and measures that can be taken to 
prevent or mitigate harm.
    (11) Adverse reactions. (i) A list of the most frequently occurring 
adverse reactions, as described in paragraph (c)(7) of this section, 
along with the criteria used to determine inclusion (e.g., incidence 
rate). Adverse reactions important for other reasons (e.g., because they 
are serious or frequently lead to discontinuation or dosage adjustment) 
must not be repeated under this heading in Highlights if they are 
included elsewhere in Highlights (e.g., Warnings and Precautions, 
Contraindications).
    (ii) For drug products other than vaccines, the verbatim statement 
``To report SUSPECTED ADVERSE REACTIONS, contact (insert name of 
manufacturer) at (insert manufacturer's phone number) or FDA at (insert 
current FDA phone number and Web address for voluntary reporting of 
adverse reactions).''
    (iii) For vaccines, the verbatim statement ``To report SUSPECTED 
ADVERSE REACTIONS, contact (insert name of manufacturer) at (insert 
manufacturer's phone number) or VAERS at (insert the current VAERS phone 
number and Web address for voluntary reporting of adverse reactions).''
    (iv) For manufacturers with a Web site for voluntary reporting of 
adverse reactions, the Web address of the direct link to the site.
    (12) Drug interactions. A concise summary of the information 
required under paragraph (c)(8) of this section, with any appropriate 
subheadings.
    (13) Use in specific populations. A concise summary of the 
information required under paragraph (c)(9) of this section, with any 
appropriate subheadings.
    (14) Patient counseling information statement. The verbatim 
statement ``See 17 for Patient Counseling Information'' or, if the 
product has FDA-approved patient labeling, the verbatim statement ``See 
17 for Patient Counseling Information and (insert either FDA-approved 
patient labeling or Medication Guide).''
    (15) Revision date. The date of the most recent revision of the 
labeling, identified as such, placed at the end of Highlights.
    (b) Full prescribing information: Contents. Contents must contain a 
list of each heading and subheading required in the full prescribing 
information under Sec.  201.56(d)(1), if not omitted under Sec.  
201.56(d)(4), preceded by the identifying number required under Sec.  
201.56(d)(1). Contents must also contain any additional subheading(s) 
included in the full prescribing information preceded by the identifying 
number assigned in accordance with Sec.  201.56(d)(2).
    (c) Full prescribing information. The full prescribing information 
must contain the information in the order required under paragraphs 
(c)(1) through (c)(18) of this section, together with the headings, 
subheadings, and identifying numbers required under Sec.  201.56(d)(1), 
unless omitted under Sec.  201.56(d)(4). If additional subheadings are 
used within a labeling section, they must be preceded by the identifying 
number assigned in accordance with Sec.  201.56(d)(2).
    (1) Boxed warning. Certain contraindications or serious warnings, 
particularly those that may lead to death or serious injury, may be 
required by the FDA to be presented in a box. The boxed warning 
ordinarily must be based on clinical data, but serious animal toxicity 
may also be the basis of a boxed warning in the absence of clinical 
data. The box must contain, in uppercase letters, a heading inside the 
box that includes the word ``WARNING'' and conveys the general focus of 
the information in the box. The box must briefly explain the risk and 
refer to more detailed information in the ``Contraindications'' or 
``Warnings and Precautions'' section, accompanied by the identifying 
number for the section or subsection containing the detailed 
information.
    (2) 1 Indications and usage. This section must state that the drug 
is indicated for the treatment, prevention, mitigation, cure, or 
diagnosis of a recognized disease or condition, or of a manifestation of 
a recognized disease or condition, or for the relief of symptoms 
associated with a recognized disease or condition.

[[Page 27]]

    (i) This section must include the following information when the 
conditions listed are applicable:
    (A) If the drug is used for an indication only in conjunction with a 
primary mode of therapy (e.g., diet, surgery, behavior changes, or some 
other drug), a statement that the drug is indicated as an adjunct to 
that mode of therapy.
    (B) If evidence is available to support the safety and effectiveness 
of the drug or biological product only in selected subgroups of the 
larger population (e.g., patients with mild disease or patients in a 
special age group), or if the indication is approved based on a 
surrogate endpoint under Sec.  314.510 or Sec.  601.41 of this chapter, 
a succinct description of the limitations of usefulness of the drug and 
any uncertainty about anticipated clinical benefits, with reference to 
the ``Clinical Studies'' section for a discussion of the available 
evidence.
    (C) If specific tests are necessary for selection or monitoring of 
the patients who need the drug (e.g., microbe susceptibility tests), the 
identity of such tests.
    (D) If information on limitations of use or uncertainty about 
anticipated clinical benefits is relevant to the recommended intervals 
between doses, to the appropriate duration of treatment when such 
treatment should be limited, or to any modification of dosage, a concise 
description of the information with reference to the more detailed 
information in the ``Dosage and Administration'' section.
    (E) If safety considerations are such that the drug should be 
reserved for specific situations (e.g., cases refractory to other 
drugs), a statement of the information.
    (F) If there are specific conditions that should be met before the 
drug is used on a long term basis (e.g., demonstration of responsiveness 
to the drug in a short term trial in a given patient), a statement of 
the conditions; or, if the indications for long term use are different 
from those for short term use, a statement of the specific indications 
for each use.
    (ii) If there is a common belief that the drug may be effective for 
a certain use or if there is a common use of the drug for a condition, 
but the preponderance of evidence related to the use or condition shows 
that the drug is ineffective or that the therapeutic benefits of the 
product do not generally outweigh its risks, FDA may require that this 
section state that there is a lack of evidence that the drug is 
effective or safe for that use or condition.
    (iii) Any statements comparing the safety or effectiveness of the 
drug with other agents for the same indication must, except for 
biological products, be supported by substantial evidence derived from 
adequate and well-controlled studies as defined in Sec.  314.126(b) of 
this chapter unless this requirement is waived under Sec.  201.58 or 
Sec.  314.126(c) of this chapter. For biological products, such 
statements must be supported by substantial evidence.
    (iv) For drug products other than biological products, all 
indications listed in this section must be supported by substantial 
evidence of effectiveness based on adequate and well-controlled studies 
as defined in Sec.  314.126(b) of this chapter unless the requirement is 
waived under Sec.  201.58 or Sec.  314.126(c) of this chapter. 
Indications or uses must not be implied or suggested in other sections 
of the labeling if not included in this section.
    (v) For biological products, all indications listed in this section 
must be supported by substantial evidence of effectiveness. Indications 
or uses must not be implied or suggested in other sections of the 
labeling if not included in this section.
    (3) 2 Dosage and administration. (i) This section must state the 
recommended dose and, as appropriate:
    (A) The dosage range,
    (B) An upper limit beyond which safety and effectiveness have not 
been established, or beyond which increasing the dose does not result in 
increasing effectiveness,
    (C) Dosages for each indication and subpopulation,
    (D) The intervals recommended between doses,
    (E) The optimal method of titrating dosage,
    (F) The usual duration of treatment when treatment duration should 
be limited,

[[Page 28]]

    (G) Dosing recommendations based on clinical pharmacologic data 
(e.g., clinically significant food effects),
    (H) Modification of dosage needed because of drug interactions or in 
special patient populations (e.g., in children, in geriatric age groups, 
in groups defined by genetic characteristics, or in patients with renal 
or hepatic disease),
    (I) Important considerations concerning compliance with the dosage 
regimen,
    (J) Efficacious or toxic concentration ranges and therapeutic 
concentration windows of the drug or its metabolites, if established and 
clinically significant. Information on therapeutic drug concentration 
monitoring (TDM) must also be included in this section when TDM is 
necessary.
    (ii) Dosing regimens must not be implied or suggested in other 
sections of the labeling if not included in this section.
    (iii) Radiation dosimetry information must be stated for both the 
patient receiving a radioactive drug and the person administering it.
    (iv) This section must also contain specific direction on dilution, 
preparation (including the strength of the final dosage solution, when 
prepared according to instructions, in terms of milligrams of active 
ingredient per milliliter of reconstituted solution, unless another 
measure of the strength is more appropriate), and administration of the 
dosage form, if needed (e.g., the rate of administration of parenteral 
drug in milligrams per minute; storage conditions for stability of the 
reconstituted drug, when important; essential information on drug 
incompatibilities if the drug is mixed in vitro with other drugs or 
diluents; and the following verbatim statement for parenterals: 
``Parenteral drug products should be inspected visually for particulate 
matter and discoloration prior to administration, whenever solution and 
container permit.'')
    (4) 3 Dosage forms and strengths. This section must contain 
information on the available dosage forms to which the labeling applies 
and for which the manufacturer or distributor is responsible, including:
    (i) The strength or potency of the dosage form in metric system 
(e.g., 10 milligram tablets), and, if the apothecary system is used, a 
statement of the strength in parentheses after the metric designation; 
and
    (ii) A description of the identifying characteristics of the dosage 
forms, including shape, color, coating, scoring, and imprinting, when 
applicable. The National Drug Code number(s) for the drug product must 
not be included in this section.
    (5) 4 Contraindications. This section must describe any situations 
in which the drug should not be used because the risk of use (e.g., 
certain potentially fatal adverse reactions) clearly outweighs any 
possible therapeutic benefit. Those situations include use of the drug 
in patients who, because of their particular age, sex, concomitant 
therapy, disease state, or other condition, have a substantial risk of 
being harmed by the drug and for whom no potential benefit makes the 
risk acceptable. Known hazards and not theoretical possibilities must be 
listed (e.g., if severe hypersensitivity to the drug has not been 
demonstrated, it should not be listed as a contraindication). If no 
contraindications are known, this section must state ``None.''
    (6) 5 Warnings and precautions. (i) General. This section must 
describe clinically significant adverse reactions (including any that 
are potentially fatal, are serious even if infrequent, or can be 
prevented or mitigated through appropriate use of the drug), other 
potential safety hazards (including those that are expected for the 
pharmacological class or those resulting from drug/drug interactions), 
limitations in use imposed by them (e.g., avoiding certain concomitant 
therapy), and steps that should be taken if they occur (e.g., dosage 
modification). The frequency of all clinically significant adverse 
reactions and the approximate mortality and morbidity rates for patients 
experiencing the reaction, if known and necessary for the safe and 
effective use of the drug, must be expressed as provided under paragraph 
(c)(7) of this section. In accordance with Sec. Sec.  314.70 and 601.12 
of this chapter, the labeling must be revised to include a warning about 
a clinically significant hazard as soon as there is reasonable evidence 
of a causal association with a

[[Page 29]]

drug; a causal relationship need not have been definitely established. A 
specific warning relating to a use not provided for under the 
``Indications and Usage'' section may be required by FDA in accordance 
with sections 201(n) and 502(a) of the act if the drug is commonly 
prescribed for a disease or condition and such usage is associated with 
a clinically significant risk or hazard.
    (ii) Other special care precautions. This section must contain 
information regarding any special care to be exercised by the 
practitioner for safe and effective use of the drug (e.g., precautions 
not required under any other specific section or subsection).
    (iii) Monitoring: Laboratory tests. This section must identify any 
laboratory tests helpful in following the patient's response or in 
identifying possible adverse reactions. If appropriate, information must 
be provided on such factors as the range of normal and abnormal values 
expected in the particular situation and the recommended frequency with 
which tests should be performed before, during, and after therapy.
    (iv) Interference with laboratory tests. This section must briefly 
note information on any known interference by the product with 
laboratory tests and reference the section where the detailed 
information is presented (e.g., ``Drug Interactions'' section).
    (7) 6 Adverse reactions. This section must describe the overall 
adverse reaction profile of the drug based on the entire safety 
database. For purposes of prescription drug labeling, an adverse 
reaction is an undesirable effect, reasonably associated with use of a 
drug, that may occur as part of the pharmacological action of the drug 
or may be unpredictable in its occurrence. This definition does not 
include all adverse events observed during use of a drug, only those 
adverse events for which there is some basis to believe there is a 
causal relationship between the drug and the occurrence of the adverse 
event.
    (i) Listing of adverse reactions. This section must list the adverse 
reactions that occur with the drug and with drugs in the same 
pharmacologically active and chemically related class, if applicable. 
The list or lists must be preceded by the information necessary to 
interpret the adverse reactions (e.g., for clinical trials, total number 
exposed, extent and nature of exposure).
    (ii) Categorization of adverse reactions. Within a listing, adverse 
reactions must be categorized by body system, by severity of the 
reaction, or in order of decreasing frequency, or by a combination of 
these, as appropriate. Within a category, adverse reactions must be 
listed in decreasing order of frequency. If frequency information cannot 
be reliably determined, adverse reactions must be listed in decreasing 
order of severity.
    (A) Clinical trials experience. This section must list the adverse 
reactions identified in clinical trials that occurred at or above a 
specified rate appropriate to the safety database. The rate of 
occurrence of an adverse reaction for the drug and comparators (e.g., 
placebo) must be presented, unless such data cannot be determined or 
presentation of comparator rates would be misleading. If adverse 
reactions that occurred below the specified rate are included, they must 
be included in a separate listing. If comparative rates of occurrence 
cannot be reliably determined (e.g., adverse reactions were observed 
only in the uncontrolled trial portion of the overall safety database), 
adverse reactions must be grouped within specified frequency ranges as 
appropriate to the safety database for the drug (e.g., adverse reactions 
occurring at a rate of less than 1/100, adverse reactions occurring at a 
rate of less than 1/500) or descriptively identified, if frequency 
ranges cannot be determined. For adverse reactions with significant 
clinical implications, the listings must be supplemented with additional 
detail about the nature, frequency, and severity of the adverse reaction 
and the relationship of the adverse reaction to drug dose and 
demographic characteristics, if data are available and important.
    (B) Postmarketing experience. This section of the labeling must list 
the adverse reactions, as defined in paragraph (c)(7) of this section, 
that are identified from domestic and foreign spontaneous reports. This 
listing must be separate

[[Page 30]]

from the listing of adverse reactions identified in clinical trials.
    (iii) Comparisons of adverse reactions between drugs. For drug 
products other than biological products, any claim comparing the drug to 
which the labeling applies with other drugs in terms of frequency, 
severity, or character of adverse reactions must be based on adequate 
and well-controlled studies as defined in Sec.  314.126(b) of this 
chapter unless this requirement is waived under Sec.  201.58 or Sec.  
314.126(c) of this chapter. For biological products, any such claim must 
be based on substantial evidence.
    (8) 7 Drug interactions. (i) This section must contain a description 
of clinically significant interactions, either observed or predicted, 
with other prescription or over-the-counter drugs, classes of drugs, or 
foods (e.g., dietary supplements, grapefruit juice), and specific 
practical instructions for preventing or managing them. The mechanism(s) 
of the interaction, if known, must be briefly described. Interactions 
that are described in the ``Contraindications'' or ``Warnings and 
Precautions'' sections must be discussed in more detail under this 
section. Details of drug interaction pharmacokinetic studies that are 
included in the ``Clinical Pharmacology'' section that are pertinent to 
clinical use of the drug must not be repeated in this section.
    (ii) This section must also contain practical guidance on known 
interference of the drug with laboratory tests.
    (9) 8 Use in specific populations. This section must contain the 
following subsections:
    (i) 8.1 Pregnancy. This subsection of the labeling must contain the 
following information in the following order under the subheadings 
``Pregnancy Exposure Registry,'' ``Risk Summary,'' ``Clinical 
Considerations,'' and ``Data'':
    (A) Pregnancy exposure registry. If there is a scientifically 
acceptable pregnancy exposure registry for the drug, contact information 
needed to enroll in the registry or to obtain information about the 
registry must be provided following the statement: ``There is a 
pregnancy exposure registry that monitors pregnancy outcomes in women 
exposed to (name of drug) during pregnancy.''
    (B) Risk summary. The Risk Summary must contain risk statement(s) 
based on data from all relevant sources (human, animal, and/or 
pharmacologic) that describe, for the drug, the risk of adverse 
developmental outcomes (i.e., structural abnormalities, embryo-fetal 
and/or infant mortality, functional impairment, alterations to growth). 
When multiple data sources are available, the statements must be 
presented in the following order: Human, animal, pharmacologic. The 
source(s) of the data must be stated. The labeling must state the 
percentage range of live births in the United States with a major birth 
defect and the percentage range of pregnancies in the United States that 
end in miscarriage, regardless of drug exposure. If such information is 
available for the population(s) for which the drug is labeled, it must 
also be included. When use of a drug is contraindicated during 
pregnancy, this information must be stated first in the Risk Summary. 
When applicable, risk statements as described in paragraphs 
(c)(9)(i)(B)(1) and (2) of this section must include a cross-reference 
to additional details in the relevant portion of the ``Data'' subheading 
in the ``Pregnancy'' subsection of the labeling. If data demonstrate 
that a drug is not systemically absorbed following a particular route of 
administration, the Risk Summary must contain only the following 
statement: ``(Name of drug) is not absorbed systemically following 
(route of administration), and maternal use is not expected to result in 
fetal exposure to the drug.''
    (1) Risk statement based on human data. When human data are 
available that establish the presence or absence of any adverse 
developmental outcome(s) associated with maternal use of the drug, the 
Risk Summary must summarize the specific developmental outcome(s); their 
incidence; and the effects of dose, duration of exposure, and 
gestational timing of exposure. If human data indicate that there is an 
increased risk for a specific adverse developmental outcome in infants 
born to women exposed to the drug during pregnancy, this risk must be 
quantitatively compared to the risk for the same outcome in infants born 
to women who were not exposed to the

[[Page 31]]

drug but who have the disease or condition for which the drug is 
indicated to be used. When risk information is not available for women 
with the disease or condition for which the drug is indicated, the risk 
for the specific outcome must be compared to the rate at which the 
outcome occurs in the general population. The Risk Summary must state 
when there are no human data or when available human data do not 
establish the presence or absence of drug-associated risk.
    (2) Risk statement based on animal data. When animal data are 
available, the Risk Summary must summarize the findings in animals and 
based on these findings, describe, for the drug, the potential risk of 
any adverse developmental outcome(s) in humans. This statement must 
include: The number and type(s) of species affected, timing of exposure, 
animal doses expressed in terms of human dose or exposure equivalents, 
and outcomes for pregnant animals and offspring. When animal studies do 
not meet current standards for nonclinical developmental toxicity 
studies, the Risk Summary must so state. When there are no animal data, 
the Risk Summary must so state.
    (3) Risk statement based on pharmacology. When the drug has a well-
understood mechanism of action that may result in adverse developmental 
outcome(s), the Risk Summary must explain the mechanism of action and 
the potential associated risks.
    (C) Clinical considerations. Under the subheading ``Clinical 
Considerations,'' the labeling must provide relevant information, to the 
extent it is available, under the headings ``Disease-associated maternal 
and/or embryo/fetal risk,'' ``Dose adjustments during pregnancy and the 
postpartum period,'' ``Maternal adverse reactions,'' ``Fetal/Neonatal 
adverse reactions,'' and ``Labor or delivery'':
    (1) Disease-associated maternal and/or embryo/fetal risk. If there 
is a serious known or potential risk to the pregnant woman and/or the 
embryo/fetus associated with the disease or condition for which the drug 
is indicated to be used, the labeling must describe the risk.
    (2) Dose adjustments during pregnancy and the postpartum period. If 
there are pharmacokinetic data that support dose adjustment(s) during 
pregnancy and the postpartum period, a summary of this information must 
be provided.
    (3) Maternal adverse reactions. If use of the drug is associated 
with a maternal adverse reaction that is unique to pregnancy or if a 
known adverse reaction occurs with increased frequency or severity in 
pregnant women, the labeling must describe the adverse reaction and 
available intervention(s) for monitoring or mitigating the reaction. The 
labeling must describe, if known, the effect of dose, timing, and 
duration of exposure on the risk to the pregnant woman of experiencing 
the adverse reaction.
    (4) Fetal/Neonatal adverse reactions. If it is known or anticipated 
that treatment of the pregnant woman increases or may increase the risk 
of an adverse reaction in the fetus or neonate, the labeling must 
describe the adverse reaction, the potential severity and reversibility 
of the adverse reaction, and available intervention(s) for monitoring or 
mitigating the reaction. The labeling must describe, if known, the 
effect of dose, timing, and duration of exposure on the risk.
    (5) Labor or delivery. If the drug is expected to affect labor or 
delivery, the labeling must provide information about the effect of the 
drug on the pregnant woman and the fetus or neonate; the effect of the 
drug on the duration of labor and delivery; any increased risk of 
adverse reactions, including their potential severity and reversibility; 
and must provide information about available intervention(s) that can 
mitigate these effects and/or adverse reactions. The information 
described under this heading is not required for drugs approved for use 
only during labor and delivery.
    (D) Data--(1) ``Data'' subheading. Under the subheading ``Data,'' 
the labeling must describe the data that are the basis for the Risk 
Summary and Clinical Considerations.
    (2) Human and animal data headings. Human and animal data must be 
presented separately, beneath the headings ``Human Data'' and ``Animal 
Data,'' and human data must be presented first.

[[Page 32]]

    (3) Description of human data. For human data, the labeling must 
describe adverse developmental outcomes, adverse reactions, and other 
adverse effects. To the extent applicable, the labeling must describe 
the types of studies or reports, number of subjects and the duration of 
each study, exposure information, and limitations of the data. Both 
positive and negative study findings must be included.
    (4) Description of animal data. For animal data, the labeling must 
describe the following: Types of studies, animal species, dose, duration 
and timing of exposure, study findings, presence or absence of maternal 
toxicity, and limitations of the data. Description of maternal and 
offspring findings must include dose-response and severity of adverse 
developmental outcomes. Animal doses or exposures must be described in 
terms of human dose or exposure equivalents and the basis for those 
calculations must be included.
    (ii) 8.2 Lactation. This subsection of the labeling must contain the 
following information in the following order under the subheadings 
``Risk Summary,'' ``Clinical Considerations,'' and ``Data'':
    (A) Risk summary. When relevant human and/or animal lactation data 
are available, the Risk Summary must include a cross-reference to the 
``Data'' subheading in the ``Lactation'' subsection of the labeling. 
When human data are available, animal data must not be included unless 
the animal model is specifically known to be predictive for humans. When 
use of a drug is contraindicated during breastfeeding, this information 
must be stated first in the Risk Summary.
    (1) Drug not absorbed systemically. If data demonstrate that the 
drug is not systemically absorbed by the mother, the Risk Summary must 
contain only the following statement: ``(Name of drug) is not absorbed 
systemically by the mother following (route of administration), and 
breastfeeding is not expected to result in exposure of the child to 
(name of drug).''
    (2) Drug absorbed systemically. If the drug is absorbed 
systemically, the Risk Summary must describe the following to the extent 
relevant information is available:
    (i) Presence of drug in human milk. The Risk Summary must state 
whether the drug and/or its active metabolite(s) are present in human 
milk. If there are no data to assess this, the Risk Summary must so 
state. If studies demonstrate that the drug and/or its active 
metabolite(s) are not detectable in human milk, the Risk Summary must 
state the limits of the assay used. If studies demonstrate the presence 
of the drug and/or its active metabolite(s) in human milk, the Risk 
Summary must state the concentration of the drug and/or its active 
metabolite(s) in human milk and the actual or estimated daily dose for 
an infant fed exclusively with human milk. The actual or estimated 
amount of the drug and/or its active metabolite(s) ingested by the 
infant must be compared to the labeled infant or pediatric dose, if 
available, or to the maternal dose. If studies demonstrate the presence 
of the drug and/or its active metabolite(s) in human milk but the drug 
and/or its active metabolite(s) are not expected to be systemically 
bioavailable to the breast-fed child, the Risk Summary must describe the 
disposition of the drug and/or its active metabolite(s). If only animal 
lactation data are available, the Risk Summary must state only whether 
or not the drug and/or its active metabolite(s) were detected in animal 
milk and specify the animal species.
    (ii) Effects of drug on the breast-fed child. The Risk Summary must 
include information, on the known or predicted effects on the child from 
exposure to the drug and/or its active metabolite(s) through human milk 
or from contact with breast or nipple skin (for topical products). The 
Risk Summary also must include information on systemic and/or local 
adverse reactions. If there are no data to assess the effects of the 
drug and/or its active metabolite(s) on the breast-fed child, the Risk 
Summary must so state.
    (iii) Effects of drug on milk production. The Risk Summary must 
describe the effects of the drug and/or its active metabolite(s) on milk 
production. If there are no data to assess the effects of the drug and/
or its active metabolite(s) on milk production, the Risk Summary must so 
state.

[[Page 33]]

    (3) Risk and benefit statement. For drugs absorbed systemically, 
unless breastfeeding is contraindicated during drug therapy, the 
following risk and benefit statement must appear at the end of the Risk 
Summary: ``The developmental and health benefits of breastfeeding should 
be considered along with the mother's clinical need for (name of drug) 
and any potential adverse effects on the breast-fed child from (name of 
drug) or from the underlying maternal condition.''
    (B) Clinical considerations. Under ``Clinical Considerations,'' the 
following information must be provided to the extent it is available and 
relevant:
    (1) Minimizing exposure. The labeling must describe ways to minimize 
exposure in the breast-fed child if: The drug and/or its active 
metabolite(s) are present in human milk in clinically relevant 
concentrations; the drug does not have an established safety profile in 
infants; and the drug is used either intermittently, in single doses, or 
for short courses of therapy. When applicable, the labeling must also 
describe ways to minimize a breast-fed child's oral intake of topical 
drugs applied to the breast or nipple skin.
    (2) Monitoring for adverse reactions. The labeling must describe 
available intervention(s) for monitoring or mitigating the adverse 
reaction(s) presented in the Risk Summary.
    (C) Data. Under the subheading ``Data,'' the labeling must describe 
the data that are the basis for the Risk Summary and Clinical 
Considerations.
    (iii) 8.3 Females and males of reproductive potential. When 
pregnancy testing and/or contraception are required or recommended 
before, during, or after drug therapy and/or when there are human and/or 
animal data that suggest drug-associated fertility effects, this 
subsection of labeling must contain this information under the 
subheadings ``Pregnancy Testing,'' ``Contraception,'' and 
``Infertility,'' in that order.
    (iv) 8.4 Pediatric use. (A) Pediatric population(s)/pediatric 
patient(s): For the purposes of paragraphs (c)(9)(iv)(B) through 
(c)(9)(iv)(H) of this section, the terms pediatric population(s) and 
pediatric patient(s) are defined as the pediatric age group, from birth 
to 16 years, including age groups often called neonates, infants, 
children, and adolescents.
    (B) If there is a specific pediatric indication different from those 
approved for adults that is supported by adequate and well-controlled 
studies in the pediatric population, it must be described under the 
``Indications and Usage'' section, and appropriate pediatric dosage 
information must be given under the ``Dosage and Administration'' 
section. The ``Pediatric use'' subsection must cite any limitations on 
the pediatric indication, need for specific monitoring, specific hazards 
associated with use of the drug in any subsets of the pediatric 
population (e.g., neonates), differences between pediatric and adult 
responses to the drug, and other information related to the safe and 
effective pediatric use of the drug. Data summarized in this subsection 
should be discussed in more detail, if appropriate, under the ``Clinical 
Pharmacology'' or ``Clinical Studies'' section. As appropriate, this 
information must also be contained in the ``Contraindications'' and/or 
``Warnings and Precautions'' section(s).
    (C) If there are specific statements on pediatric use of the drug 
for an indication also approved for adults that are based on adequate 
and well-controlled studies in the pediatric population, they must be 
summarized in the ``Pediatric use'' subsection and discussed in more 
detail, if appropriate, under the ``Clinical Pharmacology'' and 
``Clinical Studies'' sections. Appropriate pediatric dosage must be 
given under the ``Dosage and Administration'' section. The ``Pediatric 
use'' subsection of the labeling must also cite any limitations on the 
pediatric use statement, need for specific monitoring, specific hazards 
associated with use of the drug in any subsets of the pediatric 
population (e.g., neonates), differences between pediatric and adult 
responses to the drug, and other information related to the safe and 
effective pediatric use of the drug. As appropriate, this information 
must also be contained in the ``Contraindications'' and/or ``Warnings 
and Precautions'' section(s).
    (D)(1) When a drug is approved for pediatric use based on adequate 
and well-

[[Page 34]]

controlled studies in adults with other information supporting pediatric 
use, the ``Pediatric use'' subsection of the labeling must contain 
either the following statement or a reasonable alternative:
    The safety and effectiveness of (drug name) have been established in 
the age groups ___ to ___ (note any limitations, e.g., no data for 
pediatric patients under 2, or only applicable to certain indications 
approved in adults). Use of (drug name) in these age groups is supported 
by evidence from adequate and well-controlled studies of (drug name) in 
adults with additional data (insert wording that accurately describes 
the data submitted to support a finding of substantial evidence of 
effectiveness in the pediatric population).
    (2) Data summarized in the preceding prescribed statement in this 
subsection must be discussed in more detail, if appropriate, under the 
``Clinical Pharmacology'' or the ``Clinical Studies'' section. For 
example, pediatric pharmacokinetic or pharmacodynamic studies and dose 
response information should be described in the ``Clinical 
Pharmacology'' section. Pediatric dosing instructions must be included 
in the ``Dosage and Administration'' section. Any differences between 
pediatric and adult responses, need for specific monitoring, dosing 
adjustments, and any other information related to safe and effective use 
of the drug in pediatric patients must be cited briefly in the 
``Pediatric use'' subsection and, as appropriate, in the 
``Contraindications,'' ``Warnings and Precautions,'' and ``Dosage and 
Administration'' sections.
    (E) If the requirements for a finding of substantial evidence to 
support a pediatric indication or a pediatric use statement have not 
been met for a particular pediatric population, the ``Pediatric use'' 
subsection must contain an appropriate statement such as ``Safety and 
effectiveness in pediatric patients below the age of (__) have not been 
established.'' If use of the drug in this pediatric population is 
associated with a specific hazard, the hazard must be described in this 
subsection, or, if appropriate, the hazard must be stated in the 
``Contraindications'' or ``Warnings and Precautions'' section and this 
subsection must refer to it.
    (F) If the requirements for a finding of substantial evidence to 
support a pediatric indication or a pediatric use statement have not 
been met for any pediatric population, this subsection must contain the 
following statement: ``Safety and effectiveness in pediatric patients 
have not been established.'' If use of the drug in premature or neonatal 
infants, or other pediatric subgroups, is associated with a specific 
hazard, the hazard must be described in this subsection, or, if 
appropriate, the hazard must be stated in the ``Contraindications'' or 
``Warnings and Precautions'' section and this subsection must refer to 
it.
    (G) If the sponsor believes that none of the statements described in 
paragraphs (c)(9)(iv)(B) through (c)(9)(iv)(F) of this section are 
appropriate or relevant to the labeling of a particular drug, the 
sponsor must provide reasons for omission of the statements and may 
propose alternative statement(s). FDA may permit use of an alternative 
statement if FDA determines that no statement described in those 
paragraphs is appropriate or relevant to the drug's labeling and that 
the alternative statement is accurate and appropriate.
    (H) If the drug product contains one or more inactive ingredients 
that present an increased risk of toxic effects to neonates or other 
pediatric subgroups, a special note of this risk must be made, generally 
in the ``Contraindications'' or ``Warnings and Precautions'' section.
    (v) 8.5 Geriatric use. (A) A specific geriatric indication, if any, 
that is supported by adequate and well-controlled studies in the 
geriatric population must be described under the ``Indications and 
Usage'' section, and appropriate geriatric dosage must be stated under 
the ``Dosage and Administration'' section. The ``Geriatric use'' 
subsection must cite any limitations on the geriatric indication, need 
for specific monitoring, specific hazards associated with the geriatric 
indication, and other information related to the safe and effective use 
of the drug in the geriatric population. Unless otherwise noted, 
information contained in the ``Geriatric use'' subsection must pertain 
to use of the drug in persons 65 years of age and older. Data summarized 
in this subsection must be discussed in more detail, if appropriate, 
under ``Clinical Pharmacology'' or the

[[Page 35]]

``Clinical Studies'' section. As appropriate, this information must also 
be contained in the ``Warnings and Precautions'' and/or 
``Contraindications'' section(s).
    (B) Specific statements on geriatric use of the drug for an 
indication approved for adults generally, as distinguished from a 
specific geriatric indication, must be contained in the ``Geriatric 
use'' subsection and must reflect all information available to the 
sponsor that is relevant to the appropriate use of the drug in elderly 
patients. This information includes detailed results from controlled 
studies that are available to the sponsor and pertinent information from 
well-documented studies obtained from a literature search. Controlled 
studies include those that are part of the marketing application and 
other relevant studies available to the sponsor that have not been 
previously submitted in the investigational new drug application, new 
drug application, biologics license application, or a supplement or 
amendment to one of these applications (e.g., postmarketing studies or 
adverse drug reaction reports). The ``Geriatric use'' subsection must 
contain the following statement(s) or reasonable alternative, as 
applicable, taking into account available information:
    (1) If clinical studies did not include sufficient numbers of 
subjects aged 65 and over to determine whether elderly subjects respond 
differently from younger subjects, and other reported clinical 
experience has not identified such differences, the ``Geriatric use'' 
subsection must include the following statement:
    Clinical studies of (name of drug) did not include sufficient 
numbers of subjects aged 65 and over to determine whether they respond 
differently from younger subjects. Other reported clinical experience 
has not identified differences in responses between the elderly and 
younger patients. In general, dose selection for an elderly patient 
should be cautious, usually starting at the low end of the dosing range, 
reflecting the greater frequency of decreased hepatic, renal, or cardiac 
function, and of concomitant disease or other drug therapy.
    (2) If clinical studies (including studies that are part of 
marketing applications and other relevant studies available to the 
sponsor that have not been submitted in the sponsor's applications) 
included enough elderly subjects to make it likely that differences in 
safety or effectiveness between elderly and younger subjects would have 
been detected, but no such differences (in safety or effectiveness) were 
observed, and other reported clinical experience has not identified such 
differences, the ``Geriatric use'' subsection must contain the following 
statement:
    Of the total number of subjects in clinical studies of (name of 
drug), __ percent were 65 and over, while __ percent were 75 and over. 
(Alternatively, the labeling may state the total number of subjects 
included in the studies who were 65 and over and 75 and over.) No 
overall differences in safety or effectiveness were observed between 
these subjects and younger subjects, and other reported clinical 
experience has not identified differences in responses between the 
elderly and younger patients, but greater sensitivity of some older 
individuals cannot be ruled out.
    (3) If evidence from clinical studies and other reported clinical 
experience available to the sponsor indicates that use of the drug in 
elderly patients is associated with differences in safety or 
effectiveness, or requires specific monitoring or dosage adjustment, the 
``Geriatric use'' subsection must contain a brief description of 
observed differences or specific monitoring or dosage requirements and, 
as appropriate, must refer to more detailed discussions in the 
``Contraindications,'' ``Warnings and Precautions,'' ``Dosage and 
Administration,'' or other sections.
    (C)(1) If specific pharmacokinetic or pharmacodynamic studies have 
been carried out in the elderly, they must be described briefly in the 
``Geriatric use'' subsection and in detail under the ``Clinical 
Pharmacology'' section. The ``Clinical Pharmacology'' and ``Drug 
Interactions'' sections ordinarily contain information on drug/disease 
and drug/drug interactions that is particularly relevant to the elderly, 
who are more likely to have concomitant illness and to use concomitant 
drugs.
    (2) If a drug is known to be substantially excreted by the kidney, 
the ``Geriatric use'' subsection must include the statement:

[[Page 36]]

    This drug is known to be substantially excreted by the kidney, and 
the risk of adverse reactions to this drug may be greater in patients 
with impaired renal function. Because elderly patients are more likely 
to have decreased renal function, care should be taken in dose 
selection, and it may be useful to monitor renal function.
    (D) If use of the drug in the elderly appears to cause a specific 
hazard, the hazard must be described in the ``Geriatric use'' 
subsection, or, if appropriate, the hazard must be stated in the 
``Contraindications'' or ``Warnings and Precautions'' section, and the 
``Geriatric use'' subsection must refer to those sections.
    (E) Labeling under paragraphs (c)(9)(v)(A) through (c)(9)(v)(C) of 
this section may include statements, if they are necessary for safe and 
effective use of the drug, and reflect good clinical practice or past 
experience in a particular situation, e.g., for a sedating drug, it 
could be stated that:
    Sedating drugs may cause confusion and over-sedation in the elderly; 
elderly patients generally should be started on low doses of (name of 
drug) and observed closely.
    (F) If the sponsor believes that none of the requirements described 
in paragraphs (c)(9)(v)(A) through (c)(9)(v)(E) of this section are 
appropriate or relevant to the labeling of a particular drug, the 
sponsor must provide reasons for omission of the statements and may 
propose an alternative statement. FDA may permit omission of the 
statements if FDA determines that no statement described in those 
paragraphs is appropriate or relevant to the drug's labeling. FDA may 
permit use of an alternative statement if the agency determines that 
such statement is accurate and appropriate.
    (vi) Additional subsections. Additional subsections may be included, 
as appropriate, if sufficient data are available concerning the use of 
the drug in other specified subpopulations (e.g., renal or hepatic 
impairment).
    (10) 9 Drug abuse and dependence. This section must contain the 
following information, as appropriate:
    (i) 9.1 Controlled substance. If the drug is controlled by the Drug 
Enforcement Administration, the schedule in which it is controlled must 
be stated.
    (ii) 9.2 Abuse. This subsection must state the types of abuse that 
can occur with the drug and the adverse reactions pertinent to them, and 
must identify particularly susceptible patient populations. This 
subsection must be based primarily on human data and human experience, 
but pertinent animal data may also be used.
    (iii) 9.3 Dependence. This subsection must describe characteristic 
effects resulting from both psychological and physical dependence that 
occur with the drug and must identify the quantity of the drug over a 
period of time that may lead to tolerance or dependence, or both. 
Details must be provided on the adverse effects of chronic abuse and the 
effects of abrupt withdrawal. Procedures necessary to diagnose the 
dependent state and the principles of treating the effects of abrupt 
withdrawal must be described.
    (11) 10 Overdosage. This section must be based on human data. If 
human data are unavailable, appropriate animal and in vitro data may be 
used. The following specific information must be provided:
    (i) Signs, symptoms, and laboratory findings associated with an 
overdosage of the drug;
    (ii) Complications that can occur with the drug (for example, organ 
toxicity or delayed acidosis);
    (iii) Concentrations of the drug in biologic fluids associated with 
toxicity or death; physiologic variables influencing excretion of the 
drug, such as urine pH; and factors that influence the dose response 
relationship of the drug, such as tolerance. The pharmacokinetic data 
given in the ``Clinical Pharmacology'' section also may be referenced 
here, if applicable to overdoses;
    (iv) The amount of the drug in a single dose that is ordinarily 
associated with symptoms of overdosage and the amount of the drug in a 
single dose that is likely to be life threatening;
    (v) Whether the drug is dialyzable; and
    (vi) Recommended general treatment procedures and specific measures 
for support of vital functions (e.g., proven antidotes, gastric lavage, 
forced diuresis, or as per Poison Control Center). Such recommendations 
must be based on data available for the specific drug or experience with 
pharmacologically

[[Page 37]]

related drugs. Unqualified recommendations for which data are lacking 
for the specific drug or class of drugs must not be stated.
    (12) 11 Description. (i) This section must contain:
    (A) The proprietary name and the established name, if any, as 
defined in section 502(e)(2) of the act, of the drug or, for biological 
products, the proper name (as defined in Sec.  600.3 of this chapter) 
and any appropriate descriptors;
    (B) The type of dosage form(s) and the route(s) of administration to 
which the labeling applies;
    (C) The same qualitative and/or quantitative ingredient information 
as required under Sec.  201.100(b) for drug labels or Sec. Sec.  610.60 
and 610.61 of this chapter for biological product labels;
    (D) If the product is sterile, a statement of that fact;
    (E) The pharmacological or therapeutic class of the drug;
    (F) For drug products other than biological products, the chemical 
name and structural formula of the drug; and
    (G) If the product is radioactive, a statement of the important 
nuclear physical characteristics, such as the principal radiation 
emission data, external radiation, and physical decay characteristics.
    (ii) If appropriate, other important chemical or physical 
information, such as physical constants or pH, must be stated.
    (13) 12 Clinical pharmacology. (i) This section must contain 
information relating to the human clinical pharmacology and actions of 
the drug in humans. Pharmacologic information based on in vitro data 
using human biomaterials or pharmacologic animal models, or relevant 
details about in vivo study designs or results (e.g., drug interaction 
studies), may be included in this section if essential to understand 
dosing or drug interaction information presented in other sections of 
the labeling. This section must include the following subsections:
    (A) 12.1 Mechanism of action. This subsection must summarize what is 
known about the established mechanism(s) of the drug's action in humans 
at various levels (e.g., receptor, membrane, tissue, organ, whole body). 
If the mechanism of action is not known, this subsection must contain a 
statement about the lack of information.
    (B) 12.2 Pharmacodynamics. This subsection must include a 
description of any biochemical or physiologic pharmacologic effects of 
the drug or active metabolites related to the drug's clinical effect in 
preventing, diagnosing, mitigating, curing, or treating disease, or 
those related to adverse effects or toxicity. Exposure-response 
relationships (e.g., concentration-response, dose-response) and time 
course of pharmacodynamic response (including short-term clinical 
response) must be included if known. If this information is unknown, 
this subsection must contain a statement about the lack of information. 
Detailed dosing or monitoring recommendations based on pharmacodynamic 
information that appear in other sections (e.g., ``Warnings and 
Precautions'' or ``Dosage and Administration'') must not be repeated in 
this subsection, but the location of such recommendations must be 
referenced.
    (C) 12.3 Pharmacokinetics. This subsection must describe the 
clinically significant pharmacokinetics of a drug or active metabolites, 
(i.e., pertinent absorption, distribution, metabolism, and excretion 
parameters). Information regarding bioavailability, the effect of food, 
minimum concentration (Cmin), maximum concentration 
(Cmax), time to maximum concentration (Tmax), area 
under the curve (AUC), pertinent half-lives (t1/2), time to 
reach steady state, extent of accumulation, route(s) of elimination, 
clearance (renal, hepatic, total), mechanisms of clearance (e.g., 
specific enzyme systems), drug/drug and drug/food (e.g., dietary 
supplements, grapefruit juice) pharmacokinetic interactions (including 
inhibition, induction, and genetic characteristics), and volume of 
distribution (Vd) must be presented if clinically 
significant. Information regarding nonlinearity in pharmacokinetic 
parameters, changes in pharmacokinetics over time, and binding (plasma 
protein, erythrocyte) parameters must also be presented if clinically 
significant. This section must also include the results of 
pharmacokinetic studies (e.g., of metabolism or interaction) that 
establish

[[Page 38]]

the absence of an effect, including pertinent human studies and in vitro 
data. Dosing recommendations based on clinically significant factors 
that change the product's pharmacokinetics (e.g., age, gender, race, 
hepatic or renal dysfunction, concomitant therapy) that appear in other 
sections (e.g., ``Warnings and Precautions,'' ``Dosage and 
Administration'' or ``Use in Specific Populations'') must not be 
repeated in this subsection, but the location of such recommendations 
must be referenced.
    (ii) Data that demonstrate activity or effectiveness in in vitro or 
animal tests and that have not been shown by adequate and well-
controlled clinical studies to be pertinent to clinical use may be 
included under this section only under the following circumstances:
    (A) In vitro data for anti-infective drugs may be included if the 
data are immediately preceded by the statement ``The following in vitro 
data are available but their clinical significance is unknown.''
    (B) For other classes of drugs, in vitro and animal data that have 
not been shown by adequate and well-controlled studies, as defined in 
Sec.  314.126(b) of this chapter, to be necessary for the safe and 
effective use may be included in this section only if a waiver is 
granted under Sec.  201.58 or Sec.  314.126(c) of this chapter.
    (14) 13 Nonclinical toxicology. This section must contain the 
following subsections as appropriate:
    (i) 13.1 Carcinogenesis, mutagenesis, impairment of fertility. This 
subsection must state whether long term studies in animals have been 
performed to evaluate carcinogenic potential and, if so, the species and 
results. If results from reproduction studies or other data in animals 
raise concern about mutagenesis or impairment of fertility in either 
males or females, this must be described. Any precautionary statement on 
these topics must include practical, relevant advice to the prescriber 
on the significance of these animal findings. Human data suggesting that 
the drug may be carcinogenic or mutagenic, or suggesting that it impairs 
fertility, as described in the ``Warnings and Precautions'' section, 
must not be included in this subsection of the labeling.
    (ii) 13.2 Animal toxicology and/or pharmacology. Significant animal 
data necessary for safe and effective use of the drug in humans that is 
not incorporated in other sections of labeling must be included in this 
section (e.g., specifics about studies used to support approval under 
Sec.  314.600 or Sec.  601.90 of this chapter, the absence of chronic 
animal toxicity data for a drug that is administered over prolonged 
periods or is implanted in the body).
    (15) 14 Clinical studies. This section must discuss those clinical 
studies that facilitate an understanding of how to use the drug safely 
and effectively. Ordinarily, this section will describe the studies that 
support effectiveness for the labeled indication(s), including 
discussion of study design, population, endpoints, and results, but must 
not include an encyclopedic listing of all, or even most, studies 
performed as part of the product's clinical development program. If a 
specific important clinical study is mentioned in any section of the 
labeling required under Sec. Sec.  201.56 and 201.57 because the study 
is essential to an understandable presentation of the information in 
that section of the labeling, any detailed discussion of the study must 
appear in this section.
    (i) For drug products other than biological products, any clinical 
study that is discussed in prescription drug labeling that relates to an 
indication for or use of the drug must be adequate and well-controlled 
as described in Sec.  314.126(b) of this chapter and must not imply or 
suggest indications or uses or dosing regimens not stated in the 
``Indications and Usage'' or ``Dosage and Administration'' section. For 
biological products, any clinical study that is discussed that relates 
to an indication for or use of the biological product must constitute or 
contribute to substantial evidence and must not imply or suggest 
indications or uses or dosing regimens not stated in the ``Indications 
and Usage'' or ``Dosage and Administration'' section.
    (ii) Any discussion of a clinical study that relates to a risk from 
the use of the drug must also refer to the other sections of the 
labeling where the risk is identified or discussed.

[[Page 39]]

    (16) 15 References. When prescription drug labeling must summarize 
or otherwise rely on a recommendation by an authoritative scientific 
body, or on a standardized methodology, scale, or technique, because the 
information is important to prescribing decisions, the labeling may 
include a reference to the source of the information.
    (17) 16 How supplied/storage and handling. This section must contain 
information on the available dosage forms to which the labeling applies 
and for which the manufacturer or distributor is responsible. The 
information must include, as appropriate:
    (i) The strength or potency of the dosage form in metric system 
(e.g., 10 milligram tablets) and, if the apothecary system is used, a 
statement of the strength in parentheses after the metric designation;
    (ii) The units in which the dosage form is ordinarily available for 
prescribing by practitioners (e.g., bottles of 100);
    (iii) Appropriate information to facilitate identification of the 
dosage forms, such as shape, color, coating, scoring, imprinting, and 
National Drug Code number; and
    (iv) Special handling and storage conditions.
    (18) 17 Patient counseling information. This section must contain 
information necessary for patients to use the drug safely and 
effectively (e.g., precautions concerning driving or the concomitant use 
of other substances that may have harmful additive effects). Any FDA-
approved patient labeling must be referenced in this section and the 
full text of such patient labeling must be reprinted immediately 
following this section or, alternatively, accompany the prescription 
drug labeling. Any FDA-approved patient labeling printed immediately 
following this section or accompanying the labeling is subject to the 
type size requirements in paragraph (d)(6) of this section, except for a 
Medication Guide to be detached and distributed to patients in 
compliance with Sec.  208.24 of this chapter. Medication Guides for 
distribution to patients are subject to the type size requirements set 
forth in Sec.  208.20 of this chapter.
    (d) Format requirements. All labeling information required under 
paragraphs (a), (b), and (c) of this section must be printed in 
accordance with the following specifications:
    (1) All headings and subheadings required by paragraphs (a) and (c) 
of this section must be highlighted by bold type that prominently 
distinguishes the headings and subheadings from other labeling 
information. Reverse type is not permitted as a form of highlighting.
    (2) A horizontal line must separate the information required by 
paragraphs (a), (b), and (c) of this section.
    (3) The headings listed in paragraphs (a)(5) through (a)(13) of this 
section must be presented in the center of a horizontal line.
    (4) If there are multiple subheadings listed under paragraphs (a)(4) 
through (a)(13) of this section, each subheading must be preceded by a 
bullet point.
    (5) The labeling information required by paragraphs (a)(1) through 
(a)(4), (a)(11)(ii) through (a)(11)(iv), and (a)(14) of this section 
must be in bold print.
    (6) The letter height or type size for all labeling information, 
headings, and subheadings set forth in paragraphs (a), (b), and (c) of 
this section must be a minimum of 8 points, except for labeling 
information that is on or within the package from which the drug is to 
be dispensed, which must be a minimum of 6 points.
    (7) The identifying numbers required by Sec.  201.56(d) and 
paragraphs (c)(1) through (c)(18) of this section must be presented in 
bold print and must precede the heading or subheading by at least two 
square em's (i.e., two squares of the size of the letter ``m'' in 8 
point type).
    (8) The information required by paragraph (a) of this section, not 
including the information required under paragraph (a)(4) of this 
section, must be limited in length to an amount that, if printed in 2 
columns on a standard sized piece of typing paper (8\1/2\ by 11 inches), 
single spaced, in 8 point type with \1/2\-inch margins on all sides and 
between columns, would fit on one-half of the page.
    (9) Sections or subsections of labeling that are identified as 
containing recent major changes under paragraph (a)(5) of this section 
must be highlighted in the full prescribing information by the

[[Page 40]]

inclusion of a vertical line on the left edge of the new or modified 
text.
    (10) For the information required by paragraph (b) of this section, 
each section heading must be in bold print. Each subheading within a 
section must be indented and not bolded.

[71 FR 3988, Jan. 24, 2006, as amended at 79 FR 72101, Dec. 4, 2014]



Sec.  201.58  Waiver of labeling requirements.

    An applicant may ask the Food and Drug Administration to waive any 
requirement under Sec. Sec.  201.56, 201.57, and 201.80. A waiver 
request must be submitted in writing to the Director (or the Director's 
designee), Center for Drug Evaluation and Research, Food and Drug 
Administration, Central Document Room, 5901-B Ammendale Rd., Beltsville, 
MD 20705-1266, or, if applicable, the Director (or the Director's 
designee), Food and Drug Administration, Center for Biologics Evaluation 
and Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 
71, Rm. G112, Silver Spring, MD 20993-0002. The waiver must be granted 
or denied in writing by the Director or the Director's designee.

[71 FR 3996, Jan. 24, 2006, as amended at 74 FR 13112, Mar. 26, 2009; 80 
FR 18090, Apr. 3, 2015]



       Subpart C_Labeling Requirements for Over-the-Counter Drugs

    Source: 41 FR 6908, Feb. 13, 1976, unless otherwise noted.



Sec.  201.60  Principal display panel.

    The term principal display panel, as it applies to over-the-counter 
drugs in package form and as used in this part, means the part of a 
label that is most likely to be displayed, presented, shown, or examined 
under customary conditions of display for retail sale. The principal 
display panel shall be large enough to accommodate all the mandatory 
label information required to be placed thereon by this part with 
clarity and conspicuousness and without obscuring designs, vignettes, or 
crowding. Where packages bear alternate principal display panels, 
information required to be placed on the principal display panel shall 
be duplicated on each principal display panel. For the purpose of 
obtaining uniform type size in declaring the quantity of contents for 
all packages of substantially the same size, the term area of the 
principal display panel means the area of the side or surface that bears 
the principal display panel, which area shall be:
    (a) In the case of a rectangular package where one entire side 
properly can be considered to be the principal display panel side, the 
product of the height times the width of that side;
    (b) In the case of a cylindrical or nearly cylindrical container, 40 
percent of the product of the height of the container times the 
circumference; and
    (c) In the case of any other shape of container, 40 percent of the 
total surface of the container: Provided, however, That where such 
container presents an obvious ``principal display panel'' such as the 
top of a triangular or circular package, the area shall consist of the 
entire top surface.

In determining the area of the principal display panel, exclude tops, 
bottoms, flanges at the tops and bottoms of cans, and shoulders and 
necks of bottles or jars. In the case of cylindrical or nearly 
cylindrical containers, information required by this part to appear on 
the principal display panel shall appear within that 40 percent of the 
circumference which is most likely to be displayed, presented, shown, or 
examined under customary conditions of display for retail sale.



Sec.  201.61  Statement of identity.

    (a) The principal display panel of an over-the-counter drug in 
package form shall bear as one of its principal features a statement of 
the identity of the commodity.
    (b) Such statement of identity shall be in terms of the established 
name of the drug, if any there be, followed by an accurate statement of 
the general pharmacological category(ies) of the drug or the principal 
intended action(s) of the drug. In the case of an over-the-counter drug 
that is a mixture and that has no established name, this requirement 
shall be deemed to be satisfied by

[[Page 41]]

a prominent and conspicuous statement of the general pharmacological 
action(s) of the mixture or of its principal intended action(s) in terms 
that are meaningful to the layman. Such statements shall be placed in 
direct conjunction with the most prominent display of the proprietary 
name or designation and shall employ terms descriptive of general 
pharmacological category(ies) or principal intended action(s); for 
example, ``antacid,'' ``analgesic,'' ``decongestant,'' 
``antihistaminic,'' etc. The indications for use shall be included in 
the directions for use of the drug, as required by section 502(f)(1) of 
the act and by the regulations in this part.
    (c) The statement of identity shall be presented in bold face type 
on the principal display panel, shall be in a size reasonably related to 
the most prominent printed matter on such panel, and shall be in lines 
generally parallel to the base on which the package rests as it is 
designed to be displayed.



Sec.  201.62  Declaration of net quantity of contents.

    (a) The label of an over-the-counter drug in package form shall bear 
a declaration of the net quantity of contents. This shall be expressed 
in the terms of weight, measure, numerical count, or a combination or 
numerical count and weight, measure, or size. The statement of quantity 
of drugs in tablet, capsule, ampule, or other unit form and the quantity 
of devices shall be expressed in terms of numerical count; the statement 
of quantity for drugs in other dosage forms shall be in terms of weight 
if the drug is solid, semisolid, or viscous, or in terms of fluid 
measure if the drug is liquid. The drug quantity statement shall be 
augmented when necessary to give accurate information as to the strength 
of such drug in the package; for example, to differentiate between 
several strengths of the same drug ``100 tablets, 5 grains each'' or 
``100 capsules, 125 milligrams each'' or ``100 capsules, 250 milligrams 
each'': Provided, That:
    (1) In the case of a firmly established, general consumer usage and 
trade custom of declaring the quantity of a drug in terms of linear 
measure or measure of area, such respective term may be used. Such term 
shall be augmented when necessary for accuracy of information by a 
statement of the weight, measure, or size of the individual units or of 
the entire drug; for example, the net quantity of adhesive tape in 
package form shall be expressed in terms of linear measure augmented by 
a statement of its width.
    (2) Whenever the Commissioner determines for a specific packaged 
drug that an existing practice of declaring net quantity of contents by 
weight, measure, numerical count, or a combination of these does not 
facilitate value comparisons by consumers, he shall by regulation 
designate the appropriate term or terms to be used for such article.
    (b) Statements of weight of the contents shall be expressed in terms 
of avoirdupois pound and ounce. A statement of liquid measure of the 
contents shall be expressed in terms of the U.S. gallon of 231 cubic 
inches and quart, pint, and fluid-ounce subdivisions thereof, and shall 
express the volume at 68 [deg]F (20 [deg]C). See also paragraph (p) of 
this section.
    (c) The declaration may contain common or decimal fractions. A 
common fraction shall be in terms of halves, quarters, eights, 
sixteenths, or thirty-seconds; except that if there exists a firmly 
established, general consumer usage and trade custom of employing 
different common fractions in the net quantity declaration of a 
particular commodity, they may be employed. A common fraction shall be 
reduced to its lowest terms; a decimal fraction shall not be carried out 
to more than two places. A statement that includes small fractions of an 
ounce shall be deemed to permit smaller variations than one which does 
not include such fractions.
    (d) The declaration shall be located on the principal display panel 
of the label, and with respect to packages bearing alternate principal 
panels it shall be duplicated on each principal display panel.
    (e) The declaration shall appear as a distinct item on the principal 
display panel, shall be separated, by at least a space equal to the 
height of the lettering used in the declaration, from

[[Page 42]]

other printed label information appearing above or below the declaration 
and, by at least a space equal to twice the width of the letter ``N'' of 
the style of type used in the quantity of contents statement, from other 
printed label information appearing to the left or right of the 
declaration. It shall not include any term qualifying a unit of weight, 
measure, or count, such as ``giant pint'' and ``full quart'', that tends 
to exaggerate the amount of the drug in the container. It shall be 
placed on the principal display panel within the bottom 30 percent of 
the area of the label panel in lines generally parallel to the base on 
which the package rests as it is designed to be displayed: Provided, 
That:
    (1) On packages having a principal display panel of 5 square inches 
or less the requirement for placement within the bottom 30 percent of 
the area of the label panel shall not apply when the declaration of net 
quantity of contents meets the other requirements of this part; and
    (2) In the case of a drug that is marketed with both outer and inner 
retail containers bearing the mandatory label information required by 
this part and the inner container is not intended to be sold separately, 
the net quantity of contents placement requirement of this section 
applicable to such inner container is waived.
    (3) The principal display panel of a drug marketed on a display card 
to which the immediate container is affixed may be considered to be the 
display panel of the card, and the type size of the net quantity of 
contents statement is governed by the dimensions of the display card.
    (f) The declaration shall accurately reveal the quantity of drug or 
device in the package exclusive of wrappers and other material packed 
therewith: Provided, That in the case of drugs packed in containers 
designed to deliver the drug under pressure, the declaration shall state 
the net quantity of the contents that will be expelled when the 
instructions for use as shown on the container are followed. The 
propellant is included in the net quantity declaration.
    (g) The declaration shall appear in conspicuous and easily legible 
boldface print or type in distinct contrast (by typography, layout, 
color, embossing, or molding) to other matter on the package; except 
that a declaration of net quantity blown, embossed, or molded on a glass 
or plastic surface is permissible when all label information is so 
formed on the surface. Requirements of conspicuousness and legibility 
shall include the specifications that:
    (1) The ratio of height to width of the letter shall not exceed a 
differential of 3 units to 1 unit, i.e., no more than 3 times as high as 
it is wide.
    (2) Letter heights pertain to upper case or capital letters. When 
upper and lower case or all lower case letters are used, it is the lower 
case letter ``o'' or its equivalent that shall meet the minimum 
standards.
    (3) When fractions are used, each component numeral shall meet one-
half the minimum height standards.
    (h) The declaration shall be in letters and numerals in a type size 
established in relationship to the area of the principal display panel 
of the package and shall be uniform for all packages of substantially 
the same size by complying with the following type specifications:
    (1) Not less than one-sixteenth inch in height on packages the 
principal display panel of which has an area of 5 square inches or less.
    (2) Not less than one-eighth inch in height on packages the 
principal display panel of which has an area of more than five but not 
more than 25 square inches.
    (3) Not less than three-sixteenths inch in height on packages the 
principal display panel of which has an area of more than 25 but not 
more than 100 square inches.
    (4) Not less than one-fourth inch in height on packages the 
principal display panel of which has an area of more than 100 square 
inches, except not less than one-half inch in height if the area is more 
than 400 square inches.


Where the declaration is blown, embossed, or molded on a glass or 
plastic surface rather than by printing, typing, or coloring, the 
lettering sizes specified in paragraphs (h) (1) through (4) of this 
section shall be increased by one-sixteenth of an inch.

[[Page 43]]

    (i) On packages containing less than 4 pounds or 1 gallon and 
labeled in terms of weight or fluid measure:
    (1) The declaration shall be expressed both in ounces, with 
identification by weight or by liquid measure and, if applicable (1 
pound or 1 pint or more) followed in parentheses by a declaration in 
pounds for weight units, with any remainder in terms of ounces or common 
or decimal fractions of the pound (see examples set forth in paragraphs 
(k) (1) and (2) of this section), or in the case of liquid measure, in 
the largest whole units (quarts, quarts and pints, or pints, as 
appropriate) with any remainder in terms of fluid ounces or common or 
decimal fractions of the pint or quart (see examples set forth in 
paragraphs (k) (3) and (4) of this section). If the net weight of the 
package is less than 1 ounce avoirdupois or the net fluid measure is 
less than 1 fluid ounce, the declaration shall be in terms of common or 
decimal fractions of the respective ounce and not in terms of drams.
    (2) The declaration may appear in more than one line. The term net 
weight shall be used when stating the net quantity of contents in terms 
of weight. Use of the terms net or net contents in terms of fluid 
measure or numerical count is optional. It is sufficient to distinguish 
avoirdupois ounce from fluid ounce through association of terms; for 
example, ``Net wt. 6 oz'' or ``6 oz net wt.,'' and ``6 fl oz'' or ``net 
contents 6 fl oz''.
    (j) On packages containing 4 pounds or 1 gallon or more and labeled 
in terms of weight or fluid measure, the declaration shall be expressed 
in pounds for weight units with any remainder in terms of ounces or 
common or decimal fractions of the pound; in the case of fluid measure, 
it shall be expressed in the largest whole unit (gallons, followed by 
common or decimal fractions of a gallon or by the next smaller whole 
unit or units (quarts or quarts and pints)) with any remainder in terms 
of fluid ounces or common or decimal fractions of the pint or quart; see 
paragraph (k)(5) of this section.
    (k) Examples:
    (1) A declaration of 1\1/2\ pounds weight shall be expressed as 
``Net wt. 24 oz (1 lb 8 oz),'' or ``Net wt. 24 oz (1\1/2\ lb)'' or ``Net 
wt. 24 oz (1.5 lb)''.
    (2) A declaration of three-fourths pound avoirdupois weight shall be 
expressed as ``Net wt. 12 oz''.
    (3) A declaration of 1 quart liquid measure shall be expressed as 
``Net contents 32 fl oz (1 qt)'' or ``32 fl oz (1 qt)''.
    (4) A declaration of 1\3/4\ quarts liquid measure shall be expressed 
as ``Net contents 56 fl oz (1 qt 1 pt 8 oz)'' or ``Net contents 56 fl oz 
(1 qt 1.5 pt),'' but not in terms of quart and ounce such as ``Net 56 fl 
oz (1 qt 24 oz).''
    (5) A declaration of 2\1/2\ gallons liquid measure shall be 
expressed as ``Net contents 2 gal 2 qt,'' ``Net contents 2.5 gallons,'' 
or ``Net contents 2\1/2\ gal'' but not as ``2 gal 4 pt''.
    (l) For quantities, the following abbreviations and none other may 
be employed. Periods and plural forms are optional:

Gallon gal
quart qt
pint pt
ounce oz
pound lb
grain gr
kilogram kg
gram g
milligram mg
microgram mcg
liter l
milliliter ml
cubic centimeter cc
yard yd
feet or foot ft
inch in
meter m
centimeter cm
millimeter mm
fluid fl
square sq
weight wt

    (m) On packages labeled in terms of linear measure, the declaration 
shall be expressed both in terms of inches and, if applicable (1 foot or 
more), the largest whole units (yards, yards and feet, feet). The 
declaration in terms of the largest whole units shall be in parentheses 
following the declaration in terms of inches and any remainder shall be 
in terms of inches or common or decimal fractions of the foot or yard; 
if applicable, as in the case of adhesive tape, the initial declaration 
in linear inches shall be preceded by a statement of the width. Examples 
of linear measure are ``86 inches (2 yd 1 ft 2 in),'' ``90 inches (2\1/
2\ yd),'' ``30 inches (2.5 ft),'' `` \3/4\ inch by 36 in (1 yd),'' etc.
    (n) On packages labeled in terms of area measure, the declaration 
shall be expressed both in terms of square inches and, if applicable (1 
square foot or more), the largest whole square unit (square yards, 
square yards and square

[[Page 44]]

feet, square feet). The declaration in terms of the largest whole units 
shall be in parentheses following the declaration in terms of square 
inches and any remainder shall be in terms of square inches or common or 
decimal fractions of the square foot or square yard; for example, ``158 
sq inches (1 sq ft 14 sq in).''
    (o) Nothing in this section shall prohibit supplemental statements 
at locations other than the principal display panel(s) describing in 
nondeceptive terms the net quantity of contents, provided that such 
supplemental statements of net quantity of contents shall not include 
any term qualifying a unit of weight, measure, or count that tends to 
exaggerate the amount of the drug contained in the package; for example, 
``giant pint'' and ``full quart.'' Dual or combination declarations of 
net quantity of contents as provided for in paragraphs (a) and (i) of 
this section are not regarded as supplemental net quantity statements 
and shall be located on the principal display panel.
    (p) A separate statement of net quantity of contents in terms of the 
metric system of weight or measure is not regarded as a supplemental 
statement and an accurate statement of the net quantity of contents in 
terms of the metric system of weight or measure may also appear on the 
principal display panel or on other panels.
    (q) The declaration of net quantity of contents shall express an 
accurate statement of the quantity of contents of the package. 
Reasonable variations caused by loss or gain of moisture during the 
course of good distribution practice or by unavoidable deviations in 
good manufacturing practice will be recognized. Variations from stated 
quantity of contents shall not be unreasonably large.
    (r) A drug shall be exempt from compliance with the net quantity 
declaration required by this section if it is an ointment labeled 
``sample,'' ``physician's sample,'' or a substantially similar statement 
and the contents of the package do not exceed 8 grams.



Sec.  201.63  Pregnancy/breast-feeding warning.

    (a) The labeling for all over-the-counter (OTC) drug products that 
are intended for systemic absorption, unless specifically exempted, 
shall contain a general warning under the heading ``Warning'' (or 
``Warnings'' if it appears with additional warning statements) as 
follows: ``If pregnant or breast-feeding, ask a health professional 
before use.'' [first four words of this statement in bold type] In 
addition to the written warning, a symbol that conveys the intent of the 
warning may be used in labeling.
    (b) Where a specific warning relating to use during pregnancy or 
while nursing has been established for a particular drug product in a 
new drug application (NDA) or for a product covered by an OTC drug final 
monograph in part 330 of this chapter, the specific warning shall be 
used in place of the warning in paragraph (a) of this section, unless 
otherwise stated in the NDA or in the final OTC drug monograph.
    (c) The following OTC drugs are exempt from the provisions of 
paragraph (a) of this section:
    (1) Drugs that are intended to benefit the fetus or nursing infant 
during the period of pregnancy or nursing.
    (2) Drugs that are labeled exclusively for pediatric use.
    (d) The Food and Drug Administration will grant an exemption from 
paragraph (a) of this section where appropriate upon petition under the 
provisions of Sec.  10.30 of this chapter. Decisions with respect to 
requests for exemptions shall be maintained in a permanent file for 
public review by the Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    (e) The labeling of orally or rectally administered OTC aspirin and 
aspirin-containing drug products must bear a warning that immediately 
follows the general warning identified in paragraph (a) of this section. 
The warning shall be as follows:

    ``It is especially important not to use'' (select ``aspirin'' or 
``carbaspirin calcium,'' as appropriate) ``during the last 3 months of 
pregnancy unless definitely directed to do so by a doctor because it may 
cause problems in

[[Page 45]]

the unborn child or complications during delivery.''

[47 FR 54757, Dec. 3, 1982, as amended at 55 FR 27784, July 5, 1990; 59 
FR 14364, Mar. 28, 1994; 64 FR 13286, Mar. 17, 1999; 68 FR 24879, May 9, 
2003; 88 FR 45065, July 14, 2023]



Sec.  201.64  Sodium labeling.

    (a) The labeling of over-the-counter (OTC) drug products intended 
for oral ingestion shall contain the sodium content per dosage unit 
(e.g., tablet, teaspoonful) if the sodium content of a single maximum 
recommended dose of the product (which may be one or more dosage units) 
is 5 milligrams or more. OTC drug products intended for oral ingestion 
include gum and lozenge dosage forms, but do not include dentifrices, 
mouthwashes, or mouth rinses.
    (b) The sodium content shall be expressed in milligrams per dosage 
unit and shall include the total amount of sodium regardless of the 
source, i.e., from both active and inactive ingredients. The sodium 
content shall be rounded-off to the nearest whole number. The sodium 
content per dosage unit shall follow the heading ``Other information'' 
as stated in Sec.  201.66(c)(7).
    (c) The labeling of OTC drug products intended for oral ingestion 
shall contain the following statement under the heading ``Warning'' (or 
``Warnings'' if it appears with additional warning statements) if the 
amount of sodium present in the labeled maximum daily dose of the 
product is more than 140 milligrams: ``Ask a doctor before use if you 
have [in bold type] [bullet] \1\ a sodium-restricted diet''. The 
warnings in Sec. Sec.  201.64(c), 201.70(c), 201.71(c), and 201.72(c) 
may be combined, if applicable, provided the ingredients are listed in 
alphabetical order, e g., a calcium or sodium restricted diet.
---------------------------------------------------------------------------

    \1\ See Sec.  201 .66(b)(4) of this chapter for definition of bullet 
symbol.
---------------------------------------------------------------------------

    (d) The term sodium free may be used in the labeling of OTC drug 
products intended for oral ingestion if the amount of sodium in the 
labeled maximum daily dose is 5 milligrams or less and the amount of 
sodium per dosage unit is 0 milligram (when rounded-off in accord with 
paragraph (b) of this section).
    (e) The term very low sodium may be used in the labeling of OTC drug 
products intended for oral ingestion if the amount of sodium in the 
labeled maximum daily dose is 35 milligrams or less.
    (f) The term low sodium may be used in the labeling of OTC drug 
products intended for oral ingestion if the amount of sodium in the 
labeled maximum daily dose is 140 milligrams or less.
    (g) The term salt is not synonymous with the term sodium and shall 
not be used interchangeably or substituted for the term sodium.
    (h) The terms sodium free, very low sodium, and low sodium shall be 
in print size and style no larger than the product's statement of 
identity and shall not be unduly prominent in print size or style 
compared to the statement of identity.
    (i) Any product subject to this paragraph that contains sodium 
bicarbonate, sodium phosphate, or sodium biphosphate as an active 
ingredient for oral ingestion and that is not labeled as required by 
this paragraph and that is initially introduced or initially delivered 
for introduction into interstate commerce after April 22, 1997, is 
misbranded under sections 201(n) and 502 (a) and (f) of the Federal 
Food, Drug, and Cosmetic Act (the act).
    (j) Any product subject to paragraphs (a) through (h) of this 
section that is not labeled as required and that is initially introduced 
or initially delivered for introduction into interstate commerce after 
the following dates is misbranded under sections 201(n) and 502(a) and 
(f) of the Federal Food, Drug, and Cosmetic Act.
    (1) As of the date of approval of the application for any single 
entity and combination products subject to drug marketing applications 
approved on or after April 23, 2004.
    (2) Septemeber 24, 2005, for all OTC drug products subject to any 
OTC drug monograph, not yet the subject of any OTC drug monograph, or 
subject to drug marketing applications approved before April 23, 2004.
    (k) The labeling of OTC drug products intended for rectal 
administration containing dibasic sodium phosphate and/or monobasic 
sodium phosphate

[[Page 46]]

shall contain the sodium content per delivered dose if the sodium 
content is 5 milligrams or more. The sodium content shall be expressed 
in milligrams or grams. If less than 1 gram, milligrams should be used. 
The sodium content shall be rounded-off to the nearest whole number if 
expressed in milligrams (or nearest tenth of a gram if expressed in 
grams). The sodium content per delivered dose shall follow the heading 
``Other information'' as stated in Sec.  201.66(c)(7). Any product 
subject to this paragraph that contains dibasic sodium phosphate and/or 
monobasic sodium phosphate as an active ingredient intended for rectal 
administration and that is not labeled as required by this paragraph and 
that is initially introduced or initially delivered for introduction 
into interstate commerce after November 29, 2005, is misbranded under 
sections 201(n) and 502(a) and (f) of the act.

[61 FR 17806, Apr. 22, 1996, as amended at 62 FR 19925, Apr. 24, 1997; 
64 FR 13286, Mar. 17, 1999; 69 FR 13724, Mar. 24, 2004; 69 FR 69280, 
Nov. 29, 2004]



Sec.  201.66  Format and content requirements for over-the-counter(OTC)
drug product labeling.

    (a) Scope. This section sets forth the content and format 
requirements for the labeling of all OTC drug products. Where an OTC 
drug product is the subject of an applicable monograph or regulation 
that contains content and format requirements that conflict with this 
section, the content and format requirements in this section must be 
followed unless otherwise specifically provided in the applicable 
monograph or regulation.
    (b) Definitions. The following definitions apply to this section:
    (1) Act means the Federal Food, Drug, and Cosmetic Act (secs. 201 et 
seq. (21 U.S.C. 321 et seq.)).
    (2) Active ingredient means any component that is intended to 
furnish pharmacological activity or other direct effect in the 
diagnosis, cure, mitigation, treatment, or prevention of disease, or to 
affect the structure or any function of the body of humans. The term 
includes those components that may undergo chemical change in the 
manufacture of the drug product and be present in the drug product in a 
modified form intended to furnish the specified activity or effect.
    (3) Approved drug application means a new drug (NDA) or abbreviated 
new drug (ANDA) application approved under section 505 of the act (21 
U.S.C. 355).
    (4) Bullet means a geometric symbol that precedes each statement in 
a list of statements. For purposes of this section, the bullet style is 
limited to solid squares or solid circles, in the format set forth in 
paragraph (d)(4) of this section.
    (5) Established name of a drug or ingredient thereof means the 
applicable official name designated under section 508 of the act (21 
U.S.C. 358), or, if there is no designated official name and the drug or 
ingredient is recognized in an official compendium, the official title 
of the drug or ingredient in such compendium, or, if there is no 
designated official name and the drug or ingredient is not recognized in 
an official compendium, the common or usual name of the drug or 
ingredient.
    (6) FDA means the Food and Drug Administration.
    (7) Heading means the required statements in quotation marks listed 
in paragraphs (c)(2) through (c)(9) of this section, excluding 
subheadings (as defined in paragraph (a)(9) of this section).
    (8) Inactive ingredient means any component other than an active 
ingredient.
    (9) Subheading means the required statements in quotation marks 
listed in paragraphs (c)(5)(ii) through (c)(5)(vii) of this section.
    (10) Drug facts labeling means the title, headings, subheadings, and 
information required under or otherwise described in paragraph (c) of 
this section.
    (11) Title means the heading listed at the top of the required OTC 
drug product labeling, as set forth in paragraph (c)(1) of this section.
    (12) Total surface area available to bear labeling means all 
surfaces of the outside container of the retail package or, if there is 
no such outside container, all surfaces of the immediate container or 
container wrapper except for the flanges at the tops and bottoms of cans 
and the shoulders and necks of bottles and jars.

[[Page 47]]

    (c) Content requirements. The outside container or wrapper of the 
retail package, or the immediate container label if there is no outside 
container or wrapper, shall contain the title, headings, subheadings, 
and information set forth in paragraphs (c)(1) through (c)(8) of this 
section, and may contain the information under the heading in paragraph 
(c)(9) of this section, in the order listed.
    (1) (Title) ``Drug Facts''. If the drug facts labeling appears on 
more than one panel, the title ``Drug Facts (continued)'' shall appear 
at the top of each subsequent panel containing such information.
    (2) ``Active ingredient'' or ``Active ingredients'' ``(in each 
[insert the dosage unit stated in the directions for use (e.g., tablet, 
5 mL teaspoonful) or in each gram as stated in Sec. Sec.  333.110 and 
333.120 of this chapter])'', followed by the established name of each 
active ingredient and the quantity of each active ingredient per dosage 
unit. Unless otherwise provided in an applicable OTC drug monograph or 
approved drug application, products marketed without discrete dosage 
units (e.g., topicals) shall state the proportion (rather than the 
quantity) of each active ingredient.
    (3) ``Purpose'' or ``Purposes'', followed by the general 
pharmacological category(ies) or the principal intended action(s) of the 
drug or, where the drug consists of more than one ingredient, the 
general pharmacological categories or the principal intended actions of 
each active ingredient. When an OTC drug monograph contains a statement 
of identity, the pharmacological action described in the statement of 
identity shall also be stated as the purpose of the active ingredient.
    (4) ``Use'' or ``Uses'', followed by the indication(s) for the 
specific drug product.
    (5) ``Warning'' or ``Warnings'', followed by one or more of the 
following, if applicable:
    (i) ``For external use only'' [in bold type] for topical drug 
products not intended for ingestion, or ``For'' (select one of the 
following, as appropriate: ``rectal'' or ``vaginal'') ``use only'' [in 
bold type].
    (ii) All applicable warnings listed in paragraphs (c)(5)(ii)(A) 
through (c)(5)(ii)(G) of this section with the appropriate subheadings 
highlighted in bold type:
    (A) Reye's syndrome warning for drug products containing salicylates 
set forth in Sec.  201.314(h)(1). This warning shall follow the 
subheading ``Reye's syndrome:''
    (B) Allergic reaction and asthma alert warnings. Allergic reaction 
warnings set forth in any applicable OTC drug monograph or approved drug 
application for any product that requires a separate allergy warning. 
This warning shall follow the subheading ``Allergy alert:'' The asthma 
alert warning set forth in Sec. Sec.  341.76(c)(5) and 341.76(c)(6) of 
this chapter. This warning shall follow the subheading ``Asthma alert:''
    (C) Flammability warning, with appropriate flammability signal 
word(s) (e.g., Sec. Sec.  341.74(c)(5)(iii), 344.52(c), 358.150(c), and 
358.550(c) of this chapter). This warning shall follow a subheading 
containing the appropriate flammability signal word(s) described in an 
applicable OTC drug monograph or approved drug application.
    (D) Water soluble gums warning set forth in Sec.  201.319. This 
warning shall follow the subheading ``Choking:''
    (E) Liver warning set forth in Sec.  201.326(a)(1)(iii) and/or 
stomach bleeding warning set forth in Sec.  201.326(a)(2)(iii). The 
liver warning shall follow the subheading ``Liver warning:'' and the 
stomach bleeding warning shall follow the subheading ``Stomach bleeding 
warning:''
    (F) Sore throat warning set forth in Sec.  201.315. This warning 
shall follow the subheading ``Sore throat warning:''
    (G) Warning for drug products containing sodium phosphates set forth 
in Sec.  201.307(b)(2)(i) or (b)(2)(ii). This warning shall follow the 
subheading ``Dosage warning:''
    (H) Sexually transmitted diseases (STDs) warning for vaginal 
contraceptive and spermicide drug products containing nonoxynol 9 set 
forth in Sec.  201.325(b)(2). This warning shall follow the subheading 
``Sexually transmitted diseases (STDs) alert:''
    (iii) ``Do not use'' [in bold type], followed by all 
contraindications for use

[[Page 48]]

with the product. These contraindications are absolute and are intended 
for situations in which consumers should not use the product unless a 
prior diagnosis has been established by a doctor or for situations in 
which certain consumers should not use the product under any 
circumstances regardless of whether a doctor or health professional is 
consulted.
    (iv) ``Ask a doctor before use if you have'' [in bold type] or, for 
products labeled only for use in children under 12 years of age, ``Ask a 
doctor before use if the child has'' [in bold type], followed by all 
warnings for persons with certain preexisting conditions (excluding 
pregnancy) and all warnings for persons experiencing certain symptoms. 
The warnings under this heading are those intended only for situations 
in which consumers should not use the product until a doctor is 
consulted.
    (v) ``Ask a doctor or pharmacist before use if you are'' [in bold 
type] or, for products labeled only for use in children under 12 years 
of age, ``Ask a doctor or pharmacist before use if the child is'' [in 
bold type], followed by all drug-drug and drug-food interaction 
warnings.
    (vi) ``When using this product'' [in bold type], followed by the 
side effects that the consumer may experience, and the substances (e.g., 
alcohol) or activities (e.g., operating machinery, driving a car, 
warnings set forth in Sec.  369.21 of this chapter for drugs in 
dispensers pressurized by gaseous propellants) to avoid while using the 
product.
    (vii) ``Stop use and ask a doctor if'' [in bold type], followed by 
any signs of toxicity or other reactions that would necessitate 
immediately discontinuing use of the product. For all OTC drug products 
under an approved drug application whose packaging does not include a 
toll-free number through which consumers can report complaints to the 
manufacturer or distributor of the drug product, the following text 
shall immediately follow the subheading: ``[Bullet] side effects occur. 
You may report side effects to FDA at 1-800-FDA-1088.'' The telephone 
number must appear in a minimum 6-point bold letter height or type size.
    (viii) Any required warnings in an applicable OTC drug monograph, 
other OTC drug regulations, or approved drug application that do not fit 
within one of the categories listed in paragraphs (c)(5)(i) through 
(c)(5)(vii), (c)(5)(ix), and (c)(5)(x) of this section.
    (ix) The pregnancy/breast-feeding warning set forth in Sec.  
201.63(a); the third trimester warning set forth in Sec.  201.63(e) for 
products containing aspirin or carbaspirin calcium; the third trimester 
warning set forth in approved drug applications for products containing 
ketoprofen, naproxen sodium, and ibuprofen (not intended exclusively for 
use in children).
    (x) The ``Keep out of reach of children'' warning and the accidental 
overdose/ingestion warning set forth in Sec.  330.1(g) of this chapter.
    (6) ``Directions'', followed by the directions for use described in 
an applicable OTC drug monograph or approved drug application.
    (7) ``Other information'', followed by additional information that 
is not included under paragraphs (c)(2) through (c)(6), (c)(8), and 
(c)(9) of this section, but which is required by or is made optional 
under an applicable OTC drug monograph, other OTC drug regulation, or is 
included in the labeling of an approved drug application.
    (i) Required information about certain ingredients in OTC drug 
products (e.g., sodium in Sec.  201.64(b), calcium in Sec.  201.70(b), 
magnesium in Sec.  201.71(b), and potassium in Sec.  201.72(b)) shall 
appear as follows: ``each (insert appropriate dosage unit) contains:'' 
[in bold type (insert name(s) of ingredient(s) (in alphabetical order) 
and the quantity of each ingredient). This information shall be the 
first statement under this heading.
    (ii) The phenylalanine/aspartame content required by Sec.  
201.21(b), if applicable, shall appear as the next item of information.
    (iii) Additional information that is authorized to appear under this 
heading shall appear as the next item(s) of information. There is no 
required order for this subsequent information.
    (8) ``Inactive ingredients'', followed by a listing of the 
established name of each inactive ingredient. If the product is an OTC 
drug product that is not also a cosmetic product, then the inactive 
ingredients shall be listed in alphabetical order. If the product is an 
OTC

[[Page 49]]

drug product that is also a cosmetic product, then the inactive 
ingredients shall be listed as set forth in Sec.  701.3(a) or (f) of 
this chapter, the names of cosmetic ingredients shall be determined in 
accordance with Sec.  701.3(c) of this chapter, and the provisions in 
Sec.  701.3(e), (g), (h), (l), (m), (n), and (o) of this chapter and 
Sec.  720.8 of this chapter may also apply, as appropriate. If there is 
a difference in the labeling provisions in this Sec.  201.66 and 
Sec. Sec.  701.3 and 720.8 of this chapter, the labeling provisions in 
this Sec.  201.66 shall be used.
    (9) ``Questions?'' or ``Questions or comments?'', followed by the 
telephone number of a source to answer questions about the product. It 
is recommended that the days of the week and times of the day when a 
person is available to respond to questions also be included. A graphic 
of a telephone or telephone receiver may appear before the heading. The 
telephone number must appear in a minimum 6-point bold type.
    (d) Format requirements. The title, headings, subheadings, and 
information set forth in paragraphs (c)(1) through (c)(9) of this 
section shall be presented on OTC drug products in accordance with the 
following specifications. In the interest of uniformity of presentation, 
FDA strongly reccommends that the Drug Facts labeling be presented using 
the graphic specifications set forth in appendix A to part 201.
    (1) The title ``Drug Facts'' or ``Drug Facts (continued)'' shall use 
uppercase letters for the first letter of the words ``Drug'' and 
``Facts.'' All headings and subheadings in paragraphs (c)(2) through 
(c)(9) of this section shall use an uppercase letter for the first 
letter in the first word and lowercase letters for all other words. The 
title, headings, and subheadings in paragraphs (c)(1), (c)(2), and 
(c)(4) through (c)(9) of this section shall be left justified.
    (2) The letter height or type size for the title ``Drug Facts'' 
shall appear in a type size larger than the largest type size used in 
the Drug Facts labeling. The letter height or type size for the title 
``Drug Facts (continued)'' shall be no smaller than 8-point type. The 
letter height or type size for the headings in paragraphs (c)(2) through 
(c)(9) of this section shall be the larger of either 8-point or greater 
type, or 2-point sizes greater than the point size of the text. The 
letter height or type size for the subheadings and all other information 
described in paragraphs (c)(2) through (c)(9) of this section shall be 
no smaller than 6-point type.
    (3) The title, heading, subheadings, and information in paragraphs 
(c)(1) through (c)(9) of this section shall be legible and clearly 
presented, shall have at least 0.5-point leading (i.e., space between 
two lines of text), and shall not have letters that touch. The type 
style for the title, headings, subheadings, and all other required 
information described in paragraphs (c)(2) through (c)(9) of this 
section shall be any single, clear, easy-to-read type style, with no 
more than 39 characters per inch. The title and headings shall be in 
bold italic, and the subheadings shall be in bold type, except that the 
word ``(continued)'' in the title ``Drug Facts (continued)'' shall be 
regular type. The type shall be all black or one color printed on a 
white or other contrasting background, except that the title and the 
headings may be presented in a single, alternative, contrasting color 
unless otherwise provided in an approved drug application, OTC drug 
monograph (e.g., current requirements for bold print in Sec. Sec.  
341.76 and 341.80 of this chapter), or other OTC drug regulation (e.g., 
the requirement for a box and red letters in Sec.  201.308(c)(1)).
    (4) When there is more than one statement, each individual statement 
listed under the headings and subheadings in paragraphs (c)(4) through 
(c)(7) of this section shall be preceded by a solid square or solid 
circle bullet of 5-point type size. Bullets shall be presented in the 
same shape and color throughout the labeling. The first bulleted 
statement on each horizontal line of text shall be either left justified 
or separated from an appropriate heading or subheading by at least two 
square ``ems'' (i.e., two squares of the size of the letter ``M''). If 
more than one bulleted statement is placed on the same horizontal line, 
the end of one bulleted statement shall be separated from the beginning 
of the next bulleted statement by at least two square ``ems'' and the 
complete additional

[[Page 50]]

bulleted statement(s) shall not continue to the next line of text. 
Additional bulleted statements appearing on each subsequent horizontal 
line of text under a heading or subheading shall be vertically aligned 
with the bulleted statements appearing on the previous line.
    (5) The title, headings, subheadings, and information set forth in 
paragraphs (c)(1) through (c)(9) of this section may appear on more than 
one panel on the outside container of the retail package, or the 
immediate container label if there is no outside container or wrapper. 
The continuation of the required content and format onto multiple panels 
must retain the required order and flow of headings, subheadings, and 
information. A visual graphic (e.g., an arrow) shall be used to signal 
the continuation of the Drug Facts labeling to the next adjacent panel.
    (6) The heading and information required under paragraph (c)(2) of 
this section shall appear immediately adjacent and to the left of the 
heading and information required under paragraph (c)(3) of this section. 
The active ingredients and purposes shall be aligned under the 
appropriate headings such that the heading and information required 
under paragraph (c)(2) of this section shall be left justified and the 
heading and information required under paragraph (c)(3) of this section 
shall be right justified. If the OTC drug product contains more than one 
active ingredient, the active ingredients shall be listed in 
alphabetical order. If more than one active ingredient has the same 
purpose, the purpose need not be repeated for each active ingredient, 
provided the information is presented in a manner that readily 
associates each active ingredient with its purpose (i.e., through the 
use of brackets, dot leaders, or other graphical features). The 
information described in paragraphs (c)(4) and (c)(6) through (c)(9) of 
this section may start on the same line as the required headings. None 
of the information described in paragraph (c)(5) of this section shall 
appear on the same line as the ``Warning'' or ``Warnings'' heading.
    (7) Graphical images (e.g., the UPC symbol) and information not 
described in paragraphs (c)(1) through (c)(9) of this section shall not 
appear in or in any way interrupt the required title, headings, 
subheadings, and information in paragraphs (c)(1) through (c)(9) of this 
section. Hyphens shall not be used except to punctuate compound words.
    (8) The information described in paragraphs (c)(1) through (c)(9) of 
this section shall be set off in a box or similar enclosure by the use 
of a barline. A distinctive horizontal barline extending to each end of 
the ``Drug Facts'' box or similar enclosure shall provide separation 
between each of the headings listed in paragraphs (c)(2) through (c)(9) 
of this section. When a heading listed in paragraphs (c)(2) through 
(c)(9) of this section appears on a subsequent panel immediately after 
the ``Drug Facts (continued)'' title, a horizontal hairline shall follow 
the title and immediately precede the heading. A horizontal hairline 
extending within two spaces on either side of the ``Drug Facts'' box or 
similar enclosure shall immediately follow the title and shall 
immediately precede each of the subheadings set forth in paragraph 
(c)(5) of this section, except the subheadings in paragraphs 
(c)(5)(ii)(A) through (c)(5)(ii)(G) of this section.
    (9) The information set forth in paragraph (c)(6) of this section 
under the heading ``Directions'' shall appear in a table format when 
dosage directions are provided for three or more age groups or 
populations. The last line of the table may be the horizontal barline 
immediately preceding the heading of the next section of the labeling.
    (10) If the title, headings, subheadings, and information in 
paragraphs (c)(1) through (c)(9) of this section, printed in accordance 
with the specifications in paragraphs (d)(1) through (d)(9) of this 
section, and any other FDA required information for drug products, and, 
as appropriate, cosmetic products, other than information required to 
appear on a principle display panel, requires more than 60 percent of 
the total surface area available to bear labeling, then the Drug Facts 
labeling shall be printed in accordance with the specifications set 
forth in paragraphs (d)(10)(i) through (d)(10)(v) of this section. In 
determining whether

[[Page 51]]

more than 60 percent of the total surface area available to bear 
labeling is required, the indications for use listed under the 
``Use(s)'' heading, as set forth in paragraph (c)(4) of this section, 
shall be limited to the minimum required uses reflected in the 
applicable monograph, as provided in Sec.  330.1(c)(2) of this chapter.
    (i) Paragraphs (d)(1), (d)(5), (d)(6), and (d)(7) of this section 
shall apply.
    (ii) Paragraph (d)(2) of this section shall apply except that the 
letter height or type size for the title ``Drug Facts (continued)'' 
shall be no smaller than 7-point type and the headings in paragraphs 
(c)(2) through (c)(9) of this section shall be the larger of either 7-
point or greater type, or 1-point size greater than the point size of 
the text.
    (iii) Paragraph (d)(3) of this section shall apply except that less 
than 0.5-point leading may be used, provided the ascenders and 
descenders do not touch.
    (iv) Paragraph (d)(4) of this section shall apply except that if 
more than one bulleted statement is placed on the same horizontal line, 
the additional bulleted statements may continue to the next line of 
text, and except that the bullets under each heading or subheading need 
not be vertically aligned.
    (v) Paragraph (d)(8) of this section shall apply except that the box 
or similar enclosure required in paragraph (d)(8) of this section may be 
omitted if the Drug Facts labeling is set off from the rest of the 
labeling by use of color contrast.
    (11)(i) The following labeling outlines the various provisions in 
paragraphs (c) and (d) of this section:
[GRAPHIC] [TIFF OMITTED] TR17MR99.003

    (ii) The following sample label illustrates the provisions in 
paragraphs (c) and (d) of this section:

[[Page 52]]

[GRAPHIC] [TIFF OMITTED] TR17MR99.004

    (iii) The following sample label illustrates the provisions in 
paragraphs (c) and (d) of this section, including paragraph (d)(10) of 
this section, which permits modifications for small packages:

[[Page 53]]

[GRAPHIC] [TIFF OMITTED] TR17MR99.005

    (iv) The following sample label illustrates the provisions in 
paragraphs (c) and (d) of this section for a drug product marketed with 
cosmetic claims:

[[Page 54]]

[GRAPHIC] [TIFF OMITTED] TR17MR99.006

    (e) Exemptions and deferrals. FDA on its own initiative or in 
response to a written request from any manufacturer, packer, or 
distributor, may exempt or defer, based on the circumstances presented, 
one or more specific requirements set forth in this section on the basis 
that the requirement is inapplicable, impracticable, or contrary to 
public health or safety. Requests for exemptions shall be submitted in 
three copies in the form of an ``Application for Exemption'' to the Food 
and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 
20852. The request shall be clearly identified on the envelope as a 
``Request for Exemption from 21 CFR 201.66 (OTC Labeling Format)'' and 
shall be directed to Docket No. 98N-0337. A separate request shall be 
submitted for each OTC drug product. Sponsors of a product marketed 
under an approved drug application shall also submit a single copy of 
the exemption request to their application. Decisions on exemptions and 
deferrals will be maintained in a permanent file in this docket for 
public review. Exemption and deferral requests shall:
    (1) Document why a particular requirement is inapplicable, 
impracticable, or is contrary to public health or safety; and
    (2) Include a representation of the proposed labeling, including any 
outserts, panel extensions, or other graphical or packaging techniques 
intended to be used with the product.
    (f) Interchangeable terms and connecting terms. The terms listed in 
Sec.  330.1(i) of this chapter may be used

[[Page 55]]

interchangeably in the labeling of OTC drug products, provided such use 
does not alter the meaning of the labeling that has been established and 
identified in an applicable OTC drug monograph or by regulation. The 
terms listed in Sec.  330.1(j) of this chapter may be deleted from the 
labeling of OTC drug products when the labeling is revised to comply 
with this section, provided such deletion does not alter the meaning of 
the labeling that has been established and identified in an applicable 
OTC drug monograph or by regulation. The terms listed in Sec.  330.1(i) 
and (j) of this chapter shall not be used to change in any way the 
specific title, headings, and subheadings required under paragraphs 
(c)(1) through (c)(9) of this section.
    (g) Regulatory action. An OTC drug product that is not in compliance 
with the format and content requirements in this section is subject to 
regulatory action.

[64 FR 13286, Mar. 17, 1999, as amended at 65 FR 8, Jan. 3, 2000; 65 FR 
48904, Aug. 10, 2000; 69 FR 13733, Mar. 24, 2004; 72 FR 71785, Dec. 19, 
2007; 73 FR 403, Jan. 3, 2008; 74 FR 19407, Apr. 29, 2009; 76 FR 44487, 
July 26, 2011]



Sec.  201.70  Calcium labeling.

    (a) The labeling of over-the-counter (OTC) drug products intended 
for oral ingestion shall contain the calcium content per dosage unit 
(e.g., tablet, teaspoonful) if the calcium content of a single maximum 
recommended dose of the product (which may be one or more dosage units) 
is 20 milligrams or more. OTC drug products intended for oral ingestion 
include gum and lozenge dosage forms, but do not include dentifrices, 
mouthwashes, or mouth rinses.
    (b) The calcium content shall be expressed in milligrams or grams 
per dosage unit and shall include the total amount of calcium regardless 
of the source, i.e., from both active and inactive ingredients. If the 
dosage unit contains less than 1 gram of calcium, milligrams should be 
used. The calcium content per dosage unit shall be rounded-off to the 
nearest 5 milligrams (or nearest tenth of a gram if over 1 gram). The 
calcium content per dosage unit shall follow the heading ``Other 
information'' as stated in Sec.  201.66(c)(7).
    (c) The labeling of OTC drug products intended for oral ingestion 
shall contain the following statement under the heading ``Warning'' (or 
``Warnings'' if it appears with additional warning statements) if the 
amount of calcium present in the labeled maximum daily dose of the 
product is more than 3.2 grams: ``Ask a doctor before use if you have 
[in bold type] [bullet] \1\ kidney stones [bullet] a calcium-restricted 
diet''. The warnings in Sec. Sec.  201.64(c), 201.70(c), 201.71(c), and 
201.72(c) may be combined, if applicable, provided the ingredients are 
listed in alphabetical order, e.g., a calcium or sodium restricted diet.
---------------------------------------------------------------------------

    \1\ See Sec.  201.66(b)(4) of this chapter for definition of bullet 
symbol.
---------------------------------------------------------------------------

    (d) Any product subject to this paragraph that is not labeled as 
required by this paragraph and that is initially introduced or initially 
delivered for introduction into interstate commerce after the following 
dates is misbranded under sections 201(n) and 502(a) and (f) of the 
Federal Food, Drug, and Cosmetic Act.
    (1) As of the date of approval of the application for any single 
entity and combination products subject to drug marketing applications 
approved on or after April 23, 2004.
    (2) September 24, 2005, for all OTC drug products subject to any OTC 
drug monograph, not yet the subject of any OTC drug monograph, or 
subject to drug marketing applications approved before April 23, 2004.

[69 FR 13733, Mar. 24, 2004]



Sec.  201.71  Magnesium labeling.

    (a) The labeling of over-the-counter (OTC) drug products intended 
for oral ingestion shall contain the magnesium content per dosage unit 
(e.g., tablet, teaspoonful) if the magnesium content of a single maximum 
recommended dose of the product (which may be one or more dosage units) 
is 8 milligrams or more. OTC drug products intended for oral ingestion 
include gum and lozenge dosage forms, but do not include dentifrices, 
mouthwashes, or mouth rinses.
    (b) The magnesium content shall be expressed in milligrams or grams 
per dosage unit and shall include the total

[[Page 56]]

amount of magnesium regardless of the source, i.e., from both active and 
inactive ingredients. If the dosage unit contains less than 1 gram of 
magnesium, milligrams should be used. The magnesium content shall be 
rounded-off to the nearest 5 milligrams (or nearest tenth of a gram if 
over 1 gram). The magnesium content per dosage unit shall follow the 
heading ``Other information'' as stated in Sec.  201.66(c)(7).
    (c) The labeling of OTC drug products intended for oral ingestion 
shall contain the following statement under the heading ``Warning'' (or 
``Warnings'' if it appears with additional warning statements) if the 
amount of magnesium present in the labeled maximum daily dose of the 
product is more than 600 milligrams: ``Ask a doctor before use if you 
have [in bold type] [bullet] \1\ kidney disease [bullet] a magnesium-
restricted diet''. The warnings in Sec. Sec.  201.64(c), 201.70(c), 
201.71(c), and 201.72(c) may be combined, if applicable, provided the 
ingredients are listed in alphabetical order, e.g., a magnesium or 
potassium-restricted diet.
---------------------------------------------------------------------------

    \1\ See Sec.  201.66(b)(4) of this chapter for definition of bullet 
symbol.
---------------------------------------------------------------------------

    (d) Any product subject to this paragraph that is not labeled as 
required by this paragraph and that is initially introduced or initially 
delivered for introduction into interstate commerce after the following 
dates is misbranded under sections 201(n) and 502(a) and (f) of the 
Federal Food, Drug, and Cosmetic Act.
    (1) As of the date of approval of the application for any single 
entity and combination products subject to drug marketing applications 
approved on or after April 23, 2004.
    (2) September 24. 2005, for all OTC drug products subject to any OTC 
drug monograph, not yet the subject of any OTC drug monograph, or 
subject to drug marketing applications approved before April 23, 2004.

[69 FR 13734, Mar. 24, 2004]



Sec.  201.72  Potassium labeling.

    (a) The labeling of over-the-counter (OTC) drug products intended 
for oral ingestion shall contain the potassium content per dosage unit 
(e.g., tablet, teaspoonful) if the potassium content of a single maximum 
recommended dose of the product (which may be one or more dosage units) 
is 5 milligrams or more. OTC drug products intended for oral ingestion 
include gum and lozenge dosage forms, but do not include dentifrices, 
mouthwashes, or mouth rinses.
    (b) The potassium content shall be expressed in milligrams or grams 
per dosage unit and shall include the total amount of potassium 
regardless of the source, i.e., from both active and inactive 
ingredients. If the dosage unit contains less than 1 gram of potassium, 
milligrams should be used. The potassium content shall be rounded-off to 
the nearest 5 milligrams (or nearest tenth of a gram if over 1 gram). 
The potassium content per dosage unit shall follow the heading ``Other 
information'' as stated in Sec.  201.66(c)(7).
    (c) The labeling of OTC drug products intended for oral ingestion 
shall contain the following statement under the heading ``Warning'' (or 
``Warnings'' if it appears with additional warning statements) if the 
amount of potassium present in the labeled maximum daily dose of the 
product is more than 975 milligrams: ``Ask a doctor before use if you 
have [in bold type] [bullet] \1\ kidney disease [bullet] a potassium-
restricted diet''. The warnings in Sec. Sec.  201.64(c), 201.70(c), 
201.71(c), and 201.72(c) may be combined, if applicable, provided the 
ingredients are listed in alphabetical order, e.g., a magnesium or 
potassium-restricted diet.
---------------------------------------------------------------------------

    \1\ See Sec.  201.66(b)(4) of this chapter for definition of bullet 
symbol.
---------------------------------------------------------------------------

    (d) Any product subject to this paragraph that is not labeled as 
required by this paragraph and that is initially introduced or initially 
delivered for introduction into interstate commerce after the following 
dates is misbranded under sections 201(n) and 502(a) and (f) of the 
Federal Food, Drug, and Cosmetic Act.
    (1) As of the date of approval of the application for any single 
entity and combination products subject to drug marketing applications 
approved on or after April 23, 2004.
    (2) September 24, 2005, for all OTC drug products subject to any OTC 
drug monograph, not yet the subject of any

[[Page 57]]

OTC drug monograph, or subject to drug marketing applications approved 
before April 23, 2004.

[69 FR 13734, Mar. 24, 2004]



Sec.  201.80  Specific requirements on content and format of labeling
for human prescription drug and biological products; older drugs not
described in Sec. 201.56(b)(1).

    Each section heading listed in Sec.  201.56(d), if not omitted under 
Sec.  201.56(d)(3), shall contain the following information in the 
following order:
    (a) Description. (1) Under this section heading, the labeling shall 
contain:
    (i) The proprietary name and the established name, if any, as 
defined in section 502(e)(2) of the act, of the drug;
    (ii) The type of dosage form and the route of administration to 
which the labeling applies;
    (iii) The same qualitative and/or quantitative ingredient 
information as required under Sec.  201.100(b) for labels;
    (iv) If the product is sterile, a statement of that fact;
    (v) The pharmacological or therapeutic class of the drug;
    (vi) The chemical name and structural formula of the drug;
    (vii) If the product is radioactive, a statement of the important 
nuclear physical characteristics, such as the principal radiation 
emission data, external radiation, and physical decay characteristics.
    (2) If appropriate, other important chemical or physical 
information, such as physical constants, or pH, shall be stated.
    (b) Clinical Pharmacology. (1) Under this section heading, the 
labeling shall contain a concise factual summary of the clinical 
pharmacology and actions of the drug in humans. The summary may include 
information based on in vitro and/or animal data if the information is 
essential to a description of the biochemical and/or physiological mode 
of action of the drug or is otherwise pertinent to human therapeutics. 
Pharmacokinetic information that is important to safe and effective use 
of the drug is required, if known, e.g., degree and rate of absorption, 
pathways of biotransformation, percentage of dose as unchanged drug and 
metabolites, rate or half-time of elimination, concentration in body 
fluids associated with therapeutic and/or toxic effects, degree of 
binding to plasma proteins, degree of uptake by a particular organ or in 
the fetus, and passage across the blood brain barrier. Inclusion of 
pharmacokinetic information is restricted to that which relates to 
clinical use of the drug. If the pharmacological mode of action of the 
drug is unknown or if important metabolic or pharmacokinetic data in 
humans are unavailable, the labeling shall contain a statement about the 
lack of information.
    (2) Data that demonstrate activity or effectiveness in in vitro or 
animal tests and that have not been shown by adequate and well-
controlled clinical studies to be pertinent to clinical use may be 
included under this section of the labeling only under the following 
circumstances:
    (i) In vitro data for anti-infective drugs may be included if the 
data are immediately preceded by the statement ``The following in vitro 
data are available but their clinical significance is unknown.''
    (ii) For other classes of drugs, in vitro and animal data that have 
not been shown by adequate and well-controlled clinical studies, as 
defined in Sec.  314.126(b) of this chapter, to be pertinent to clinical 
use may be used only if a waiver is granted under Sec.  201.58 or Sec.  
314.126(c) of this chapter.
    (c) Indications and Usage. (1) Under this section heading, the 
labeling shall state that:
    (i) The drug is indicated in the treatment, prevention, or diagnosis 
of a recognized disease or condition, e.g., penicillin is indicated for 
the treatment of pneumonia due to susceptible pneumococci; and/or
    (ii) The drug is indicated for the treatment, prevention, or 
diagnosis of an important manifestation of a disease or condition, e.g., 
chlorothiazide is indicated for the treatment of edema in patients with 
congestive heart failure; and/or
    (iii) The drug is indicated for the relief of symptoms associated 
with a disease or syndrome, e.g., chlorpheniramine is indicated for the 
symptomatic relief of nasal congestion

[[Page 58]]

in patients with vasomotor rhinitis; and/or
    (iv) The drug, if used for a particular indication only in 
conjuction with a primary mode of therapy, e.g., diet, surgery, or some 
other drug, is an adjunct to the mode of therapy.
    (2)(i) For drug products other than biological products, all 
indications listed in this section must be supported by substantial 
evidence of effectiveness based on adequate and well-controlled studies 
as defined in Sec.  314.126(b) of this chapter unless the requirement is 
waived under Sec.  201.58 or Sec.  314.126(c) of this chapter. 
Indications or uses must not be implied or suggested in other sections 
of labeling if not included in this section.
    (ii) For biological products, all indications listed in this section 
must be supported by substantial evidence of effectiveness. Indications 
or uses must not be implied or suggested in other sections of labeling 
if not included in this section.
    (3) This section of the labeling shall also contain the following 
additional information:
    (i) If evidence is available to support the safety and effectiveness 
of the drug only in selected subgroups of the larger population with a 
disease, syndrome, or symptom under consideration, e.g., patients with 
mild disease or patients in a special age group, the labeling shall 
describe the available evidence and state the limitations of usefulness 
of the drug. The labeling shall also identify specific tests needed for 
selection or monitoring of the patients who need the drug, e.g., microbe 
susceptibility tests. Information on the approximate kind, degree, and 
duration of improvement to be anticipated shall be stated if available 
and shall be based on substantial evidence derived from adequate and 
well-controlled studies as defined in Sec.  314.126(b) of this chapter 
unless the requirement is waived under Sec.  201.58 or Sec.  314.126(c) 
of this chapter. If the information is relevant to the recommended 
intervals between doses, the usual duration of treatment, or any 
modification of dosage, it shall be stated in the ``Dosage and 
Administration'' section of the labeling and referenced in this section.
    (ii) If safety considerations are such that the drug should be 
reserved for certain situations, e.g., cases refractory to other drugs, 
this information shall be stated in this section.
    (iii) If there are specific conditions that should be met before the 
drug is used on a long-term basis, e.g., demonstration of responsiveness 
to the drug in a short-term trial, the labeling shall identify the 
conditions; or, if the indications for long-term use are different from 
those for short-term use, the labeling shall identify the specific 
indications for each use.
    (iv) If there is a common belief that the drug may be effective for 
a certain use or if there is a common use of the drug for a condition, 
but the preponderance of evidence related to the use or condition shows 
that the drug is ineffective, the Food and Drug Administration may 
require that the labeling state that there is a lack of evidence that 
the drug is effective for that use or condition.
    (v) Any statements comparing the safety or effectiveness, either 
greater or less, of the drug with other agents for the same indication 
shall be supported by adequate and well-controlled studies as defined in 
Sec.  314.126(b) of this chapter unless this requirement is waived under 
Sec.  201.58 or Sec.  314.126(c) of this chapter.
    (d) Contraindications. Under this section heading, the labeling 
shall describe those situations in which the drug should not be used 
because the risk of use clearly outweighs any possible benefit. These 
situations include administration of the drug to patients known to have 
a hypersensitivity to it; use of the drug in patients who, because of 
their particular age, sex, concomitant therapy, disease state, or other 
condition, have a substantial risk of being harmed by it; or continued 
use of the drug in the face of an unacceptably hazardous adverse 
reaction. Known hazards and not theoretical possibilities shall be 
listed, e.g., if hypersensitivity to the drug has not been demonstrated, 
it should not be listed as a contraindication. If no contraindications 
are known, this section of the labeling shall state ``None known.''
    (e) Warnings. Under this section heading, the labeling shall 
describe serious

[[Page 59]]

adverse reactions and potential safety hazards, limitations in use 
imposed by them, and steps that should be taken if they occur. The 
labeling shall be revised to include a warning as soon as there is 
reasonable evidence of an association of a serious hazard with a drug; a 
causal relationship need not have been proved. A specific warning 
relating to a use not provided for under the ``Indications and Usage'' 
section of the labeling may be required by the Food and Drug 
Administration if the drug is commonly prescribed for a disease or 
condition, and there is lack of substantial evidence of effectivenes for 
that disease or condition, and such usage is associated with serious 
risk or hazard. Special problems, particularly those that may lead to 
death or serious injury, may be required by the Food and Drug 
Administration to be placed in a prominently displayed box. The boxed 
warning ordinarily shall be based on clinical data, but serious animal 
toxicity may also be the basis of a boxed warning in the absence of 
clinical data. If a boxed warning is required, its location will be 
specified by the Food and Drug Administration. The frequency of these 
serious adverse reactions and, if known, the approximate mortality and 
morbidity rates for patients sustaining the reaction, which are 
important to safe and effective use of the drug, shall be expressed as 
provided under the ``Adverse Reactions'' section of the labeling.
    (f) Precautions. Under this section heading, the labeling shall 
contain the following subsections as appropriate for the drug:
    (1) General. This subsection of the labeling shall contain 
information regarding any special care to be exercised by the 
practitioner for safe and effective use of the drug, e.g., precautions 
not required under any other specific section or subsection of the 
labeling.
    (2) Information for patients. This subsection must contain 
information necessary for patients to use the drug safely and 
effectively (e.g., precautions concerning driving or the concomitant use 
of other substances that may have harmful additive effects). Any FDA-
approved patient labeling must be referenced in this section and the 
full text of such patient labeling must be reprinted immediately 
following the last section of labeling or, alternatively, accompany the 
prescription drug labeling. The type size requirement for the Medication 
Guide set forth in Sec.  208.20 of this chapter does not apply to the 
Medication Guide that is reprinted in or accompanying the prescription 
drug labeling unless such Medication Guide is to be detached and 
distributed to patients in compliance with Sec.  208.24 of this chapter.
    (3) Laboratory tests. This subsection of the labeling shall identify 
any laboratory tests that may be helpful in following the patient's 
response or in identifying possible adverse reactions. If appropriate, 
information shall be provided on such factors as the range of normal and 
abnormal values expected in the particular situation and the recommended 
frequency with which tests should be done before, during, and after 
therapy.
    (4)(i) Drug interactions. This subsection of the labeling shall 
contain specific practical guidance for the physician on preventing 
clinically significant drug/drug and drug/food interactions that may 
occur in vivo in patients taking the drug. Specific drugs or classes of 
drugs with which the drug to which the labeling applies may interact in 
vivo shall be identified, and the mechanism(s) of the interaction shall 
be briefly described. Information in this subsection of the labeling 
shall be limited to that pertaining to clinical use of the drug in 
patients. Drug interactions supported only by animal or in vitro 
experiments may not ordinarily be included, but animal or in vitro data 
may be used if shown to be clinically relevant. Drug incompatibilities, 
i.e., drug interactions that may occur when drugs are mixed in vitro, as 
in a solution for intravenous administration, shall be discussed under 
the ``Dosage and Administration'' section of the labeling rather than 
under this subsection of the labeling.
    (ii) Drug/laboratory test interactions. This subsection of the 
labeling shall contain practical guidance on known interference of the 
drug with laboratory tests.

[[Page 60]]

    (5) Carcinogenesis, mutagenesis, impairment of fertility. This 
subsection of the labeling shall state whether long-term studies in 
animals have been performed to evaluate carcinogenic potential and, if 
so, the species and results. If reproduction studies or other data in 
animals reveal a problem or potential problem concerning mutagenesis or 
impairment of fertility in either males or females, the information 
shall be described. Any precautionary statement on these topics shall 
include practical, relevant advice to the physician on the significance 
of these animal findings. If there is evidence from human data that the 
drug may be carcinogenic or mutagenic or that it impairs fertility, this 
information shall be included under the ``Warnings'' section of the 
labeling. Also, under ``Precautions,'' the labeling shall state: ``See 
`Warnings' section for information on carcinogenesis, mutagenesis, and 
impairment of fertility.''
    (6) Pregnancy. This subsection of the labeling may be omitted only 
if the drug is not absorbed systemically and the drug is not known to 
have a potential for indirect harm to the fetus. For all other drugs, 
this subsection of the labeling shall contain the following information:
    (i) Teratogenic effects. Under this heading the labeling shall 
identify one of the following categories that applies to the drug, and 
the labeling shall bear the statement required under the category:
    (a) If adequate and well-controlled studies in pregnant women have 
failed to demonstrate a risk to the fetus in the first trimester of 
pregnancy (and there is no evidence of a risk in later trimesters), the 
labeling shall state: ``Studies in pregnant women have not shown that 
(name of drug) increases the risk of fetal abnormalities if administered 
during the first (second, third, or all) trimester(s) of pregnancy. If 
this drug is used during pregnancy, the possibility of fetal harm 
appears remote. Because studies cannot rule out the possibility of harm, 
however, (name of drug) should be used during pregnancy only if clearly 
needed.'' The labeling shall also contain a description of the human 
studies. If animal reproduction studies are available and they fail to 
demonstrate a risk to the fetus, the labeling shall also state: 
``Reproduction studies have been performed in (kinds of animal(s)) at 
doses up to (x) times the human dose and have revealed no evidence of 
impaired fertility or harm to the fetus due to (name of drug).'' The 
labeling shall also contain a description of available data on the 
effect of the drug on the later growth, development, and functional 
maturation of the child.
    (b) If animal reproduction studies have failed to demonstrate a risk 
to the fetus and there are no adequate and well-controlled studies in 
pregnant women, the labeling shall state: `` Reproduction studies have 
been performed in (kind(s) of animal(s)) at doses up to (x) times the 
human dose and have revealed no evidence of impaired fertility or harm 
to the fetus due to (name of drug). There are, however, no adequate and 
well-controlled studies in pregnant women. Because animal reproduction 
studies are not always predictive of human response, this drug should be 
used during pregnancy only if clearly needed.'' If animal reproduction 
studies have shown an adverse effect (other than decrease in fertility), 
but adequate and well-controlled studies in pregnant women have failed 
to demonstrate a risk to the fetus during the first trimester of 
pregnancy (and there is no evidence of a risk in later trimesters), the 
labeling shall state: ``Reproduction studies in (kind(s) of animal(s)) 
have shown (describe findings) at (x) times the human dose. Studies in 
pregnant women, however, have not shown that (name of drug) increases 
the risk of abnormalities when administered during the first (second, 
third, or all) trimester(s) of pregnancy. Despite the animal findings, 
it would appear that the possibility of fetal harm is remote, if the 
drug is used during pregnancy. Nevertheless, because the studies in 
humans cannot rule out the possibility of harm, (name of drug) should be 
used during pregnancy only if clearly needed.'' The labeling shall also 
contain a description of the human studies and a description of 
available data on the effect of the drug on the later growth, 
development, and functional maturation of the child.

[[Page 61]]

    (c) If animal reproduction studies have shown an adverse effect on 
the fetus, if there are no adequate and well-controlled studies in 
humans, and if the benefits from the use of the drug in pregnant women 
may be acceptable despite its potential risks, the labeling shall state: 
`` (Name of drug) has been shown to be teratogenic (or to have an 
embryocidal effect or other adverse effect) in (name(s) of species) when 
given in doses (x) times the human dose. There are no adequate and well-
controlled studies in pregnant women. (Name of drug) should be used 
during pregnancy only if the potential benefit justifies the potential 
risk to the fetus.'' The labeling shall contain a description of the 
animal studies. If there are no animal reproduction studies and no 
adequate and well-controlled studies in humans, the labeling shall 
state: ``Animal reproduction studies have not been conducted with (name 
of drug). It is also not known whether (name of drug) can cause fetal 
harm when administered to a pregnant woman or can affect reproduction 
capacity. (Name of drug) should be given to a pregnant woman only if 
clearly needed.'' The labeling shall contain a description of any 
available data on the effect of the drug on the later growth, 
development, and functional maturation of the child.
    (d) If there is positive evidence of human fetal risk based on 
adverse reaction data from investigational or marketing experience or 
studies in humans, but the potential benefits from the use of the drug 
in pregnant women may be acceptable despite its potential risks (for 
example, if the drug is needed in a life-threatening situation or 
serious disease for which safer drugs cannot be used or are 
ineffective), the labeling shall state: `` See `Warnings' section.'' 
Under the ``Warnings'' section, the labeling states: ``(Name of drug) 
can cause fetal harm when administered to a pregnant woman. (Describe 
the human data and any pertinent animal data.) If this drug is used 
during pregnancy, or if the patient becomes pregnant while taking this 
drug, the patient should be apprised of the potential hazard to the 
fetus.''
    (e) If studies in animals or humans have demonstrated fetal 
abnormalities or if there is positive evidence of fetal risk based on 
adverse reaction reports from investigational or marketing experience, 
or both, and the risk of the use of the drug in a pregnant woman clearly 
outweighs any possible benefit (for example, safer drugs or other forms 
of therapy are available), the labeling shall state: `` See 
`Contraindications' section.'' Under ``Contraindications,'' the labeling 
shall state: ``(Name of drug) may (can) cause fetal harm when 
administered to a pregnant woman. (Describe the human data and any 
pertinant animal data.) (Name of drug) is contraindicated in women who 
are or may become pregnant. If this drug is used during pregnancy, or if 
the patient becomes pregnant while taking this drug, the patient should 
be apprised of the potential hazard to the fetus.''
    (ii) Nonteratogenic effects. Under this heading the labeling shall 
contain other information on the drug's effects on reproduction and the 
drug's use during pregnancy that is not required specifically by one of 
the pregnancy categories, if the information is relevant to the safe and 
effective use of the drug. Information required under this heading shall 
include nonteratogenic effects in the fetus or newborn infant (for 
example, withdrawal symptoms or hypoglycemia) that may occur because of 
a pregnant woman's chronic use of the drug for a preexisting condition 
or disease.
    (7) Labor and delivery. If the drug has a recognized use during 
labor or delivery (vaginal or abdominal delivery), whether or not the 
use is stated in the indications section of the labeling, this 
subsection of the labeling shall describe the available information 
about the effect of the drug on the mother and the fetus, on the 
duration of labor or delivery, on the possibility that forceps delivery 
or other intervention or resuscitation of the newborn will be necessary, 
and the effect of the drug on the later growth, development, and 
functional maturation of the child. If any information required under 
this subsection is unknown, this subsection of the labeling shall state 
that the information is unknown.
    (8) Nursing mothers. (i) If a drug is absorbed systemically, this 
subsection of

[[Page 62]]

the labeling shall contain, if known, information about excretion of the 
drug in human milk and effects on the nursing infant. Pertinent adverse 
effects observed in animal offspring shall be described.
    (ii) If a drug is absorbed systemically and is known to be excreted 
in human milk, this subsection of the labeling shall contain one of the 
following statements, as appropriate. If the drug is associated with 
serious adverse reactions or if the drug has a known tumorigenic 
potential, the labeling shall state: ``Because of the potential for 
serious adverse reactions in nursing infants from (name of drug) (or, 
``Because of the potential for tumorigenicity shown for (name of drug) 
in (animal or human) studies), a decision should be made whether to 
discontinue nursing or to discontinue the drug, taking into account the 
importance of the drug to the mother.'' If the drug is not associated 
with serious adverse reactions and does not have a known tumorigenic 
potential, the labeling shall state: ``Caution should be exercised when 
(name of drug) is administered to a nursing woman.''
    (iii) If a drug is absorbed systemically and information on 
excretion in human milk is unknown, this subsection of the labeling 
shall contain one of the following statements, as appropriate. If the 
drug is associated with serious adverse reactions or has a known 
tumorigenic potential, the labeling shall state: ``It is not known 
whether this drug is excreted in human milk. Because many drugs are 
excreted in human milk and because of the potential for serious adverse 
reactions in nursing infants from (name of drug) (or, ``Because of the 
potential for tumorigenicity shown for (name of drug) in (animal or 
human) studies), a decision should be made whether to discontinue 
nursing or to discontinue the drug, taking into account the importance 
of the drug to the mother.'' If the drug is not associated with serious 
adverse reactions and does not have a known tumorigenic potential, the 
labeling shall state: ``It is not known whether this drug is excreted in 
human milk. Because many drugs are excreted in human milk, caution 
should be exercised when (name of drug) is administered to a nursing 
woman.''
    (9) Pediatric use. (i) Pediatric population(s)/pediatric patient(s): 
For the purposes of paragraphs (f)(9)(ii) through (f)(9)(viii) of this 
section, the terms pediatric population(s) and pediatric patient(s) are 
defined as the pediatric age group, from birth to 16 years, including 
age groups often called neonates, infants, children, and adolescents.
    (ii) If there is a specific pediatric indication (i.e., an 
indication different from those approved for adults) that is supported 
by adequate and well-controlled studies in the pediatric population, it 
shall be described under the ``Indications and Usage'' section of the 
labeling, and appropriate pediatric dosage information shall be given 
under the ``Dosage and Administration'' section of the labeling. The 
``Pediatric use'' subsection shall cite any limitations on the pediatric 
indication, need for specific monitoring, specific hazards associated 
with use of the drug in any subsets of the pediatric population (e.g., 
neonates), differences between pediatric and adult responses to the 
drug, and other information related to the safe and effective pediatric 
use of the drug. Data summarized in this subsection of the labeling 
should be discussed in more detail, if appropriate, under the ``Clinical 
Pharmacology'' or ``Clinical Studies'' section. As appropriate, this 
information shall also be contained in the ``Contraindications,'' 
``Warnings,'' and elsewhere in the ``Precautions'' sections.
    (iii) If there are specific statements on pediatric use of the drug 
for an indication also approved for adults that are based on adequate 
and well-controlled studies in the pediatric population, they shall be 
summarized in the ``Pediatric use'' subsection of the labeling and 
discussed in more detail, if appropriate, under the ``Clinical 
Pharmacology'' and ``Clinical Studies'' sections. Appropriate pediatric 
dosage shall be given under the ``Dosage and Administration'' section of 
the labeling. The ``Pediatric use'' subsection of the labeling shall 
also cite any limitations on the pediatric use statement, need for 
specific monitoring, specific hazards associated with use of the drug

[[Page 63]]

in any subsets of the pediatric population (e.g., neonates), differences 
between pediatric and adult responses to the drug, and other information 
related to the safe and effective pediatric use of the drug. As 
appropriate, this information shall also be contained in the 
``Contraindications,'' ``Warnings,'' and elsewhere in the 
``Precautions'' sections.
    (iv) FDA may approve a drug for pediatric use based on adequate and 
well-controlled studies in adults, with other information supporting 
pediatric use. In such cases, the agency will have concluded that the 
course of the disease and the effects of the drug, both beneficial and 
adverse, are sufficiently similar in the pediatric and adult populations 
to permit extrapolation from the adult efficacy data to pediatric 
patients. The additional information supporting pediatric use must 
ordinarily include data on the pharmacokinetics of the drug in the 
pediatric population for determination of appropriate dosage. Other 
information, such as data from pharmacodynamic studies of the drug in 
the pediatric population, data from other studies supporting the safety 
or effectiveness of the drug in pediatric patients, pertinent 
premarketing or postmarketing studies or experience, may be necessary to 
show that the drug can be used safely and effectively in pediatric 
patients. When a drug is approved for pediatric use based on adequate 
and well-controlled studies in adults with other information supporting 
pediatric use, the ``Pediatric use'' subsection of the labeling shall 
contain either the following statement, or a reasonable alternative: 
``The safety and effectiveness of (drug name) have been established in 
the age groups _ to _ (note any limitations, e.g., no data for pediatric 
patients under 2, or only applicable to certain indications approved in 
adults). Use of (drug name) in these age groups is supported by evidence 
from adequate and well-controlled studies of (drug name) in adults with 
additional data (insert wording that accurately describes the data 
submitted to support a finding of substantial evidence of effectiveness 
in the pediatric population).'' Data summarized in the preceding 
prescribed statement in this subsection of the labeling shall be 
discussed in more detail, if appropriate, under the ``Clinical 
Pharmacology'' or the ``Clinical Studies'' section. For example, 
pediatric pharmacokinetic or pharmacodynamic studies and dose-response 
information should be described in the ``Clinical Pharmacology'' 
section. Pediatric dosing instructions shall be included in the ``Dosage 
and Administration'' section of the labeling. Any differences between 
pediatric and adult responses, need for specific monitoring, dosing 
adjustments, and any other information related to safe and effective use 
of the drug in pediatric patients shall be cited briefly in the 
``Pediatric use'' subsection and, as appropriate, in the 
``Contraindications,'' ``Warnings,'' ``Precautions,'' and ``Dosage and 
Administration'' sections.
    (v) If the requirements for a finding of substantial evidence to 
support a pediatric indication or a pediatric use statement have not 
been met for a particular pediatric population, the ``Pediatric use'' 
subsection of the labeling shall contain an appropriate statement such 
as ``Safety and effectiveness in pediatric patients below the age of (_) 
have not been established.'' If use of the drug in this pediatric 
population is associated with a specific hazard, the hazard shall be 
described in this subsection of the labeling, or, if appropriate, the 
hazard shall be stated in the ``Contraindications'' or ``Warnings'' 
section of the labeling and this subsection shall refer to it.
    (vi) If the requirements for a finding of substantial evidence to 
support a pediatric indication or a pediatric use statement have not 
been met for any pediatric population, this subsection of the labeling 
shall contain the following statement: ``Safety and effectiveness in 
pediatric patients have not been established.'' If use of the drug in 
premature or neonatal infants, or other pediatric subgroups, is 
associated with a specific hazard, the hazard shall be described in this 
subsection of the labeling, or, if appropriate, the hazard shall be 
stated in the ``Contraindications'' or ``Warnings'' section of the 
labeling and this subsection shall refer to it.
    (vii) If the sponsor believes that none of the statements described 
in paragraphs (f)(9)(ii) through (f)(9)(vi) of this

[[Page 64]]

section is appropriate or relevant to the labeling of a particular drug, 
the sponsor shall provide reasons for omission of the statements and may 
propose alternative statement(s). FDA may permit use of an alternative 
statement if FDA determines that no statement described in those 
paragraphs is appropriate or relevant to the drug's labeling and that 
the alternative statement is accurate and appropriate.
    (viii) If the drug product contains one or more inactive ingredients 
that present an increased risk of toxic effects to neonates or other 
pediatric subgroups, a special note of this risk shall be made, 
generally in the ``Contraindications,'' ``Warnings,'' or ``Precautions'' 
section.
    (10) Geriatric use. (i) A specific geriatric indication, if any, 
that is supported by adequate and well-controlled studies in the 
geriatric population shall be described under the ``Indications and 
Usage'' section of the labeling, and appropriate geriatric dosage shall 
be stated under the ``Dosage and Administration'' section of the 
labeling. The ``Geriatric use'' subsection shall cite any limitations on 
the geriatric indication, need for specific monitoring, specific hazards 
associated with the geriatric indication, and other information related 
to the safe and effective use of the drug in the geriatric population. 
Unless otherwise noted, information contained in the ``Geriatric use'' 
subsection of the labeling shall pertain to use of the drug in persons 
65 years of age and older. Data summarized in this subsection of the 
labeling shall be discussed in more detail, if appropriate, under 
``Clinical Pharmacology'' or the ``Clinical Studies'' section. As 
appropriate, this information shall also be contained in 
``Contraindications,'' ``Warnings,'' and elsewhere in ``Precautions.''
    (ii) Specific statements on geriatric use of the drug for an 
indication approved for adults generally, as distinguished from a 
specific geriatric indication, shall be contained in the ``Geriatric 
use'' subsection and shall reflect all information available to the 
sponsor that is relevant to the appropriate use of the drug in elderly 
patients. This information includes detailed results from controlled 
studies that are available to the sponsor and pertinent information from 
well-documented studies obtained from a literature search. Controlled 
studies include those that are part of the marketing application and 
other relevant studies available to the sponsor that have not been 
previously submitted in the investigational new drug application, new 
drug application, biological license application, or a supplement or 
amendment to one of these applications (e.g., postmarketing studies or 
adverse drug reaction reports). The ``Geriatric use'' subsection shall 
contain the following statement(s) or reasonable alternative, as 
applicable, taking into account available information:
    (A) If clinical studies did not include sufficient numbers of 
subjects aged 65 and over to determine whether elderly subjects respond 
differently from younger subjects, and other reported clinical 
experience has not identified such differences, the ``Geriatric use'' 
subsection shall include the following statement:

    ``Clinical studies of (name of drug) did not include sufficient 
numbers of subjects aged 65 and over to determine whether they respond 
differently from younger subjects. Other reported clinical experience 
has not identified differences in responses between the elderly and 
younger patients. In general, dose selection for an elderly patient 
should be cautious, usually starting at the low end of the dosing range, 
reflecting the greater frequency of decreased hepatic, renal, or cardiac 
function, and of concomitant disease or other drug therapy.''

    (B) If clinical studies (including studies that are part of 
marketing applications and other relevant studies available to the 
sponsor that have not been submitted in the sponsor's applications) 
included enough elderly subjects to make it likely that differences in 
safety or effectiveness between elderly and younger subjects would have 
been detected, but no such differences (in safety or effectiveness) were 
observed, and other reported clinical experience has not identified such 
differences, the ``Geriatric use'' subsection shall contain the 
following statement:

    Of the total number of subjects in clinical studies of (name of 
drug), _ percent were 65 and over, while _ percent were 75 and over. 
(Alternatively, the labeling may state the total number of subjects 
included in the

[[Page 65]]

studies who were 65 and over and 75 and over.) No overall differences in 
safety or effectiveness were observed between these subjects and younger 
subjects, and other reported clinical experience has not identified 
differences in responses between the elderly and younger patients, but 
greater sensitivity of some older individuals cannot be ruled out.

    (C) If evidence from clinical studies and other reported clinical 
experience available to the sponsor indicates that use of the drug in 
elderly patients is associated with differences in safety or 
effectiveness, or requires specific monitoring or dosage adjustment, the 
``Geriatric use'' subsection of the labeling shall contain a brief 
description of observed differences or specific monitoring or dosage 
requirements and, as appropriate, shall refer to more detailed 
discussions in the ``Contraindications,'' ``Warnings,'' ``Dosage and 
Administration,'' or other sections of the labeling.
    (iii)(A) If specific pharmacokinetic or pharmacodynamic studies have 
been carried out in the elderly, they shall be described briefly in the 
``Geriatric use'' subsection of the labeling and in detail under the 
``Clinical Pharmacology'' section. The ``Clinical Pharmacology'' section 
and ``Drug interactions'' subsection of the ``Precautions'' section 
ordinarily contain information on drug-disease and drug-drug 
interactions that is particularly relevant to the elderly, who are more 
likely to have concomitant illness and to utilize concomitant drugs.
    (B) If a drug is known to be substantially excreted by the kidney, 
the ``Geriatric use'' subsection shall include the statement:

    ``This drug is known to be substantially excreted by the kidney, and 
the risk of toxic reactions to this drug may be greater in patients with 
impaired renal function. Because elderly patients are more likely to 
have decreased renal function, care should be taken in dose selection, 
and it may be useful to monitor renal function.''

    (iv) If use of the drug in the elderly appears to cause a specific 
hazard, the hazard shall be described in the ``Geriatric use'' 
subsection of the labeling, or, if appropriate, the hazard shall be 
stated in the ``Contraindications,'' ``Warnings,'' or ``Precautions'' 
section of the labeling, and the ``Geriatric use'' subsection shall 
refer to those sections.
    (v) Labeling under paragraphs (f)(10)(i) through (f)(10)(iii) of 
this section may include statements, if they would be useful in 
enhancing safe use of the drug, that reflect good clinical practice or 
past experience in a particular situation, e.g., for a sedating drug, it 
could be stated that:

    ``Sedating drugs may cause confusion and over-sedation in the 
elderly; elderly patients generally should be started on low doses of 
(name of drug) and observed closely.''

    (vi) If the sponsor believes that none of the requirements described 
in paragraphs (f)(10)(i) through (f)(10)(v) of this section is 
appropriate or relevant to the labeling of a particular drug, the 
sponsor shall provide reasons for omission of the statements and may 
propose an alternative statement. FDA may permit omission of the 
statements if FDA determines that no statement described in those 
paragraphs is appropriate or relevant to the drug's labeling. FDA may 
permit use of an alternative statement if the agency determines that 
such statement is accurate and appropriate.
    (g) Adverse Reactions. An adverse reaction is an undesirable effect, 
reasonably associated with the use of the drug, that may occur as part 
of the pharmacological action of the drug or may be unpredictable in its 
occurrence.
    (1) This section of the labeling shall list the adverse reactions 
that occur with the drug and with drugs in the same pharmacologically 
active and chemically related class, if applicable.
    (2) In this listing, adverse reactions may be categorized by organ 
system, by severity of the reaction, by frequency, or by toxicological 
mechanism, or by a combination of these, as appropriate. If frequency 
information from adequate clinical studies is available, the categories 
and the adverse reactions within each category shall be listed in 
decreasing order of frequency. An adverse reaction that is significantly 
more severe than the other reactions listed in a category, however, 
shall be listed before those reactions, regardless of its frequency. If 
frequency information from adequate clinical studies is not available, 
the categories

[[Page 66]]

and adverse reactions within each category shall be listed in decreasing 
order of severity. The approximate frequency of each adverse reaction 
shall be expressed in rough estimates or orders of magnitude essentially 
as follows: ``The most frequent adverse reaction(s) to (name of drug) is 
(are) (list reactions). This (these) occur(s) in about (e.g., one-third 
of patients; one in 30 patients; less than one-tenth of patients). Less 
frequent adverse reactions are (list reactions), which occur in 
approximately (e.g., one in 100 patients). Other adverse reactions, 
which occur rarely, in approximately (e.g., one in 1,000 patients), are 
(list reactions).'' Percent figures may not ordinarily be used unless 
they are documented by adequate and well-controlled studies as defined 
in Sec.  314.126(b) of this chapter, they are shown to reflect general 
experience, and they do not falsely imply a greater degree of accuracy 
than actually exists.
    (3) The ``Warnings'' section of the labeling or, if appropriate, the 
``Contraindications'' section of the labeling shall identify any 
potentially fatal adverse reaction.
    (4) Any claim comparing the drug to which the labeling applies with 
other drugs in terms of frequency, severity, or character of adverse 
reactions shall be based on adequate and well-controlled studies as 
defined in Sec.  314.126(b) of this chapter unless this requirement is 
waived under Sec.  201.58 or Sec.  314.126(c) of this chapter.
    (h) Drug Abuse and Dependence. Under this section heading, the 
labeling shall contain the following subsections, as appropriate for the 
drug:
    (1) Controlled Substance. If the drug is controlled by the Drug 
Enforcement Administration, the schedule in which it is controlled shall 
be stated.
    (2) Abuse. This subsection of the labeling shall be based primarily 
on human data and human experience, but pertinent animal data may also 
be used. This subsection shall state the types of abuse that can occur 
with the drug and the adverse reactions pertinent to them. Particularly 
susceptible patient populations shall be identified.
    (3) Dependence. This subsection of the labeling shall describe 
characteristic effects resulting from both psychological and physical 
dependence that occur with the drug and shall identify the quantity of 
the drug over a period of time that may lead to tolerance or dependence, 
or both. Details shall be provided on the adverse effects of chronic 
abuse and the effects of abrupt withdrawal. Procedures necessary to 
diagnose the dependent state shall be provided, and the principles of 
treating the effects of abrupt withdrawal shall be described.
    (i) Overdosage. Under this section heading, the labeling shall 
describe the signs, symptoms, and laboratory findings of acute 
overdosage and the general principles of treatment. This section shall 
be based on human data, when available. If human data are unavailable, 
appropriate animal and in vitro data may be used. Specific information 
shall be provided about the following:
    (1) Signs, symptoms, and laboratory findings associated with an 
overdosage of the drug.
    (2) Complications that can occur with the drug (for example, organ 
toxicity or delayed acidosis).
    (3) Oral LD50 of the drug in animals; concentrations of 
the drug in biologic fluids associated with toxicity and/or death; 
physiologic variables influencing excretion of the drug, such as urine 
pH; and factors that influence the dose response relationship of the 
drug, such as tolerance. The pharmacokinetic data given in the 
``Clinical Pharmacology'' section also may be referenced here, if 
applicable to overdoses.
    (4) The amount of the drug in a single dose that is ordinarily 
associated with symptoms of overdosage and the amount of the drug in a 
single dose that is likely to be life-threatening.
    (5) Whether the drug is dialyzable.
    (6) Recommended general treatment procedures and specific measures 
for support of vital functions, such as proven antidotes, gastric 
lavage, and forced diuresis. Unqualified recommendations for which data 
are lacking with the specific drug or class of drugs, especially 
treatment using another drug (for example, central nervous system 
stimulants, respiratory stimulants) may not be stated unless

[[Page 67]]

specific data or scientific rationale exists to support safe and 
effective use.
    (j) Dosage and Administration. This section of the labeling shall 
state the recommended usual dose, the usual dosage range, and, if 
appropriate, an upper limit beyond which safety and effectiveness have 
not been established; dosages shall be stated for each indication when 
appropriate. Dosing regimens must not be implied or suggested in other 
sections of labeling if not included in this section. This section shall 
also state the intervals recommended between doses, the optimal method 
of titrating dosage, the usual duration of treatment, and any 
modification of dosage needed in special patient populations, e.g., in 
children, in geriatric age groups, or in patients with renal or hepatic 
disease. Specific tables or monographs may be included to clarify dosage 
schedules. Radiation dosimetry information shall be stated for both the 
patient receiving a radioactive drug and the person administering it. 
This section shall also contain specific direction on dilution, 
preparation (including the strength of the final dosage solution, when 
prepared according to instructions, in terms of milligrams active 
ingredient per milliliter of reconstituted solution, unless another 
measure of the strength is more appropriate), and administration of the 
dosage form, if needed, e.g., the rate of administration of parenteral 
drug in milligrams per minute; storage conditions for stability of the 
drug or reconstituted drug, when important; essential information on 
drug incompatibilities if the drug is mixed in vitro with other drugs; 
and the following statement for parenterals: ``Parenteral drug products 
should be inspected visually for particulate matter and discoloration 
prior to administration, whenever solution and container permit.''
    (k) How Supplied. This section of the labeling shall contain 
information on the available dosage forms to which the labeling applies 
and for which the manufacturer or distributor is responsible. The 
information shall ordinarily include:
    (1) The strength of the dosage form, e.g., 10-milligram tablets, in 
metric system and, if the apothecary system is used, a statement of the 
strength is placed in parentheses after the metric designation;
    (2) The units in which the dosage form is ordinarily available for 
prescribing by practitioners, e.g., bottles of 100;
    (3) Appropriate information to facilitate identification of the 
dosage forms, such as shape, color, coating, scoring, and National Drug 
Code; and
    (4) Special handling and storage conditions.
    (l) Animal Pharmacology and/or Animal Toxicology. In most cases, the 
labeling need not include this section. Significant animal data 
necessary for safe and effective use of the drug in humans shall 
ordinarily be included in one or more of the other sections of the 
labeling, as appropriate. Commonly for a drug that has been marketed for 
a long time, and in rare cases for a new drug, chronic animal toxicity 
studies have not been performed or completed for a drug that is 
administered over prolonged periods or is implanted in the body. The 
unavailability of such data shall be stated in the appropriate section 
of the labeling for the drug. If the pertinent animal data cannot be 
appropriately incorporated into other sections of the labeling, this 
section may be used.
    (m) ``Clinical Studies'' and ``References''. These sections may 
appear in labeling in the place of a detailed discussion of a subject 
that is of limited interest but nonetheless important. A reference to a 
specific important clinical study may be made in any section of the 
format required under Sec. Sec.  201.56 and 201.57 if the study is 
essential to an understandable presentation of the available 
information. References may appear in sections of the labeling format, 
other than the ``Clinical Studies'' or ``References'' section, in rare 
circumstances only. A clinical study or reference may be cited in 
prescription drug labeling only under the following conditions:
    (1)(i) If the clinical study is cited in the labeling in place of a 
detailed discussion of data and information concerning an indication for 
use of the drug, the clinical study must constitute an adequate and 
well-controlled study as described in Sec.  314.126(b) of this

[[Page 68]]

chapter, except for biological products, and must not imply or suggest 
indications or uses or dosing regimens not stated in the ``Indications 
and Usage'' or ``Dosage and Administration'' section.
    (ii) When prescription drug labeling must summarize or otherwise 
rely on a recommendation by an authoritative scientific body, or on a 
standardized methodology, scale, or technique, because the information 
is important to prescribing decisions, the labeling may include a 
reference to the source of the information.
    (2) If the clinical study or reference is cited in the labeling in 
the place of a detailed discussion of data and information concerning a 
risk or risks from the use of the drug, the risk or risks shall also be 
identified or discussed in the appropriate section of the labeling for 
the drug.

[44 FR 37462, June 26, 1979, as amended at 55 FR 11576, Mar. 29, 1990; 
59 FR 64249, Dec. 13, 1994; 62 FR 45325, Aug. 27, 1997; 63 FR 66396, 
Dec. 1, 1998. Redesignated and amended at 71 FR 3988, 3996, Jan. 24, 
2006; 79 FR 72103, Dec. 4, 2014]



          Subpart D_Exemptions From Adequate Directions for Use



Sec.  201.100  Prescription drugs for human use.

    A drug subject to the requirements of section 503(b)(1) of the act 
shall be exempt from section 502(f)(1) if all the following conditions 
are met:
    (a) The drug is:
    (1)(i) In the possession of a person (or his agents or employees) 
regularly and lawfully engaged in the manufacture, transportation, 
storage, or wholesale distribution of prescription drugs; or
    (ii) In the possession of a retail, hospital, or clinic pharmacy, or 
a public health agency, regularly and lawfully engaged in dispensing 
prescription drugs; or
    (iii) In the possession of a practitioner licensed by law to 
administer or prescribe such drugs; and
    (2) It is to be dispensed in accordance with section 503(b)
    (b) The label of the drug bears:
    (1) The statement ``Rx only'' and
    (2) The recommended or usual dosage and
    (3) The route of administration, if it is not for oral use; and
    (4) The quantity or proportion of each active ingredient, as well as 
the information required by section 502 (d) and (e); and
    (5) If it is for other than oral use, the names of all inactive 
ingredients, except that:
    (i) Flavorings and perfumes may be designated as such without naming 
their components.
    (ii) Color additives may be designated as coloring without naming 
specific color components unless the naming of such components is 
required by a color additive regulation prescribed in subchapter A of 
this chapter.
    (iii) Trace amounts of harmless substances added solely for 
individual product identification need not be named. If it is intended 
for administration by parenteral injection, the quantity or proportion 
of all inactive ingredients, except that ingredients added to adjust the 
pH or to make the drug isotonic may be declared by name and a statement 
of their effect; and if the vehicle is water for injection it need not 
be named.
    (6) An identifying lot or control number from which it is possible 
to determine the complete manufacturing history of the package of the 
drug.
    (7) A statement directed to the pharmacist specifying the type of 
container to be used in dispensing the drug product to maintain its 
identity, strength, quality, and purity. Where there are standards and 
test procedures for determining that the container meets the 
requirements for specified types of containers as defined in an official 
compendium, such terms may be used. For example, ``Dispense in tight, 
light-resistant container as defined in the National Formulary''. Where 
standards and test procedures for determining the types of containers to 
be used in dispensing the drug product are not included in an official 
compendium, the specific container or types of containers known to be 
adequate to maintain the identity, strength, quality, and purity of the 
drug products shall be described. For example, ``Dispense

[[Page 69]]

in containers which (statement of specifications which clearly enable 
the dispensing pharmacist to select an adequate container)'': Provided, 
however, That in the case of containers too small or otherwise unable to 
accommodate a label with sufficient space to bear all such information, 
but which are packaged within an outer container from which they are 
removed for dispensing or use, the information required by paragraph (b) 
(2), (3), (5), and (7) of this section may be contained in other 
labeling on or within the package from which it is to be dispensed; the 
information referred to in paragraph (b)(1) of this section may be 
placed on such outer container only; and the information required by 
paragraph (b)(6) of this section may be on the crimp of the dispensing 
tube. The information required by this paragraph (b)(7) is not required 
for prescription drug products packaged in unit-dose, unit-of-use, on 
other packaging format in which the manufacturer's original package is 
designed and intended to be dispensed to patients without repackaging.
    (c)(1) Labeling on or within the package from which the drug is to 
be dispensed bears adequate information for its use, including 
indications, effects, dosages, routes, methods, and frequency and 
duration of administration, and any relevant hazards, contraindications, 
side effects, and precautions under which practitioners licensed by law 
to administer the drug can use the drug safely and for the purposes for 
which it is intended, including all purposes for which it is advertised 
or represented; and
    (2) If the article is subject to section 505 of the act, the 
labeling bearing such information is the labeling authorized by the 
approved new drug application or required as a condition for the 
certification or the exemption from certification requirements 
applicable to preparations of insulin or antibiotic drugs.
    (d) Any labeling, as defined in section 201(m) of the act, whether 
or not it is on or within a package from which the drug is to be 
dispensed, distributed by or on behalf of the manufacturer, packer, or 
distributor of the drug, that furnishes or purports to furnish 
information for use or which prescribes, recommends, or suggests a 
dosage for the use of the drug (other than dose information required by 
paragraph (b)(2) of this section and Sec.  201.105(b)(2) contains:
    (1) Adequate information for such use, including indications, 
effects, dosages, routes, methods, and frequency and duration of 
administration and any relevant warnings, hazards, contraindications, 
side effects, and precautions, under which practitioners licensed by law 
to administer the drug can use the drug safely and for the purposes for 
which it is intended, including all conditions for which it is 
advertised or represented; and if the article is subject to section 505 
of the act, the parts of the labeling providing such information are the 
same in language and emphasis as labeling approved or permitted, under 
the provisions of section 505, and any other parts of the labeling are 
consistent with and not contrary to such approved or permitted labeling; 
and
    (2) The same information concerning the ingredients of the drug as 
appears on the label and labeling on or within the package from which 
the drug is to be dispensed.
    (3) The information required, and in the format specified, by 
Sec. Sec.  201.56, 201.57, and 201.80.
    (e) All labeling described in paragraph (d) of this section bears 
conspicuously the name and place of business of the manufacturer, 
packer, or distributor, as required for the label of the drug under 
Sec.  201.1.
    (f) Reminder labeling which calls attention to the name of the drug 
product but does not include indications or dosage recommendations for 
use of the drug product is exempted from the provisions of paragraph (d) 
of this section. This reminder labeling shall contain only the 
proprietary name of the drug product, if any; the established name of 
the drug product, if any; the established name of each active ingredient 
in the drug product; and, optionally, information relating to 
quantitative ingredient statements, dosage form, quantity of package 
contents, price, the name and address of the manufacturer, packer, or 
distributor or other written, printed, or graphic matter containing no 
representation or suggestion relating to the drug product. If

[[Page 70]]

the Commissioner finds that there is evidence of significant incidence 
of fatalities or serious injury associated with the use of a particular 
prescription drug, he may withdraw this exemption by so notifying the 
manufacturer, packer, or distributor of the drug by letter. Reminder 
labeling, other than price lists and catalogs solely intended to convey 
price information including, but not limited to, those subject to the 
requirements of Sec.  200.200 of this chapter, is not permitted for a 
prescription drug product whose labeling contains a boxed warning 
relating to a serious hazard associated with the use of the drug 
product. Reminder labeling which is intended to provide consumers with 
information concerning the price charged for a prescription for a 
particular drug product shall meet all of the conditions contained in 
Sec.  200.200 of this chapter. Reminder labeling, other than that 
subject to the requirements of Sec.  200.200 of this chapter, is not 
permitted for a drug for which an announcement has been published 
pursuant to a review of the labeling claims for the drug by the National 
Academy of Sciences/National Research Council (NAS/NRC), Drug Efficacy 
Study Group, and for which no claim has been evaluated as higher than 
``possibly effective.'' If the Commissioner finds the circumstances are 
such that reminder labeling may be misleading to prescribers of drugs 
subject to NAS/NRC evaluation, such reminder labeling will not be 
allowed and the manufacturer, packer, or distributor will be notified 
either in the publication of the conclusions on the effectiveness of the 
drug or by letter.

[40 FR 13998, Mar. 27, 1975, as amended at 40 FR 58799, Dec. 18, 1975; 
42 FR 15674, Mar. 22, 1977; 43 FR 37989, Aug. 25, 1978; 44 FR 20659, 
Apr. 6, 1979; 44 FR 37467, June 26, 1979; 45 FR 25777, Apr. 15, 1980; 63 
FR 26698, May 13, 1998; 64 FR 400, Jan. 5, 1999; 67 FR 4906, Feb. 1, 
2002; 71 FR 3996, Jan. 24, 2006]



Sec.  201.105  Veterinary drugs.

    A drug subject to the requirements of section 503(f)(1) of the act 
shall be exempt from section 502(f)(1) of the act if all the following 
conditions are met:
    (a) The drug is:
    (1)(i) In the possession of a person (or his agents or employees) 
regularly and lawfully engaged in the manufacture, transportation, 
storage, or wholesale distribution of drugs that are to be used only by 
or on the prescription or other order of a licensed veterinarian; or
    (ii) In the possession of a retail, hospital, or clinic pharmacy, or 
other person authorized under State law to dispense veterinary 
prescription drugs, who is regularly and lawfully engaged in dispensing 
drugs that are to be used only by or on the prescription or other order 
of a licensed veterinarian; or
    (iii) In the possession of a licensed veterinarian for use in the 
course of his professional practice; and
    (2) To be dispensed in accordance with section 503(f) of the act.
    (b) The label of the drug bears:
    (1) The statement ``Caution: Federal law restricts this drug to use 
by or on the order of a licensed veterinarian''; and
    (2) The recommended or usual dosage; and
    (3) The route of administration, if it is not for oral use; and
    (4) The quantity or proportion of each active ingredient as well as 
the information required by section 502(e) of the act; and
    (5) If it is for other than oral use, the names of all inactive 
ingredients, except that:
    (i) Flavorings and perfumes may be designated as such without naming 
their components.
    (ii) Color additives may be designated as coloring without naming 
specific color components unless the naming of such components is 
required by a color additive regulation prescribed in subchapter A of 
this chapter.
    (iii) Trace amounts of harmless substances added solely for 
individual product identification need not be named.

If it is intended for administration by parenteral injection, the 
quantity or proportion of all inactive ingredients, except that 
ingredients added to adjust the pH or to make the drug isotonic may be 
declared by name and a statement of their effect; and if the vehicle is 
water for injection, it need not be named.

[[Page 71]]

    (6) An identifying lot or control number from which it is possible 
to determine the complete manufacturing history of the package of the 
drug;

Provided, however, That in the case of containers too small or otherwise 
unable to accommodate a label with sufficient space to bear all such 
information, but which are packaged within an outer container from which 
they are removed for dispensing or use, the information required by 
paragraphs (b) (2), (3), and (5) of this section may be contained in 
other labeling on or within the package from which it is to be so 
dispensed, and the information referred to in paragraph (b)(1) of this 
section may be placed on such outer container only, and the information 
required by paragraph (b)(6) of this section may be on the crimp of the 
dispensing tube.
    (c)(1) Labeling on or within the package from which the drug is to 
be dispensed bears adequate information for its use, including 
indications, effects, dosages, routes, methods, and frequency and 
duration of administration, and any relevant hazards, contraindications, 
side effects, and precautions under which veterinarians licensed by law 
to administer the drug can use the drug safely and for the purposes for 
which it is intended, including all purposes for which it is advertised 
or represented; and
    (2) If the article is subject to section 512 or 572 of the act, the 
labeling bearing such information is the labeling authorized by the 
approved new animal drug application or contained in the index listing: 
Provided, however, That the information required by paragraph (c)(1) of 
this section may be omitted from the dispensing package if, but only if, 
the article is a drug for which directions, hazards, warnings, and use 
information are commonly known to veterinarians licensed by law to 
administer the drug. Upon written request, stating reasonable grounds 
therefore, the Commissioner will offer an opinion on a proposal to omit 
such information from the dispensing package under this proviso.
    (d) Any labeling, as defined in section 201(m) of the act, whether 
or not it is on or within a package from which the drug is to be 
dispensed, distributed by or on behalf of the manufacturer, packer, or 
distributor of the drug, that furnishes or purports to furnish 
information for use or which prescribes, recommends, or suggests a 
dosage for the use of the drug (other than dose information required by 
paragraph (b)(2) of this section and Sec.  201.100(b)(2)) contains:
    (1) Adequate information for such use, including indications, 
effects, dosages, routes, methods, and frequency and duration of 
administration, and any relevant warnings, hazards, contraindications, 
side effects, and precautions, and including information relevant to 
compliance with the new animal drug provisions of the act, under which 
veterinarians licensed by law to administer the drug can use the drug 
safely and for the purposes for which it is intended, including all 
conditions for which it is advertised or represented; and if the article 
is subject to section 512 or 572 of the act, the parts of the labeling 
providing such information are the same in language and emphasis as 
labeling approved, permitted, or indexed under the provisions of section 
512 or 572, and any other parts of the labeling are consistent with and 
not contrary to such approved, permitted, or indexed labeling; and
    (2) The same information concerning the ingredients of the drug as 
appears on the label and labeling on or within the package from which 
the drug is to be dispensed;


Provided, however, That the information required by paragraphs (d) (1) 
and (2) of this section is not required on the so-called reminder-piece 
labeling which calls attention to the name of the drug but does not 
include indications or dosage recommendations for use of the drug.
    (e) All labeling, except labels and cartons, bearing information for 
use of the drug also bears the date of the issuance or the date of the 
latest revision of such labeling.
    (f) A prescription drug intended for both human and veterinary use 
shall comply with paragraphs (e) and (f) of this section and Sec.  
201.100.

[40 FR 13998, Mar. 27, 1975, as amended at 42 FR 15674, Mar. 22, 1977; 
57 FR 54300, Nov. 18, 1992; 72 FR 69119, Dec. 6, 2007]

[[Page 72]]



Sec.  201.115  New drugs or new animal drugs.

    A new drug shall be exempt from section 502(f)(1) of the act:
    (a) To the extent to which such exemption is claimed in an approved 
application with respect to such drug under section 505 or 512 of the 
act or an index listing with respect to such drug under section 572 of 
the act; or
    (b) If no application under section 505 or 512 of the act is 
approved and no request for addition to the index is granted under 
section 572 with respect to such drug but it complies with section 
505(i), 512(j), or 572(g) of the act and regulations thereunder.

No exemption shall apply to any other drug which would be a new drug if 
its labeling bore representations for its intended uses.

[40 FR 13998, Mar. 27, 1975, as amended at 72 FR 69119, Dec. 6, 2007]



Sec.  201.116  Drugs having commonly known directions.

    A drug shall be exempt from section 502(f)(1) of the act insofar as 
adequate directions for common uses thereof are known to the ordinary 
individual.

[41 FR 6910, Feb. 13, 1976]



Sec.  201.117  Inactive ingredients.

    A harmless drug that is ordinarily used as an inactive ingredient, 
such as a coloring, emulsifier, excipient, flavoring, lubricant, 
preservative, or solvent, in the preparation of other drugs shall be 
exempt from section 502(f)(1) of the act. This exemption shall not apply 
to any substance intended for a use which results in the preparation of 
a new drug, unless an approved new-drug application provides for such 
use.



Sec.  201.119  In vitro diagnostic products.

    (a) ``In vitro diagnostic products'' are those reagents, instruments 
and systems intended for use in the diagnosis of disease or in the 
determination of the state of health in order to cure, mitigate, treat, 
or prevent disease or its sequelae. Such products are intended for use 
in the collection, preparation and examination of specimens taken from 
the human body. These products are drugs or devices as defined in 
section 201(g) and 201(h), respectively, of the Federal Food, Drug, and 
Cosmetic Act (the act) or are a combination of drugs and devices, and 
may also be a biological product subject to section 351 of the Public 
Health Service Act.
    (b) A product intended for use in the diagnosis of disease and which 
is an in vitro diagnostic product as defined in paragraph (a) of this 
section shall be deemed to be in compliance with the requirements of 
this section and section 502(f)(1) of the act if it meets the 
requirements of Sec.  809.10 of this chapter.

[41 FR 6910, Feb. 13, 1976]



Sec.  201.120  Prescription chemicals and other prescription components.

    A drug prepared, packaged, and primarily sold as a prescription 
chemical or other component for use by registered pharmacists in 
compounding prescriptions or for dispensing in dosage unit form upon 
prescriptions shall be exempt from section 502(f)(1) of the act if all 
the following conditions are met:
    (a) The drug is an official liquid acid or official liquid alkali, 
or is not a liquid solution, emulsion, suspension, tablet, capsule, or 
other dosage unit form; and
    (b) The label of the drug bears:
    (1) The statement ``For prescription compounding''; and
    (2) If in substantially all dosage forms in which it may be 
dispensed it is subject to section 503(b)(1) of the act, the statement 
``Rx only''; or
    (3) If it is not subject to section 503(b)(1) of the act and is by 
custom among retail pharmacists sold in or from the interstate package 
for use by consumers, ``adequate directions for use'' in the conditions 
for which it is so sold.


Provided, however, That the information referred to in paragraph (b)(3) 
of this section may be contained in the labeling on or within the 
package from which it is to be dispensed.
    (c) This exemption shall not apply to any substance intended for use 
in compounding which results in a new

[[Page 73]]

drug, unless an approved new-drug application covers such use of the 
drug in compounding prescriptions.

[40 FR 13998, Mar. 27, 1975, as amended at 67 FR 4906, Feb. 1, 2002]



Sec.  201.122  Drugs for processing, repacking, or manufacturing.

    A drug in a bulk package, except tablets, capsules, or other dosage 
unit forms, intended for processing, repacking, or use in the 
manufacture of another drug shall be exempt from section 502(f)(1) of 
the act if its label bears the statement ``Caution: For manufacturing, 
processing, or repacking''; and if in substantially all dosage forms in 
which it may be dispensed it is subject to section 503(b)(1) of the act, 
the statement ``Rx only'', or if in substantially all dosage forms in 
which it may be dispensed it is subject to section 503(f)(1) of the act, 
the statement ``Caution: Federal law restricts this drug to use by or on 
the order of a licensed veterinarian''. This exemption and the exemption 
under Sec.  201.120 may be claimed for the same article. However, the 
exemption shall not apply to a substance intended for a use in 
manufacture, processing, or repacking which causes the finished article 
to be a new drug or new animal drug, unless:
    (a) An approved new drug application or new animal drug application 
or a new animal drug index listing covers the production and delivery of 
the drug substance to the application or index listing holder by persons 
named in the application or in the request for determination of 
eligibility for indexing, and, for a new drug substance, the export of 
it by such persons under Sec.  314.410 of this chapter; or
    (b) If no application is approved with respect to such new drug or 
new animal drug, and it is not listed in the index, the label statement 
``Caution: For manufacturing, processing, or repacking'' is immediately 
supplemented by the words ``in the preparation of a new drug or new 
animal drug limited by Federal law to investigational use'', and the 
delivery is made for use only in the manufacture of such new drug or new 
animal drug limited to investigational use as provided in part 312 or 
Sec.  511.1 or Sec.  516.125 of this chapter; or
    (c) A new drug application or new animal drug application or a 
request for addition to the index covering the use of the drug substance 
in the production and marketing of a finished drug product has been 
submitted but not yet approved, disapproved, granted, or denied, the 
bulk drug is not exported, and the finished drug product is not further 
distributed after it is manufactured until after the new drug 
application or new animal drug application is approved or the request 
for addition to the index is granted.

[41 FR 6911, Feb. 13, 1976, as amended at 41 FR 15844, Apr. 15, 1976; 50 
FR 7492, Feb. 22, 1985; 55 FR 11576, Mar. 29, 1990; 57 FR 54301, Nov. 
18, 1992; 67 FR 4906, Feb. 1, 2002; 72 FR 69119, Dec. 6, 2007]



Sec.  201.125  Drugs for use in teaching, law enforcement, research,
and analysis.

    A drug subject to Sec.  201.100 or Sec.  201.105, shall be exempt 
from section 502(f)(1) of the act if shipped or sold to, or in the 
possession of, persons regularly and lawfully engaged in instruction in 
pharmacy, chemistry, or medicine not involving clinical use, or engaged 
in law enforcement, or in research not involving clinical use, or in 
chemical analysis, or physical testing, and is to be used only for such 
instruction, law enforcement, research, analysis, or testing.

[41 FR 6911, Feb. 13, 1976]



Sec.  201.127  Drugs; expiration of exemptions.

    (a) If a shipment or delivery, or any part thereof, of a drug which 
is exempt under the regulations in this section is made to a person in 
whose possession the article is not exempt, or is made for any purpose 
other than those specified, such exemption shall expire, with respect to 
such shipment or delivery or part thereof, at the beginning of that 
shipment or delivery. The causing of an exemption to expire shall be 
considered an act which results in such drug being misbranded unless it 
is disposed of under circumstances in which it ceases to be a drug or 
device.
    (b) The exemptions conferred by Sec. Sec.  201.117, 201.119, 
201.120, 201.122, and 201.125 shall continue until the drugs are used 
for the purposes for which

[[Page 74]]

they are exempted, or until they are relabeled to comply with section 
502(f)(1) of the act. If, however, the drug is converted, compounded, or 
manufactured into a dosage form limited to prescription dispensing, no 
exemption shall thereafter apply to the article unless the dosage form 
is labeled as required by section 503(b) and Sec. Sec.  201.100 or 
201.105.

[41 FR 6911, Feb. 13, 1976]



Sec.  201.128  Meaning of ``intended uses''.

    The words intended uses or words of similar import in Sec. Sec.  
201.5, 201.115, 201.117, 201.119, 201.120, 201.122, and 1100.5 of this 
chapter refer to the objective intent of the persons legally responsible 
for the labeling of an article (or their representatives). The intent 
may be shown by such persons' expressions, the design or composition of 
the article, or by the circumstances surrounding the distribution of the 
article. This objective intent may, for example, be shown by labeling 
claims, advertising matter, or oral or written statements by such 
persons or their representatives. Objective intent may be shown, for 
example, by circumstances in which the article is, with the knowledge of 
such persons or their representatives, offered or used for a purpose for 
which it is neither labeled nor advertised; provided, however, that a 
firm would not be regarded as intending an unapproved new use for an 
approved drug based solely on that firm's knowledge that such drug was 
being prescribed or used by health care providers for such use. The 
intended uses of an article may change after it has been introduced into 
interstate commerce by its manufacturer. If, for example, a packer, 
distributor, or seller intends an article for different uses than those 
intended by the person from whom he or she received the article, such 
packer, distributor, or seller is required to supply adequate labeling 
in accordance with the new intended uses.

[86 FR 41401, Aug. 2, 2021]



Sec.  201.129  Drugs; exemption for radioactive drugs for research use.

    A radioactive drug intended for administration to human research 
subjects during the course of a research project intended to obtain 
basic research information regarding metabolism (including kinetics, 
distribution, and localization) of a radioactively labeled drug or 
regarding human physiology, pathophysiology, or biochemistry (but not 
intended for immediate therapeutic, diagnostic, or similar purposes), 
under the conditions set forth in Sec.  361.1 of this chapter, shall be 
exempt from section 502(f)(1) of the act if the packaging, label, and 
labeling are in compliance with Sec.  361.1(f) of this chapter.

[41 FR 6911, Feb. 13, 1976]



                       Subpart E_Other Exemptions



Sec.  201.150  Drugs; processing, labeling, or repacking.

    (a) Except as provided by paragraphs (b) and (c) of this section, a 
shipment or other delivery of a drug which is, in accordance with the 
practice of the trade, to be processed, labeled, or repacked in 
substantial quantity at an establishment other than that where 
originally processed or packed, shall be exempt, during the time of 
introduction into and movement in interstate commerce and the time of 
holding in such establishment, from compliance with the labeling and 
packaging requirements of sections 501(b) and 502 (b), (d), (e), (f), 
and (g) of the act if:
    (1) The person who introduced such shipment or delivery into 
interstate commerce is the operator of the establishment where such drug 
is to be processed, labeled, or repacked; or
    (2) In case such person is not such operator, such shipment or 
delivery is made to such establishment under a written agreement, signed 
by and containing the post-office addresses of such person and such 
operator, and containing such specifications for the processing, 
labeling, or repacking, as the case may be, of such drug in such 
establishment as will insure, if such specifications are followed, that 
such drug will not be adulterated or misbranded within the meaning of 
the act upon completion of such processing, labeling, or repacking. Such 
person and such operator shall each keep a copy of such agreement until 
2 years after the final shipment or delivery of such drug from such 
establishment, and shall

[[Page 75]]

make such copies available for inspection at any reasonable hour to any 
officer or employee of the Department who requests them.
    (b) An exemption of a shipment or other delivery of a drug under 
paragraph (a)(1) of this section shall, at the beginning of the act of 
removing such shipment or delivery, or any part thereof, from such 
establishment, become void ab initio if the drug comprising such 
shipment, delivery, or part is adulterated or misbranded within the 
meaning of the act when so removed.
    (c) An exemption of a shipment or other delivery of a drug under 
paragraph (a)(2) of this section shall become void ab initio with 
respect to the person who introduced such shipment or delivery into 
interstate commerce upon refusal by such person to make available for 
inspection a copy of the agreement, as required by such paragraph (a)(2) 
of this section.
    (d) An exemption of a shipment or other delivery of a drug under 
paragraph (a)(2) of this section shall expire:
    (1) At the beginning of the act of removing such shipment or 
delivery, or any part thereof, from such establishment if the drug 
comprising such shipment, delivery, or part is adulterated or misbranded 
within the meaning of the act when so removed; or
    (2) Upon refusal by the operator of the establishment where such 
drug is to be processed, labeled, or repacked, to make available for 
inspection a copy of the agreement, as required by such clause.

[41 FR 6911, Feb. 13, 1976, as amended at 64 FR 400, Jan. 5, 1999]



Sec.  201.161  Medical gases.

    (a) Oxygen, nitrogen, carbon dioxide, helium, and nitrous oxide 
gases intended for drug use, and medically appropriate combinations of 
any of these gases intended for drug use, are exempted from the 
requirements of Sec.  201.100(b)(2) and (3), and (c)(1), provided that, 
where applicable, the requirements of Sec. Sec.  201.328 and 
211.94(e)(2) of this chapter are met and the labeling bears, in addition 
to any other information required by the Federal Food, Drug, and 
Cosmetic Act, the following:
    (1)(i) In the case of oxygen, a warning statement providing that 
uninterrupted use of high concentrations of oxygen over a long duration, 
without monitoring its effect on oxygen content of arterial blood, may 
be harmful; that oxygen should not be used on patients who have stopped 
breathing unless used in conjunction with resuscitative equipment; and, 
in the case of oxygen that may be provided without a prescription for 
use in the event of depressurization or other environmental oxygen 
deficiency, or for oxygen deficiency or for use in emergency 
resuscitation when administered by properly trained personnel, a warning 
statement providing that oxygen may be used for emergency use only when 
administered by properly trained personnel for oxygen deficiency and 
resuscitation, and that for all other medical applications a 
prescription is required.
    (ii) In the case of nitrogen, carbon dioxide, helium, nitrous oxide, 
and medically appropriate combinations of any of the gases listed in 
paragraph (a) of this section, a warning statement providing that the 
administration of the gas or gas combination (as applicable) may be 
hazardous or contraindicated; and that the gas or gas combination (as 
applicable) should be used only by or under the supervision of a 
licensed practitioner who is experienced in the use and administration 
of the gas or gas combination (as applicable) and is familiar with the 
indications, effects, dosages, methods, and frequency and duration of 
administration, and with the hazards, contraindications, and side 
effects and the precautions to be taken.
    (2) Any needed directions concerning the conditions for storage and 
warnings against the inherent dangers in the handling of the specific 
compressed gas.
    (b) [Reserved]

[81 FR 81696, Nov. 18, 2016]

[[Page 76]]



       Subpart F_Labeling Claims for Drugs in Drug Efficacy Study



Sec.  201.200  Disclosure of drug efficacy study evaluations in labeling
and advertising.

    (a)(1) The National Academy of Sciences--National Research Council, 
Drug Efficacy Study Group, has completed an exhaustive review of 
labeling claims made for drugs marketed under new-drug and antibiotic 
drug procedures between 1938 and 1962. The results are compiled in 
``Drug Efficacy Study, A Report to the Commissioner of Food and Drugs 
from the National Academy of Sciences (1969).'' As the report notes, 
this review has made ``an audit of the state of the art of drug usage 
that has been uniquely extensive in scope and uniquely intensive in 
time'' and is applicable to more than 80 percent of the currently 
marketed drugs. The report further notes that the quality of the 
evidence of efficacy, as well as the quality of the labeling claims, is 
poor. Labeling and other promotional claims have been evaluated as 
``effective,'' ``probably effective,'' ``possibly effective,'' 
``ineffective,'' ``ineffective as a fixed combination,'' and ``effective 
but,'' and a report for each drug in the study has been submitted to the 
Commissioner.
    (2) The Food and Drug Administration is processing the reports, 
seeking voluntary action on the part of the drug manufacturers and 
distributors in the elimination or modification of unsupported 
promotional claims, and initiating administrative actions as necessary 
to require product and labeling changes.
    (3) Delays have been encountered in bringing to the attention of the 
prescribers of prescription items the conclusions of the expert panels 
that reviewed the promotional claims.
    (b) The Commissioner of Food and Drugs concludes that:
    (1) The failure to disclose in the labeling of a drug and in other 
promotional material the conclusions of the Academy experts that a claim 
is ``ineffective,'' ``possibly effective,'' ``probably effective,'' or 
``ineffective as a fixed combination,'' while labeling and promotional 
material bearing any such claim are being used, is a failure to disclose 
facts that are material in light of the representations made and causes 
the drug to be misbranded.
    (2) The Academy classification of a drug as other than ``effective'' 
for a claim for which such drug is recommended establishes that there is 
a material weight of opinion among qualified experts contrary to the 
representation made or suggested in the labeling, and failure to reveal 
this fact causes such labeling to be misleading.
    (c) Therefore, after publication in the Federal Register of a Drug 
Efficacy Study Implementation notice on a prescription drug, unless 
exempted or otherwise provided for in the notice, all package labeling 
(other than the immediate container or carton label, unless such 
labeling contains information required by Sec.  201.100(c)(1) in lieu of 
a package insert), promotional labeling, and advertisements shall 
include, as part of the information for practitioners under which the 
drug can be safely and effectively used, an appropriate qualification of 
all claims evaluated as other than ``effective'' by a panel of the 
National Academy of Sciences--National Research Council, Drug Efficacy 
Study Group, if such claims continue to be included in either the 
labeling or advertisements. However, this qualifying information will be 
required in advertisements only if promotional material is included 
therein for claims evaluated as less than ``effective'' or if such 
claims are included in the indications section of the portion of the 
advertisement containing the information required in brief summary by 
Sec.  202.1(e)(1) of this chapter. When, however, the Food and Drug 
Administration classification of such claim is ``effective'' (for 
example, on the basis of revision of the language of the claim or 
submission or existence of adequate data), such qualification is not 
necessary. When the Food and Drug Administration classification of the 
claim, as stated in the implementation notice, differs from that of the 
Academy but is other than ``effective,'' the qualifying statement shall 
refer to this classification in lieu of the Academy's classification.
    (d) For new drugs and antibiotics, supplements to provide for 
revised labeling in accord with paragraph (c) of

[[Page 77]]

this section shall be submitted under the provisions of Sec.  314.70 and 
Sec.  514.8 of this chapter within 90 days after publication of the 
implementation notice in the Federal Register or by May 15, 1972, for 
those drugs for which notices have been published and such labeling 
shall be put into use as soon as possible but not later than the end of 
the time period allowed for submitting supplements to provide for 
revised labeling.
    (e) Qualifying information required in drug labeling by paragraph 
(c) of this section in order to advise prescribers of a drug of the 
findings made by a panel of the Academy in evaluating a claim as other 
than ``effective'' shall be at least of the same size and color and 
degree of prominence as other printing in the labeling and shall be 
presented in a prominent box using one of the following formats and 
procedures:
    (1) In drug labeling the box statement may entirely replace the 
indications section and be in the following format:

                               Indications

    Based on a review of this drug by the National Academy of Sciences--
National Research Council and/or other information, FDA has classified 
the indication(s) as follows:
    Effective: (list or state in paragraph form).
    ``Probably'' effective: (list or state in paragraph form).
    ``Possibly'' effective: (list or state in paragraph form).
    Final classification of the less-than-effective indications requires 
further investigation.

    (2) Or the indication(s) for which the drug has been found effective 
may appear outside the boxed statement and be followed immediately by 
the following boxed statement:
    Based on a review of this drug by the National Academy of Sciences--
National Research Council and/or other information, FDA has classified 
the other indication(s) as follows:
    ``Probably'' effective: (list or state in paragraph form).
    ``Possibly'' effective: (list or state in paragraph form).
    Final classification of the less-than-effective indications requires 
further investigation.
    (3) In drug labeling (other than that which is required by Sec.  
201.100(c)(1)) which may contain a promotional message, the promotional 
message shall be keyed to the boxed statement by the same means as those 
provided for advertisements in paragraph (f)(2) of this section.
    (f) Qualifying information required in prescription drug advertising 
by paragraph (c) of this section shall contain a prominent boxed 
statement of the advertised indication(s) and of the limitations of 
effectiveness using the same format, language, and emphasis as that 
required in labeling by paragraph (e) of this section.
    (1) The boxed statement shall appear in (or next to) the information 
required in brief summary by Sec.  202.1(e)(1) of this chapter and shall 
have prominence at least equal to that provided for other information 
presented in the brief summary and shall have type size, captions, 
color, and other physical characteristics comparable to the information 
required in the brief summary.
    (2) Less-than-effective indication(s) in the promotional message of 
an advertisement which is a single page or less shall be keyed to the 
boxed statement by asterisk, by an appropriate statement, or by other 
suitable means providing adequate emphasis on the boxed statement. On 
each page where less-than-effective indication(s) appear in a mutiple 
page advertisement, an asterisk shall be placed after the most prominent 
mention of the indi- cation(s); if the degree of prominence does not 
vary, an asterisk shall be placed after the first mention of the 
indication. The asterisk shall refer to a notation at the bottom of the 
page which shall state ``This drug has been evaluated as probably 
effective (or possibly effective whichever is appropriate) for this 
indication'' and ``See Brief Summary'' or ``See Prescribing 
Information,'' the latter legend to be used only if the advertisement 
carries the required information for professional use as set forth in 
Sec.  201.100(c)(1).
    (3) For less-than-effective indications which are included in the 
advertisement only as a part of the information required in brief 
summary, the disclosure information shall appear in this portion of the 
advertisement in the

[[Page 78]]

same manner as is specified for labeling in paragraph (e) of this 
section.
    (g) The Commissioner may find circumstances are such that, while the 
elimination of claims evaluated as other than effective will generally 
eliminate the need for disclosure about such claims, there will be 
instances in which the change in the prescribing or promotional profile 
of the drug is so substantial as to require a disclosure of the reason 
for the change so that the purchaser or prescriber is not misled by 
being left unaware through the sponsor's silence that a basic change has 
taken place. The Food and Drug Administration will identify these 
situations in direct correspondence with the drug promoters, after which 
the failure to make the disclosure will be regarded as misleading and 
appropriate action will be taken.

[40 FR 13998, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990]



   Subpart G_Specific Labeling Requirements for Specific Drug Products



Sec.  201.300  Notice to manufacturers, packers, and distributors of
glandular preparations.

    (a) Under date of December 4, 1941, in a notice to manufacturers of 
glandular preparations, the Food and Drug Administration expressed the 
opinion that preparations of inert glandular materials intended for 
medicinal use should, in view of the requirement of section 201(n) of 
the Federal Food, Drug, and Cosmetic Act (52 Stat. 1041; 21 U.S.C. 
321(n)), be labeled with a statement of the material fact that there is 
no scientific evidence that the articles contain any therapeutic or 
physiologically active constituents. Numerous preparations of such inert 
glandular materials were subsequently marketed with disclaimers of the 
type suggested. The term inert glandular materials means preparations 
incapable of exerting an action or effect of some significant or 
measurable benefit in one way or another, i.e., in the diagnosis, cure, 
mitigation, treatment, or prevention of disease, or in affecting the 
structure or any function of the body.
    (b) Manufacturers have heretofore taken advantage of Sec.  201.100 
permitting omission of directions for use when the label bears the 
prescription legend. Section 201.100(c) requires that the labeling of 
the drug, which may include brochures readily available to licensed 
practitioners, bear information as to the use of the drug by 
practitioners licensed by law to administer it. Obviously, information 
adequate for the use of an inert glandular preparation is not available 
to practitioners licensed by law.
    (c) The Department of Health and Human Services is of the opinion 
that inert glandular materials may not be exempted from the requirements 
of section 502(f)(1) of the act that they bear adequate directions for 
use; and, accordingly, that their labeling must include among other 
things, representations as to the conditions for which such articles are 
intended to be used or as to the structure or function of the human body 
that they are intended to affect. Since any such representations 
offering these articles for use as drugs would be false or misleading, 
such articles will be considered to be misbranded if they are 
distributed for use as drugs.
    (d) The amended regulations provide also that in the case of drugs 
intended for parenteral administration there shall be no exemption from 
the requirement that their labelings bear adequate directions for use. 
Such inert glandular materials for parenteral use are therefore subject 
to the same comment as applies to those intended for oral 
administration.



Sec.  201.301  Notice to manufacturers, packers, and distributors of
estrogenic hormone preparations.

    Some drug preparations fabricated wholly or in part from estradiol 
and labeled as to potency in terms of international units or in terms of 
international units of estrone activity have been marketed. The 
international unit of the estrus-producing hormone was established by 
the International Conference on the Standardization of Sex Hormones at 
London, England, on August 1, 1932. This unit was defined as ``the 
specific estrus-producing activity contained in 0.1 gamma ( = 0.0001 
mg.)

[[Page 79]]

of the standard'' hydroxyketonic hormone found in urine (estrone). The 
International Conference declared that it did not recommend the 
determination of the activity of nonhydroxyketonic forms of estrogenic 
hormones in units of estrone because of the varying ratios between the 
activity of such nonhydroxyketonic estrogenic hormones and estrone, when 
measured by different methods on test animals. There is no international 
unit for measuring the activity of estradiol and no accepted 
relationship between its activity and that of estrone, either in test 
animals or in humans. The declaration of potency of estradiol in terms 
of international units or in terms of international units of estrone 
activity is therefore considered misleading, within the meaning of 21 
U.S.C. 352(a). The declaration of the estradiol content of an estrogenic 
hormone preparation in terms of weight is considered appropriate.



Sec.  201.302  Notice to manufacturers, packers, and distributors of
drugs for internal use which contain mineral oil.

    (a) In the past few years research studies have altered medical 
opinion as to the usefulness and harmfulness of mineral oil in the human 
body. These studies have indicated that when mineral oil is used orally 
near mealtime it interferes with absorption from the digestive tract of 
provitamin A and the fat-soluble vitamins A, D, and K, and consequently 
interferes with the utilization of calcium and phosphorus, with the 
result that the user is left liable to deficiency diseases. When so used 
in pregnancy it predisposes to hemorrhagic disease of the newborn.
    (b) There is accumulated evidence that the indiscriminate 
administration of mineral oil to infants may be followed by aspiration 
of the mineral oil and subsequent ``lipoid pneumonia.''
    (c) In view of these facts, the Department of Health and Human 
Services will regard as misbranded under the provisions of the Federal 
Food, Drug, and Cosmetic Act a drug for oral administration consisting 
in whole or in part of mineral oil, the labeling of which encourages its 
use in pregnancy or indicates or implies that such drug is for 
administration to infants.
    (d) It is also this Department's view that the act requires the 
labelings of such drugs to bear a warning against consumption other than 
at bedtime and against administration to infants. The following form of 
warning is suggested: ``Caution: To be taken only at bedtime. Do not use 
at any other time or administer to infants, except upon the advice of a 
physician.''
    (e) This statement of interpretation does not in any way exempt 
mineral oil or preparations containing mineral oil from complying in all 
other respects with the requirements of the Federal Food, Drug, and 
Cosmetic Act.



Sec.  201.303  Labeling of drug preparations containing significant
proportions of wintergreen oil.

    (a) Because methyl salicylate (wintergreen oil) manifests no 
toxicity in the minute amounts in which it is used as a flavoring, it is 
mistakenly regarded by the public as harmless even when taken in 
substantially larger amounts. Actually, it is quite toxic when taken in 
quantities of a teaspoonful or more. Wintergreen oil and preparations 
containing it have caused a number of deaths through accidental misuse 
by both adults and children. Children are particularly attracted by the 
odor and are likely to swallow these products when left within reach.
    (b) To safeguard against fatalities from this cause, the Department 
of Health and Human Services will regard as misbranded under the 
provisions of the Federal Food, Drug, and Cosmetic Act any drug 
containing more than 5 percent methyl salicylate (wintergreen oil), the 
labeling of which fails to warn that use otherwise than as directed 
therein may be dangerous and that the article should be kept out of 
reach of children to prevent accidental poisoning.
    (c) This statement of interpretation in no way exempts methyl 
salicylate (wintergreen oil) or its preparations from complying in all 
other respects with the requirements of the Federal Food, Drug, and 
Cosmetic Act.

[[Page 80]]



Sec.  201.304  Tannic acid and barium enema preparations.

    (a) It has become a widespread practice for tannic acid to be added 
to barium enemas to improve X-ray pictures. Tannic acid is capable of 
causing diminished liver function and severe liver necrosis when 
absorbed in sufficient amounts. The medical literature reports a number 
of deaths associated with the addition of tannic acid to barium enemas. 
There is a lack of scientific evidence to establish the conditions, if 
any, under which tannic acid is safe and effective for use in enemas. 
Tannic acid for rectal use to enhance X-ray visualization is regarded as 
a new drug within the meaning of section 201(p) of the Federal Food, 
Drug, and Cosmetic Act.
    (b) In view of the hazards involved when tannic acid is used in 
barium enemas, any shipments of tannic acid labeled to come within the 
exemptions under 502(f) of the Act containing such phrases as: 
``Caution: For manufacturing, processing, or repackaging,'' ``For 
prescription compounding,'' or ``Diagnostic reagent--For professional 
use only'' will be regarded by the Commissioner of Food and Drugs as 
misbranded within the meaning of section 502(f) of the Federal Food, 
Drug, and Cosmetic Act unless the label and the labeling bear 
conspicuously a warning to the effect: ``Warning-- Not for use in 
enemas.''
    (c) Any tannic acid intended for use by man and found within the 
jurisdiction of the Federal Food, Drug, and Cosmetic Act labeled 
contrary to this section after 60 days from the date of its publication 
in the Federal Register may be made the subject of regulatory 
proceedings.



Sec.  201.305  Isoproterenol inhalation preparations (pressurized 
aerosols, nebulizers, powders) for human use; warnings.

    (a) Accumulating reports have been received by the Food and Drug 
Administration and have appeared in the medical literature of severe 
paradoxical bronchoconstriction associated with repeated, excessive use 
of isoproterenol inhalation preparations in the treatment of bronchial 
asthma and other chronic bronchopulmonary disorders. The cause of this 
paradoxical reaction is unknown; it has been observed, however, that 
patients have not responded completely to other forms of therapy until 
use of the isoproterenol inhalation preparation was discontinued. In 
addition, sudden unexpected deaths have been associated with the 
excessive use of isoproterenol inhalation preparations. The mechanism of 
these deaths and their relationship, if any, to the cases of severe 
paradoxical bronchospasm are not clear. Cardiac arrest was noted in 
several of these cases of sudden death.
    (b) On the basis of the above information and after discussion with 
and concurrence of the Respiratory and Anesthetic Drugs Advisory 
Committee for Food and Drug Administration, the Commissioner of Food and 
Drugs concludes that in order for the labeling of such drugs to bear 
adequate information for their safe use, as required by Sec.  201.100, 
such labeling must include the following:

    Warning: Occasional patients have been reported to develop severe 
paradoxical airway resistance with repeated, excessive use of 
isoproterenol inhalation preparations. The cause of this refractory 
state is unknown. It is advisable that in such instances the use of this 
preparation be discontinued immediately and alternative therapy 
instituted, since in the reported cases the patients did not respond to 
other forms of therapy until the drug was withdrawn.
    Deaths have been reported following excessive use of isoproterenol 
inhalation preparations and the exact cause is unknown. Cardiac arrest 
was noted in several instances.

    (c)(1) The Commissioner also concludes that in view of the manner in 
which these preparations are self-administered for relief of attacks of 
bronchial asthma and other chronic bronchopulmonary disorders, it is 
necessary for the protection of users that warning information to 
patients be included as a part of the label and as part of any 
instructions to patients included in the package dispensed to the 
patient as follows:

    Warning: Do not exceed the dose prescribed by your physician. If 
difficulty in breathing persists, contact your physician immediately.

    (2) The warning on the label may be accomplished (i) by including it 
on the

[[Page 81]]

immediate container label with a statement directed to pharmacists not 
to remove the label or (ii) by including in the package a printed 
warning with instructions to pharmacists to place the warning on the 
container prior to dispensing.
    (d) The marketing of isoproterenol inhalation preparations may be 
continued if all the following conditions are met:
    (1) Within 30 days following the date of publication of this section 
in the Federal Register:
    (i) The label and labeling of such preparations shipped within the 
jurisdiction of the act are in accordance with paragraphs (b) and (c) of 
this section.
    (ii) The holder of an approved new-drug application for such 
preparation submits a supplement to his new-drug application to provide 
for appropriate labeling changes as described in paragraphs (b) and (c) 
of this section.
    (2) Within 90 days following the date of publication of this section 
in the Federal Register, the manufacturer, packer, or distributor of any 
drug containing isoproterenol intended for inhalation for which a new-
drug approval is not in effect submits a new-drug application containing 
satisfactory information of the kinds required by Sec.  314.50 of this 
chapter, including appropriate labeling as described in paragraphs (b) 
and (c) of this section.
    (3) The applicant submits additional information required for the 
approval of the application as may be specified in a written 
communication from the Food and Drug Administration.
    (e) After 270 days following expiration of said 90 days, regulatory 
proceedings based on section 505(a) of the Federal Food, Drug, and 
Cosmetic Act may be initiated with regard to any such drug shipped 
within the jurisdiction of the act for which an approved new-drug 
application is not in effect.

[40 FR 13998, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990]



Sec.  201.306  Potassium salt preparations intended for oral ingestion
by man.

    (a) The Food and Drug Administration will initiate no regulatory 
action with respect to the continued marketing of coated tablets 
containing potassium chloride or other potassium salts which supply 100 
milligrams or more of potassium per tablet provided all the following 
conditions are met:
    (1) Within 30 days from the date of publication of this statement of 
policy in the Federal Register:
    (i) The labeling of the drug bears the prescription caution 
statement quoted in section 503(b)(4) of the Federal Food, Drug, and 
Cosmetic Act;
    (ii) The labeling on or within the package from which the drug is to 
be dispensed bears adequate information for its use by practitioners in 
accord with the ``full disclosure'' labeling requirements of Sec.  
201.100 of this chapter, including the following warning statement:

    Warning--There have been several reports, published and unpublished, 
concerning nonspecific small-bowel lesions consisting of stenosis, with 
or without ulceration, associated with the administration of enteric-
coated thiazides with potassium salts. These lesions may occur with 
enteric-coated potassium tablets alone or when they are used with 
nonenteric-coated thiazides, or certain other oral diuretics. These 
small-bowel lesions have caused obstruction, hemorrhage, and 
perforation. Surgery was frequently required and deaths have occurred. 
Based on a large survey of physicians and hospitals, both United States 
and foreign, the incidence of these lesions is low, and a causal 
relationship in man has not been definitely established. Available 
information tends to implicate enteric-coated potassium salts, although 
lesions of this type also occur spontaneously. Therefore, coated 
potassium-containing formulations should be administered only when 
indicated, and should be discontinued immediately if abdominal pain, 
distention, nausea, vomiting, or gastrointestinal bleeding occur. Coated 
potassium tablets should be used only when adequate dietary 
supplementation is not practicable.


(Although the warning statement includes references to enteric-coated 
potassium salt preparations, it applies to any capsule or coated tablet 
of a potassium salt intended for oral ingestion without prior dilution 
with an adequate volume of liquid to preclude gastrointestinal injury.)
    (iii) Any other labeling or additional advertising for the drug 
conforms to the labeling described in paragraph (a)(1)(ii) of this 
section, in accordance with Sec. Sec.  202.1 and 201.100 of this 
chapter.

[[Page 82]]

    (2) Within 90 days from the date of publication of this statement of 
policy in the Federal Register, the manufacturer, packer, or distributor 
of the drug shall submit a new-drug application containing satisfactory 
information of the kind required by Sec.  314.50 of this chapter, with 
appropriate labeling as described in this paragraph.
    (b) The Food and Drug Administration may initiate regulatory 
proceedings after 30 days from the date of publication of this section, 
with respect to the marketing of uncoated tablets containing potassium 
chloride or other potassium salts which supply 100 milligrams or more of 
potassium per tablet or with respect to liquid preparations containing 
potassium chloride or other potassium salts which supply 20 milligrams 
or more of potassium per milliliter, labeled or intended for human use, 
unless all the following conditions are met:
    (1) The labeling of the drug bears the prescription statement quoted 
in section 503(b)(4) of the Federal Food, Drug, and Cosmetic Act; and
    (2) The labeling on or within the package from which the drug is to 
be dispensed bears adequate information for its use by practitioners in 
accord with the ``full disclosure'' labeling requirements of Sec.  
201.100 of this chapter, including a recommendation that patients be 
directed to dissolve any such tablets in an appropriate amount of liquid 
and to dilute any such liquid preparations adequately to assure against 
gastrointestinal injury associated with the oral ingestion of 
concentrated potassium salt preparations.

[40 FR 13998, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990; 
67 FR 4906, Feb. 1, 2002]



Sec.  201.307  Sodium phosphates; package size limitation, warnings,
and directions for over-the-counter sale.

    (a) Reports in the medical literature and data accumulated by the 
Food and Drug Administration indicate that multiple container sizes of 
sodium phosphates oral solution available in the marketplace have caused 
consumer confusion and appear to have been involved in several consumer 
deaths. Sodium phosphates oral solution has been marketed in 45-
milliliter (mL), 90-mL, and 240-mL container sizes. The 45-mL and 90-mL 
container sizes of sodium phosphates oral solution are often recommended 
and prescribed by physicians for bowel cleansing prior to surgery and 
diagnostic procedures of the colon. Sodium phosphates oral solution 
(adult dose 20 mL to 45 mL) is also used as an over-the-counter (OTC) 
laxative for the relief of occasional constipation. Accidental 
overdosing and deaths have occurred because the 240-mL container was 
mistakenly used instead of the 45-mL or 90-mL container. The Food and 
Drug Administration is limiting the amount of sodium phosphates oral 
solution to not more than 90 mL (3 ounces (oz)) per OTC container 
because of the serious health risks associated with the ingestion of 
larger than intended doses of this product. Further, because an overdose 
of either oral or rectal enema sodium phosphates can cause an 
electrolyte imbalance, additional warning and direction statements are 
required for the safe use of any OTC laxative drug product containing 
sodium phosphates.
    (b) Any OTC drug product for laxative or bowel cleansing use 
containing sodium phosphates as an active ingredient when marketed as 
described in paragraph (a) of this section is misbranded within the 
meaning of section 502 of the Federal Food, Drug, and Cosmetic Act 
unless packaged and labeled as follows:
    (1) Package size limitation for sodium phosphates oral solution: 
Container shall not contain more than 90 mL (3 oz).
    (2) Warnings. The following sentences shall appear in boldface type 
as the first statement under the heading ``Warnings.''
    (i) Oral dosage forms. ``Taking more than the recommended dose in 24 
hours can be harmful.''
    (ii) Rectal enema dosage forms. ``Using more than one enema in 24 
hours can be harmful.''
    (3) Directions--(i) The labeling of all orally or rectally 
administered OTC drug products containing sodium phosphates shall 
contain the following directions in boldface type immediately preceding 
the dosage information: ``Do not'' (``take'' or ``use'')

[[Page 83]]

``more unless directed by a doctor. See Warnings.''
    (ii) For products containing dibasic sodium phosphate/monobasic 
sodium phosphate identified in Sec.  334.16(d) marketed as a solution. 
Adults and children 12 years of age and over: Oral dosage is dibasic 
sodium phosphate 3.42 to 7.56 grams (g) and monobasic sodium phosphate 
9.1 to 20.2 g (20 to 45 mL dibasic sodium phosphate/monobasic sodium 
phosphate oral solution) as a single daily dose. ``Do not take more than 
45 mL (9 teaspoonfuls or 3 tablespoonfuls) in a 24-hour period.'' 
Children 10 and 11 years of age: Oral dosage is dibasic sodium phosphate 
1.71 to 3.78 g and monobasic sodium phosphate 4.5 to 10.1 g (10 to 20 mL 
dibasic sodium phosphate/monobasic sodium phosphate oral solution) as a 
single daily dose. ``Do not take more than 20 mL (4 teaspoonfuls) in a 
24-hour period.'' Children 5 to 9 years of age: Oral dosage is dibasic 
sodium phosphate 0.86 to 1.89 g and monobasic sodium phosphate 2.2 to 
5.05 g (5 to 10 mL dibasic sodium phosphate/monobasic sodium phosphate 
oral solution) as a single daily dose. ``Do not take more than 10 mL (2 
teaspoonfuls) in a 24-hour period.'' Children under 5 years of age: ask 
a doctor.
    (c) After June 22, 1998, for package size limitation and September 
18, 1998, for labeling in accord with paragraph (b) of this section, any 
such OTC drug product initially introduced or initially delivered for 
introduction into interstate commerce, or any such drug product that is 
repackaged or relabeled after these dates regardless of the date the 
product was manufactured, initially introduced, or initially delivered 
for introduction into interstate commerce, that is not in compliance 
with this section is subject to regulatory action.

[63 FR 27843, May 21, 1998]



Sec.  201.308  Ipecac syrup; warnings and directions for use for 
over-the-counter sale.

    (a) It is estimated that each year about 500,000 accidental 
poisonings occur in the United States and result in approximately 1,500 
deaths, of which over 400 are children. In the emergency treatment of 
these poisonings, ipecac syrup is considered the emetic of choice. The 
immediate availability of this drug for use in such situations is 
critical, since rapid treatment may be the difference between life and 
death. The restriction of this drug to prescription sale limits its 
availability in emergencies. On the other hand, it is the consensus of 
informed medical opinion that ipecac syrup should be used only under 
medical supervision in the emergency treatment of poisonings. In view of 
these facts, the question of whether ipecac syrup labeled as an 
emergency treatment for use in poisonings should be available over the 
counter has been controversial.
    (b) In connection with its study of this problem, the Food and Drug 
Administration has obtained the views of medical authorities. It is the 
unanimous recommendation of the American Academy of Pediatrics, the 
American Association of Poison Control Centers, the American Medical 
Association, and the Medical Advisory Board of the Food and Drug 
Administration that ipecac syrup in 1 fluid ounce containers be 
permitted to be sold without prescription so that it will be readily 
available in the household for emergency treatment of poisonings, under 
medical supervision, and that the drug be appropriately packaged and 
labeled for this purpose.
    (c) In view of the above recommendations, the Commissioner of Food 
and Drugs has determined that it is in the interest of the public health 
for ipecac syrup to be available for sale without prescription, provided 
that it is packaged in a quantity of 1 fluid ounce (30 milliliters), and 
its label bears, in addition to other required label information, the 
following, in a prominent and conspicuous manner:
    (1) A statement conspicuously boxed and in red letters, to the 
effect: ``For emergency use to cause vomiting in poisoning. Before 
using, call physician, the Poison Control Center, or hospital emergency 
room immediately for advice.''
    (2) A warning to the effect: ``Warning--Keep out of reach of 
children. Do not use in unconscious persons. Ordinarily, this drug 
should not be used if strychnine, corrosives such as alkalies (lye) and 
strong acids, or petroleum

[[Page 84]]

distillates such as kerosine, gasoline, coal oil, fuel oil, paint 
thinner, or cleaning fluid have been ingested.''
    (3) Usual dosage: 1 tablespoon (15 milliliters) in persons over 1 
year of age.



Sec.  201.309  Acetophenetidin (phenacetin)-containing preparations;
necessary warning statement.

    (a) In 1961, the Food and Drug Administration, pursuant to its 
statutory responsibility for the safety and effectiveness of drugs 
shipped in interstate commerce, began an active investigation of reports 
of possible toxic effects and renal damage due to misuse of the drug 
acetophenetidin. This study led to the decision that there was probable 
cause to conclude that misuse and prolonged use of the drug were in fact 
responsible for kidney lesions and disease. The Commissioner of Food and 
Drugs, in December 1963, appointed an ad hoc Advisory Committee of 
Inquiry on Possible Nephrotoxicity Associated With the Abuse of 
Acetophenetidin (Phenacetin)-Containing Preparations. This committee, 
composed of scientists in the fields of pharmacology and medicine, on 
April 23, 1964, submitted its findings and conclusions in the matter and 
recommended that all acetophenetidin (phenacetin)-containing 
preparations bear a warning as provided in section 502(f)(2) of the 
Federal Food, Drug, and Cosmetic Act.
    (b) On the basis of the studies made by the Food and Drug 
Administration and the report of the Advisory Committee, the 
Commissioner of Food and Drugs has concluded that it is necessary for 
the protection of users that the label and labeling of all 
acetophenetidin (phenacetin)-containing preparations bear a warning 
statement to the following effect: ``Warning--This medication may damage 
the kidneys when used in large amounts or for a long period of time. Do 
not take more than the recommended dosage, nor take regularly for longer 
than 10 days without consulting your physician.''



Sec.  201.310  Phenindione; labeling of drug preparations intended for
use by man.

    (a) Reports in the medical literature and data accumulated by the 
Food and Drug Administration indicate that phenindione, a synthetic 
anticoagulant drug, has caused a number of cases of agranulocytosis 
(with two fatalities). There are also reports implicating the drug in 
cases of hepatitis and hypersensitivity reactions. In view of the 
potentially serious effects found to be associated with preparations of 
this drug intended for use by man, the Commissioner of Food and Drugs 
will regard such preparations as misbranded within the meaning of 
section 502(f) (1) and (2) of the Federal Food, Drug, and Cosmetic Act, 
unless the label and labeling on or within the package from which the 
drug is to be dispensed, and any other labeling furnishing or purporting 
to furnish information for use of the drug, bear a conspicuous warning 
statement to the following effect: ``Warning: Agranulocytosis and 
hepatitis have been associated with the use of phenindione. Patients 
should be instructed to report promptly prodromal symptoms such as 
marked fatigue, chill, fever, and sore throat. Periodic blood studies 
and liver function tests should be performed. Use of the drug should be 
discontinued if leukopenia occurs or if evidence of hypersensitivity, 
such as dermatitis or fever, appears.''
    (b) Regulatory action may be initiated with respect to preparations 
of phenindione intended for use by man found within the jurisdiction of 
the act on or after November 25, 1961, unless such preparations are 
labeled in accordance with paragraph (a) of this section.



Sec.  201.311  [Reserved]



Sec.  201.312  Magnesium sulfate heptahydrate; label declaration on
drug products.

    Magnesium sulfate heptahydrate should be listed on the label of a 
drug product as epsom salt, which is its common or usual name.



Sec.  201.313  Estradiol labeling.

    The article presently recognized in The National Formulary under the 
heading ``Estradiol'' and which is said to be ``17-cis-beta estradiol'' 
is the same substance formerly recognized in the United States 
Pharmacopeia under the designation ``Alpha Estradiol.'' The

[[Page 85]]

substance should no longer be referred to in drug labeling as ``Alpha 
Estradiol.'' The Food and Drug Administration would not object to label 
references to the article as simply ``Estradiol''; nor would it object 
if the label of a preparation containing this substance referred to the 
presence of ``Estradiol (formerly known as Alpha Estradiol).''



Sec.  201.314  Labeling of drug preparations containing salicylates.

    (a) The label of any oral drug preparation intended for sale without 
prescription and which contains any salicylate ingredient (including 
aspirin, salicylamide, other salicylates, and combinations) must 
conspicuously bear, on a clearly contrasting background, the warning 
statement: ``Keep out of reach of children [highlighted in bold type]. 
In case of overdose, get medical help or contact a Poison Control Center 
right away,'' or ``Keep out of reach of children [highlighted in bold 
type],'' except that if the article is an aspirin preparation, it shall 
bear the first of these warning statements. Such a warning statement is 
required for compliance with section 502(f)(2) of the Federal Food, 
Drug, and Cosmetic Act and is intended to guard against accidental 
poisonings. Safety closures that prevent access to the drug by young 
children are also recommended to guard against accidental poisonings.
    (b) Effervescent preparations and preparations containing para-
aminosalicylate as the only salicylate ingredient are exempted from this 
labeling requirement.
    (c) Aspirin tablets sold as such and containing no other active 
ingredients, except tablets which cannot be readily subdivided into a 
child's dose because of their coating or size, should always bear dosage 
directions for each age group down to 3 years of age, with a statement 
such as ``For children under 3 years of age, consult your physician.'' 
It is recommended that:
    (1) Aspirin tablets especially made for pediatric use be produced 
only in 1\1/4\-grain size to reduce the hazard of errors in dosage;
    (2) By June 1, 1967, manufacturers and distributors of 1\1/4\-grain 
size aspirin tablets discontinue the distribution of such tablets in 
retail containers containing more than 36 tablets, to reduce the hazard 
of accidental poisoning;
    (3) The flavoring of 5-grain aspirin tablets or other ``adult 
aspirin tablets'' be discontinued; and
    (4) Labeling giving undue emphasis to the pleasant flavor of 
flavored aspirin tablets be discontinued.
    (d) Salicylate preparations other than aspirin tablets sold as such 
may, at the option of the distributor, be labeled for use by adults 
only. If their labeling and advertising clearly offer them for 
administration to adults only.
    (e)(1) It is the obligation of the distributor who labels a 
salicylate preparation for administration to children to make certain 
that the article is suitable for such use and labeled with adequate 
directions for use in the age group for which it is offered, but in no 
case should such an article bear directions for use in children under 3 
years of age. If the directions provide for administration to children 
as young as 3 years of age, the label should bear the statement, ``For 
children under 3 years of age consult your physician.'' However, if the 
directions provide for administration to children only of an age greater 
than 3 years (for example, the dosage instructions provide for 
administration of the article to children only down to age 6), the label 
should bear a statement such as, ``For younger children consult your 
physician.''
    (2) A statement such as, ``For children under 3 years of age consult 
your physician'' or ``For younger children consult your physician'' is 
not required on the label of an article clearly offered for 
administration to adults only.
    (f) If the labeling or advertising of a salicylate preparation 
offers it for use in arthritis or rheumatism, the label and labeling 
should clearly state that the beneficial effects claimed are limited to: 
``For the temporary relief of minor aches and pains of arthritis and 
rheumatism.'' The qualifying phrase ``for the temporary relief of minor 
aches and pains'' should appear with the same degree of prominence and 
conspicuousness as the phrase ``arthritis and rheumatism''. The label 
and labeling should bear in juxtaposition

[[Page 86]]

with such directions for use conspicuous warning statements to the 
effect: ``Caution: If pain persists for more than 10 days, or redness is 
present, or in conditions affecting children under 12 years of age, 
consult a physician immediately.'' The salicylate dosage should not 
exceed 60 grains in a 24-hour period or 10 grains in a 4-hour period. If 
the article contains other analgesics, the salicylate dosage should be 
appropriately reduced.
    (g)(1) The label of any drug containing more than 5 percent methyl 
salicylate (wintergreen oil) should bear a conspicuous warning such as: 
``Do not use otherwise than as directed.'' These drug products must also 
include the ``Keep out of reach of children'' warning and the accidental 
ingestion warning as required in Sec.  330.1(g) of this chapter.
    (2) If the preparation is a counterirritant or rubefacient, it 
should also bear a caution such as, ``Caution: Discontinue use if 
excessive irritation of the skin develops. Avoid getting into the eyes 
or on mucous membranes.'' (See also Sec.  201.303.)
    (h)(1) The labeling of orally or rectally administered over-the-
counter drug products containing aspirin or nonaspirin salicylates as 
active ingredients subject to this paragraph is required to prominently 
bear the following warning: ``Reye's syndrome [subheading in bold type]: 
Children and teenagers who have or are recovering from chicken pox or 
flu-like symptoms should not use this product. When using this product, 
if changes in behavior with nausea and vomiting occur, consult a doctor 
because these symptoms could be an early sign of Reye's syndrome, a rare 
but serious illness.''
    (2) This warning statement shall appear on the immediate container 
labeling. In cases where the immediate container is not the retail 
package, the retail package also must bear the warning statement. In 
addition, the warning statement shall appear on any labeling that 
contains warnings and, in such cases, the warning statement shall be the 
first warning statement under the heading ``Warnings.''
    (3) Over-the-counter drug products subject to this paragraph and 
labeled solely for use by children (pediatric products) shall not 
recommend the product for use in treating flu or chicken pox.
    (4) Any product subject to paragraphs (h)(1), (h)(2), and (h)(3) of 
this section that is not labeled as required by these paragraphs and 
that is initially introduced or initially delivered for introduction 
into interstate commerce after the following dates is misbranded under 
sections 201(n) and 502(a) and (f) of the Federal Food, Drug, and 
Cosmetic Act.
    (i) Compliance by October 18, 2004, for OTC drug products containing 
aspirin and nonaspirin salicylates as an active ingredient and marketed 
under a new drug application or abbreviated new drug application.
    (ii) Compliance by April 19, 2004, for OTC antidiarrheal and 
overindulgence drug products that contain bismuth subsalicylate as an 
active ingredient and have annual sales greater than $25,000.
    (iii) Compliance by April 18, 2005, for OTC antidiarrheal and 
overindulgence drug products that contain bismuth subsalicylate as an 
active ingredient and have annual sales less than $25,000.
    (iv) Compliance dates for all other OTC drug products containing 
aspirin and nonaspirin salicylates as an active ingredient and marketed 
under an OTC drug monograph (for internal analgesic, antipyretic, and 
antirheumatic drug products, or for menstrual drug products) will be 
established when the final monographs for those products are published 
in a future issue of the Federal Register. In the interim, these 
products should continue to be labeled with the previous Reye's syndrome 
warning that appears in paragraph (h)(1) of this section.

[40 FR 13998, Mar. 27, 1985, as amended at 51 FR 8182, Mar. 7, 1986; 53 
FR 21637, June 9, 1988; 53 FR 24830, June 30, 1988; 64 FR 13291, Mar. 
17, 1999; 65 FR 8, Jan. 3, 2000; 68 FR 18869, Apr. 17, 2003]



Sec.  201.315  Over-the-counter drugs for minor sore throats;
suggested warning.

    The Food and Drug Administration has studied the problem of the 
labeling of lozenges or troches containing a local anesthetic, chewing 
gum containing aspirin, various mouth washes

[[Page 87]]

and gargles and other articles sold over the counter for the relief of 
minor irritations of the mouth or throat. It will not object to the 
labeling of suitable articles of this type ``For the temporary relief of 
minor sore throats'', provided this is immediately followed in the 
labeling with a warning statement in prominent type essentially as 
follows: ``Warning--Severe or persistent sore throat or sore throat 
accompanied by high fever, headache, nausea, and vomiting may be 
serious. Consult physician promptly. Do not use more than 2 days or 
administer to children under 3 years of age unless directed by 
physician.''



Sec.  201.316  Drugs with thyroid hormone activity for human use;
required warning.

    (a) Drugs with thyroid hormone activity have been promoted for, and 
continue to be dispensed and prescribed for, use in the treatment of 
obesity, although their safety and effectiveness for that use have never 
been established.
    (b) Drugs for human use with thyroid hormone activity are misbranded 
within the meaning of section 502 of the Federal Food, Drug, and 
Cosmetic Act unless their labeling bears the following boxed warning at 
the beginning of the ``Warnings'' section:

   ------------------------------------------------------------------
         Drugs with thyroid hormone activity, alone or together 
      with other therapeutic agents, have been used for the 
      treatment of obesity. In euthyroid patients, doses within 
      the range of daily hormonal requirements are ineffective for 
      weight reduction. Larger doses may produce serious or even 
      life-threatening manifestations of toxicity, particularly 
      when given in association with sympatho mimetic amines such 
      as those used for their anorectic effects.

   ------------------------------------------------------------------

[43 FR 22009, May 23, 1978]



Sec.  201.317  Digitalis and related cardiotonic drugs for human use
in oral dosage forms; required warning.

    (a) Digitalis and related cardiotonic drugs for human use in oral 
dosage forms have been promoted for, and continue to be dispensed and 
prescribed for, use in the treatment of obesity, although their safety 
and effectiveness for that use have never been established.
    (b) Digitalis and related cardiotonic drugs for human use in oral 
dosage forms are misbranded within the meaning of section 502 of the 
Federal Food, Drug, and Cosmetic Act unless their labeling bears the 
following boxed warning at the beginning of the ``Warnings'' section:

   ------------------------------------------------------------------
         Digitalis alone or with other drugs has been used in the 
      treatment of obesity. This use of digoxin or other digitalis 
      glycosides is unwarranted. Moreover, since they may cause 
      potentially fatal arrhythmias or other adverse effects, the 
      use of these drugs in the treatment of obesity is dangerous.

   ------------------------------------------------------------------
    (c) This section does not apply to digoxin products for oral use.

[43 FR 22009, May 23, 1978, as amended at 85 FR 72907, Nov. 16, 2020]



Sec.  201.319  Water-soluble gums, hydrophilic gums, and hydrophilic
mucilloids (including, but not limited to agar, alginic acid, calcium 
polycarbophil, 
          carboxymethylcellulose sodium, carrageenan, chondrus, 
          glucomannan ((B-1,4 linked) polymannose acetate), guar gum, 
          karaya gum, kelp, methylcellulose, plantago seed (psyllium), 
          polycarbophil tragacanth, and xanthan gum) as active 
          ingredients; required warnings and directions.

    (a) Reports in the medical literature and data accumulated by the 
Food and Drug Administration indicate that esophageal obstruction and 
asphyxiation have been associated with the ingestion of water-soluble 
gums, hydrophilic gums, and hydrophilic mucilloids including, but not 
limited to, agar, alginic acid, calcium polycarbophil, 
carboxymethylcellulose sodium, carrageenan, chondrus, glucomannan ((B-
1,4 linked) polymannose acetate), guar gum, karaya gum, kelp, 
methylcellulose, plantago seed (psyllium), polycarbophil, tragacanth, 
and xanthan gum. Esophageal obstruction and asphyxiation due to orally-
administered drug products containing water-

[[Page 88]]

soluble gums, hydrophilic gums, and hydrophilic mucilloids as active 
ingredients are significant health risks when these products are taken 
without adequate fluid or when they are used by individuals with 
esophageal narrowing or dysfunction, or with difficulty in swallowing. 
Additional labeling is needed for the safe and effective use of any OTC 
drug product for human use containing a water-soluble gum, hydrophilic 
gum, or hydrophilic mucilloid as an active ingredient when marketed in a 
dry or incompletely hydrated form to include, but not limited to, the 
following dosage forms: Capsules, granules, powders, tablets, and 
wafers. Granular dosage forms containing psyllium are not generally 
recognized as safe and effective as OTC laxatives (see Sec.  
310.545(a)(12)(i)(B) of this chapter) and may not be marketed without an 
approved new drug application because the warnings and directions in 
paragraph (b) of this section have been found inadequate for these 
products.
    (b) Any drug products for human use containing a water-soluble gum, 
hydrophilic gum, or hydrophilic mucilloid as an active ingredient in an 
oral dosage form when marketed in a dry or incompletely hydrated form as 
described in paragraph (a) of this section are misbranded within the 
meaning of section 502 of the Federal Food, Drug, and Cosmetic Act 
unless their labeling bears the following warnings (under the subheading 
``Choking'') and directions:
    `` `Choking' [highlighted in bold type]: Taking this product without 
adequate fluid may cause it to swell and block your throat or esophagus 
and may cause choking. Do not take this product if you have difficulty 
in swallowing. If you experience chest pain, vomiting, or difficulty in 
swallowing or breathing after taking this product, seek immediate 
medical attention;'' and
    `` `Directions' [highlighted in bold type]:'' (Select one of the 
following, as appropriate: ``Take'' or ``Mix'') ``this product (child or 
adult dose) with at least 8 ounces (a full glass) of water or other 
fluid. Taking this product without enough liquid may cause choking. See 
choking warning.''

    (c) After February 28, 1994, any such OTC drug product initially 
introduced or initially delivered for introduction into interstate 
commerce, or any such drug product that is repackaged or relabeled after 
this date regardless of the date the product was manufactured, initially 
introduced, or initially delivered for introduction into interstate 
commerce, that is not in compliance with this section is subject to 
regulatory action.

[58 FR 45201, Aug. 26, 1993, as amended at 64 FR 13292, Mar. 17, 1999; 
72 FR 14674, Mar. 29, 2007]



Sec.  201.320  Warning statements for drug products containing or
manufactured with chlorofluorocarbons or other ozone-depleting
substances.

    (a)(1) All drug products containing or manufactured with 
chlorofluorocarbons, halons, carbon tetrachloride, methyl chloride, or 
any other class I substance designated by the Environmental Protection 
Agency (EPA) shall, except as provided in paragraph (b) or (c) of this 
section, bear the following warning statement:

    Warning: Contains [or Manufactured with, if applicable] [insert name 
of substance], a substance which harms public health and the environment 
by destroying ozone in the upper atmosphere.

    (2) The warning statement shall be clearly legible and conspicuous 
on the product, its immediate container, its outer packaging, or other 
labeling in accordance with the requirements of 40 CFR part 82 and 
appear with such prominence and conspicuousness as to render it likely 
to be read and understood by consumers under normal conditions of 
purchase.
    (b)(1) For prescription drug products for human use, the following 
alternative warning statement may be used:

    Note: The indented statement below is required by the Federal 
government's Clean Air Act for all products containing or manufactured 
with chlorofluorocarbons (CFC's) [or name of other class I substance, if 
applicable]:

    This product contains [or is manufactured with, if applicable] 
[insert name of substance], a substance which harms the environment by 
destroying ozone in the upper atmosphere.
    Your physician has determined that this product is likely to help 
your personal

[[Page 89]]

health. USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE 
BY YOUR PHYSICIAN. If you have any questions about alternatives, consult 
with your physician.

    (2) The warning statement shall be clearly legible and conspicuous 
on the product, its immediate container, its outer packaging, or other 
labeling in accordance with the requirements of 40 CFR part 82 and 
appear with such prominence and conspicuousness as to render it likely 
to be read and understood by consumers under normal conditions of 
purchase.
    (3) If the warning statement in paragraph (b)(1) of this section is 
used, the following warning statement must be placed on the package 
labeling intended to be read by the physician (physician package insert) 
after the ``How supplied'' section, which describes special handling and 
storage conditions on the physician labeling:

    Note: The indented statement below is required by the Federal 
government's Clean Air Act for all products containing or manufactured 
with chlorofluorocarbons (CFC's) [or name of other class I substance, if 
applicable]:

    Warning: Contains [or Manufactured with, if applicable] [insert name 
of substance], a substance which harms public health and the environment 
by destroying ozone in the upper atmosphere.
    A notice similar to the above WARNING has been placed in the 
information for the patient [or patient information leaflet, if 
applicable] of this product under the Environmental Protection Agency's 
(EPA's) regulations. The patient's warning states that the patient 
should consult his or her physician if there are questions about 
alternatives.

    (c)(1) For over-the-counter drug products for human use, the 
following alternative warning statement may be used:

    Note: The indented statement below is required by the Federal 
government's Clean Air Act for all products containing or manufactured 
with chlorofluorocarbons (CFC's) [or other class I substance, if 
applicable]:

    Warning: Contains [or Manufactured with, if applicable] [insert name 
of substance], a substance which harms public health and environment by 
destroying ozone in the upper atmosphere.
    CONSULT WITH YOUR PHYSICIAN OR HEALTH PROFESSIONAL IF YOU HAVE ANY 
QUESTION ABOUT THE USE OF THIS PRODUCT.

    (2) The warning statement shall be clearly legible and conspicuous 
on the product, its immediate container, its outer packaging, or other 
labeling in accordance with the requirements of 40 CFR part 82 and 
appear with such prominence and conspicuousness as to render it likely 
to be read and understood by consumers under normal conditions of 
purchase.
    (d) This section does not replace or relieve a person from any 
requirements imposed under 40 CFR part 82.

[61 FR 20100, May 3, 1996]



Sec.  201.323  Aluminum in large and small volume parenterals used
in total parenteral nutrition.

    (a) The aluminum content of large volume parenteral (LVP) drug 
products used in total parenteral nutrition (TPN) therapy must not 
exceed 25 micrograms per liter ([micro]g/L).
    (b) The package insert of LVP's used in TPN therapy must state that 
the drug product contains no more than 25 [micro]g/L of aluminum. This 
information must be contained in the ``Precautions'' section of the 
labeling of all large volume parenterals used in TPN therapy.
    (c) Except as provided in paragraph (d) of this section, the maximum 
level of aluminum present at expiry must be stated on the immediate 
container label of all small volume parenteral (SVP) drug products and 
pharmacy bulk packages (PBPs) used in the preparation of TPN solutions. 
The aluminum content must be stated as follows: ``Contains no more than 
__ [micro]g/L of aluminum.'' The immediate container label of all SVP's 
and PBP's that are lyophilized powders used in the preparation of TPN 
solutions must contain the following statement: ``When reconstituted in 
accordance with the package insert instructions, the concentration of 
aluminum will be no more than __ [micro]g/L.'' This maximum level of 
aluminum must be stated as the highest of:
    (1) The highest level for the batches produced during the last 3 
years;
    (2) The highest level for the latest five batches, or

[[Page 90]]

    (3) The maximum historical level, but only until completion of 
production of the first five batches after July 26, 2004.
    (d) If the maximum level of aluminum is 25 [micro]g/L or less, 
instead of stating the exact amount of aluminum as required in paragraph 
(c) of this section, the immediate container label may state: ``Contains 
no more than 25 [micro]g/L of aluminum.'' If the SVP or PBP is a 
lyophilized powder, the immediate container label may state: ``When 
reconstituted in accordance with the package insert instructions, the 
concentration of aluminum will be no more than 25 [micro]g/L''.
    (e) The package insert for all LVP's, all SVP's, and PBP's used in 
TPN must contain a warning statement. This warning must be contained in 
the ``Warnings'' section of the labeling. The warning must state:

    WARNING: This product contains aluminum that may be toxic. Aluminum 
may reach toxic levels with prolonged parenteral administration if 
kidney function is impaired. Premature neonates are particularly at risk 
because their kidneys are immature, and they require large amounts of 
calcium and phosphate solutions, which contain aluminum.
    Research indicates that patients with impaired kidney function, 
including premature neonates, who receive parenteral levels of aluminum 
at greater than 4 to 5 [micro]g/kg/day accumulate aluminum at levels 
associated with central nervous system and bone toxicity. Tissue loading 
may occur at even lower rates of administration.

    (f) Applicants and manufacturers must use validated assay methods to 
determine the aluminum content in parenteral drug products. The assay 
methods must comply with current good manufacturing practice 
requirements. Applicants must submit to the Food and Drug Administration 
validation of the method used and release data for several batches. 
Manufacturers of parenteral drug products not subject to an approved 
application must make assay methodology available to FDA during 
inspections. Holders of pending applications must submit an amendment 
under Sec.  314.60 or Sec.  314.96 of this chapter.

[65 FR 4110, Jan. 26, 2000, as amended at 67 FR 70691, Nov. 26, 2002; 68 
FR 32981, June 3, 2003]



Sec.  201.325  Over-the-counter drugs for vaginal contraceptive and
spermicide use containing nonoxynol 9 as the active ingredient; 
required warnings and labeling information.

    (a) Studies indicate that use of vaginal contraceptive drug products 
containing nonoxynol 9 does not protect against infection from the human 
immunodeficiency virus (HIV), the virus that causes acquired 
immunodeficiency syndrome (AIDS), or against the transmission of other 
sexually transmitted diseases (STDs). Studies also indicate that use of 
vaginal contraceptive drug products containing nonoxynol 9 can increase 
vaginal irritation, such as the disruption of the vaginal epithelium, 
and also can cause epithelial disruption when used in the rectum. These 
effects may increase the risk of transmission of the AIDS virus (HIV) 
from an infected partner. Therefore, consumers should be warned that 
these products do not protect against the transmission of the AIDS virus 
(HIV) or other STDs, that use of these products can increase vaginal and 
rectal irritation, which may increase the risk of getting the AIDS virus 
(HIV) from an HIV infected partner, and that the products are not for 
rectal use. Consumers should also be warned that these products should 
not be used by persons who have HIV/AIDS or are at high risk for HIV/
AIDS.
    (b) The labeling of OTC vaginal contraceptive and spermicide drug 
products containing nonoxynol 9 as the active ingredient, whether 
subject to the ongoing OTC drug review or an approved drug application, 
must contain the following warnings under the heading ``Warnings,'' in 
accordance with 21 CFR 201.66.
    (1) ``[bullet] For vaginal use only [bullet] Not for rectal (anal) 
use'' [both warnings in bold type].
    (2) ``Sexually transmitted diseases (STDs) alert [in bold type]: 
This product does not [word ``not'' in bold type] protect against HIV/
AIDS or other STDs and may increase the risk of getting HIV from an 
infected partner''.
    (3) ``Do not use'' [in bold type] if you or your sex partner has 
HIV/AIDS. If you do not know if you or your sex

[[Page 91]]

partner is infected, choose another form of birth control''.
    (4) ``When using this product [in bold type] [optional, bullet] you 
may get vaginal irritation (burning, itching, or a rash)''.
    (5) ``Stop use and ask a doctor if [in bold type] [optional, bullet] 
you or your partner get burning, itching, a rash, or other irritation of 
the vagina or penis''.
    (c) The labeling of this product states under the ``Other 
information'' section of the Drug Facts labeling in accordance with 
Sec.  201.66(c)(7), ``[bullet] when used correctly every time you have 
sex, latex condoms greatly reduce, but do not eliminate, the risk of 
catching or spreading HIV, the virus that causes AIDS.
    (d) The labeling of this product includes the following statements 
either on the outside container or wrapper of the retail package, under 
the ``Other information'' section of the Drug Facts labeling in 
accordance with Sec.  201.66(c)(7), or in a package insert:
    (1) ``[bullet] studies have raised safety concerns that products 
containing the spermicide nonoxynol 9 can irritate the vagina and 
rectum. Sometimes this irritation has no symptoms. This irritation may 
increase the risk of getting HIV/AIDS from an infected partner''.
    (2) ``[bullet] you can use nonoxynol 9 for birth control with or 
without a diaphragm or condom if you have sex with only one partner who 
is not infected with HIV and who has no other sexual partners or HIV 
risk factors''.
    (3) ``[bullet] use a latex condom without nonoxynol 9 if you or your 
sex partner has HIV/AIDS, multiple sex partners, or other HIV risk 
factors''.
    (4) ``[bullet] ask a health professional if you have questions about 
your best birth control and STD prevention methods''.
    (e) Any drug product subject to this section that is not labeled as 
required and that is initially introduced or initially delivered for 
introduction into interstate commerce after June 19, 2008, is misbranded 
under section 502 of the Federal Food, Drug, and Cosmetic Act (the act) 
(21 U.S.C. 352), is a new drug under section 505 of the act (21 U.S.C. 
355), and is subject to regulatory action.

[72 FR 71785, Dec. 19, 2007]



Sec.  201.326  Over-the-counter drug products containing internal
analgesic/antipyretic active ingredients; required warnings and other
labeling.

    (a) Labeling. The labeling for all over-the-counter (OTC) drug 
products containing any internal analgesic/antipyretic active 
ingredients (including, but not limited to, acetaminophen, aspirin, 
carbaspirin calcium, choline salicylate, ibuprofen, ketoprofen, 
magnesium salicylate, naproxen sodium, and sodium salicylate) alone or 
in combination must bear the following labeling in accordance with 
Sec. Sec.  201.60, 201.61, and 201.66.
    (1) Acetaminophen--(i) Statement of identity. The statement of 
identity appears in accord with Sec. Sec.  201.61 and 299.4 of this 
chapter. The ingredient name ``acetaminophen'' must appear highlighted 
(e.g., fluorescent or color contrast) or in bold type, be in lines 
generally parallel to the base on which the package rests as it is 
designed to be displayed, and be in one of the following sizes, 
whichever is greater:
    (A) At least one-quarter as large as the size of the most prominent 
printed matter on the principal display panel (PDP), or
    (B) At least as large as the size of the ``Drug Facts'' title, as 
required in Sec.  201.66(d)(2). The presence of acetaminophen must 
appear as part of the established name of the drug, as defined in Sec.  
299.4 of this chapter. Combination products containing acetaminophen and 
a nonanalgesic ingredient(s) (e.g., cough-cold) must include the name 
``acetaminophen'' and the name(s) of the other active ingredient(s) in 
the product on the PDP in accord with this paragraph. Only the name 
``acetaminophen'' must appear highlighted or in bold type, and in a 
prominent print size, as described in this paragraph.
    (ii) Active Ingredient and Purpose Headings. The information 
required under Sec.  201.66(c)(2) and (c)(3) of this chapter must be 
included under these headings. The information under these headings, but 
not the headings, may appear highlighted.

[[Page 92]]

    (iii) For products labeled for adults only. The labeling of the 
product states the following warnings under the heading ``Warnings'':
    (A) The liver warning states ``Liver warning [heading in bold type]: 
This product contains acetaminophen. Severe liver damage may occur if 
you take [bullet] more than [insert maximum number of daily dosage 
units] in 24 hours, which is the maximum daily amount [optional: `for 
this product'] [bullet] with other drugs containing acetaminophen 
[bullet] 3 or more alcoholic drinks every day while using this 
product''. This ``Liver'' warning must be the first warning under the 
``Warnings'' heading. For products that contain both acetaminophen and 
aspirin, this ``Liver'' warning must appear after the ``Reye's 
syndrome'' and ``Allergy alert'' warnings in Sec.  201.66(c)(5)(ii)(A) 
and (c)(5)(ii)(B) and before the ``Stomach bleeding'' warning in 
paragraph (a)(2)(iii)(A) of this section. If there is an outer and 
immediate container of a retail package, this warning must appear on 
both the outer and immediate containers. If the immediate container is a 
blister card, the warning must appear on the blister card and remain 
intact and readable when drug product is removed from the blister card. 
The warning does not need to be included on each blister unit.
    (B) ``Do not use with any other drug containing acetaminophen 
(prescription or nonprescription). If you are not sure whether a drug 
contains acetaminophen, ask a doctor or pharmacist.''
    (C) ``Ask a doctor before use if you have liver disease''.
    (D) ``Ask a doctor or pharmacist before use if you are taking the 
blood thinning drug warfarin'' except on the labeling of combination 
products that contain acetaminophen and NSAID(s).
    (iv) For products labeled only for children under 12 years of age.
    (A) Warnings. The labeling of the product states the following 
warnings under the heading ``Warnings'':
    (1) The liver warning states ``Liver warning [heading in bold type]: 
This product contains acetaminophen. Severe liver damage may occur if 
your child takes [bullet] more than 5 doses in 24 hours, which is the 
maximum daily amount [optional: `for this product'] [bullet] with other 
drugs containing acetaminophen''. This ``Liver'' warning must be the 
first warning under the ``Warnings'' heading. If there is an outer and 
immediate container of a retail package, this warning must appear on 
both the outer and immediate containers. If the immediate container is a 
blister card, the warning must appear on the blister card and remain 
intact and readable when drug product is removed from the blister card. 
The warning is not required to be included on each blister unit.
    (2) ``Do not use with any other drug containing acetaminophen 
(prescription or nonprescription). If you are not sure whether a drug 
contains acetaminophen, ask a doctor or pharmacist.''
    (3) ``Ask a doctor before use if your child has liver disease''.
    (4) ``Ask a doctor or pharmacist before use if your child is taking 
the blood thinning drug warfarin'' except on the labeling of combination 
products that contain acetaminophen and NSAID(s).
    (B) Directions. The labeling of the product contains the following 
information under the heading ``Directions'': ``this product does not 
contain directions or complete warnings for adult use'' [in bold type].
    (v) For products labeled for adults and children under 12 years of 
age. The labeling of the product states all of the warnings in 
paragraphs (a)(1)(iii)(A), (a)(1)(iii)(B), and (a)(1)(iii)(C) of this 
section with the following modifications:
    (A) The liver warning states ``Liver warning [heading in bold type]: 
This product contains acetaminophen. Severe liver damage may occur if 
[bullet] adult takes more than [insert maximum number of daily dosage 
units] in 24 hours, which is the maximum daily amount [optional: `for 
this product'] [bullet] child takes more than 5 doses in 24 hours 
[bullet] taken with other drugs containing acetaminophen [bullet] adult 
has 3 or more alcoholic drinks everyday while using this product.'' If 
there is an outer and immediate container of a retail package, this 
warning must appear on both the outer and immediate containers. If the 
immediate container is a blister card, the warning must appear on the 
blister

[[Page 93]]

card and remain intact and readable when drug product is removed from 
the blister card. The warning is not required to be included on each 
blister unit.
    (B) ``Ask a doctor before use if the user has liver disease.''
    (C) ``Do not use with any other drug containing acetaminophen 
(prescription or nonprescription). If you are not sure whether a drug 
contains acetaminophen, ask a doctor or pharmacist.''
    (D) ``Ask a doctor or pharmacist before use if the user is taking 
the blood thinning drug warfarin'' except on the labeling of combination 
products that contain acetaminophen and NSAID(s).
    (2) Nonsteroidal anti-inflammatory analgesic/antipyretic active 
ingredients--including, but not limited to, aspirin, carbaspirin 
calcium, choline salicylate, ibuprofen, ketoprofen, magnesium 
salicylate, naproxen sodium, and sodium salicylate.
    (i) Statement of identity. The statement of identity appears in 
accord with Sec. Sec.  201.61 and 299.4 of this chapter. The word 
``(NSAID)'' must appear highlighted (e.g., fluorescent or color 
contrast) or in bold type, be in lines generally parallel to the base on 
which the package rests as it is designed to be displayed, and be in one 
of the following sizes, whichever is greater:
    (A) At least one-quarter as large as the size of the most prominent 
printed matter on the PDP, or
    (B) At least as large as the size of the ``Drug Facts'' title, as 
required in Sec.  201.66(d)(2). The word ``(NSAID)'' must appear as part 
of the established name of the drug, as defined in Sec.  299.4 of this 
chapter, or after the general pharmacological (principal intended) 
action of the NSAID ingredient. Combination products containing an NSAID 
and a nonanalgesic ingredient(s) (e.g., cough-cold) must include the 
name of the NSAID ingredient and the word ``(NSAID)'' in accordance with 
this paragraph, and the name(s) of the other active ingredient(s) in the 
product on the PDP. Only the word ``(NSAID)'' needs to appear 
highlighted or in bold type, and in a prominent print size, as described 
in this paragraph.
    (ii) Active Ingredient and Purpose Headings. The information 
required under Sec.  201.66(c)(2) and (c)(3) of this chapter must be 
included under these headings. The active ingredient(s) section of the 
product's labeling, as defined in Sec.  201.66(c)(2), contains the term 
``(NSAID*)'' after the NSAID active ingredient with an asterisk 
statement at the end of the active ingredient(s) section that defines 
the term ``NSAID'' and states ``* nonsteroidal anti-inflammatory drug.'' 
The information under these headings may appear highlighted. However, 
the headings ``Active Ingredient'' and ``Purpose'' may not appear 
highlighted.
    (iii) For products labeled for adults only. The labeling of the 
product states the following warnings under the heading ``Warnings'':
    (A) The stomach bleeding warning states ``Stomach bleeding warning 
[heading in bold type]: This product contains an NSAID, which may cause 
severe stomach bleeding. The chance is higher if you [bullet] are age 60 
or older [bullet] have had stomach ulcers or bleeding problems [bullet] 
take a blood thinning (anticoagulant) or steroid drug [bullet] take 
other drugs containing prescription or nonprescription NSAIDs (aspirin, 
ibuprofen, naproxen, or others) [bullet] have 3 or more alcoholic drinks 
every day while using this product [bullet] take more or for a longer 
time than directed''. This ``Stomach bleeding'' warning must appear 
after the ``Reye's syndrome'' and ``Allergy alert'' warnings in Sec.  
201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). For products that contain both 
acetaminophen and aspirin, the acetaminophen ``Liver'' warning in 
paragraph (a)(1)(iii) of this section must appear before the ``Stomach 
bleeding'' warning in this paragraph. If there is an outer and immediate 
container of a retail package, this warning must appear on both the 
outer and immediate containers. If the immediate container is a blister 
card, the warning must appear on the blister card and remain intact and 
readable when drug product is removed from the blister card. The warning 
is not required to be included on each blister unit.
    (B) ``Ask a doctor before use if [bullet] stomach bleeding warning 
applies to you [bullet] you have a history of stomach problems, such as 
heartburn

[[Page 94]]

[bullet] you have high blood pressure, heart disease, liver cirrhosis, 
or kidney disease [bullet] you are taking a diuretic''.
    (C) ``Stop use and ask a doctor if [bullet] you experience any of 
the following signs of stomach bleeding:'' [add the following as second 
level of statements: ``[bullet] feel faint [bullet] vomit blood [bullet] 
have bloody or black stools [bullet] have stomach pain that does not get 
better''].
    (iv) For products labeled only for children under 12 years of age.
    (A) Warnings. The labeling of the product states the following 
warnings under the heading ``Warnings'':
    (1) The stomach bleeding warning states ``Stomach bleeding warning 
[heading in bold type]: This product contains an NSAID, which may cause 
severe stomach bleeding. The chance is higher if your child [bullet] has 
had stomach ulcers or bleeding problems [bullet] takes a blood thinning 
(anticoagulant) or steroid drug [bullet] takes other drugs containing 
prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or 
others) [bullet] takes more or for a longer time than directed''. The 
``Stomach bleeding'' warning must appear after the ``Reye's syndrome'' 
and ``Allergy alert'' warnings in Sec.  201.66(c)(5)(ii)(A) and 
(c)(5)(ii)(B). If there is an outer and immediate container of a retail 
package, this warning must appear on both the outer and immediate 
containers. If the immediate container is a blister card, the warning 
must appear on the blister card and remain intact and readable when drug 
product is removed from the blister card. The warning is not required to 
be included on each blister unit.
    (2) ``Ask a doctor before use if [bullet] stomach bleeding warning 
applies to your child [bullet] child has a history of stomach problems, 
such as heartburn [bullet] child has not been drinking fluids [bullet] 
child has lost a lot of fluid due to vomiting or diarrhea [bullet] child 
has high blood pressure, heart disease, liver cirrhosis, or kidney 
disease [bullet] child is taking a diuretic''.
    (3) ``Stop use and ask a doctor if [bullet] child experiences any of 
the following signs of stomach bleeding:'' [add the following as second 
level of statements: [bullet] feels faint [bullet] vomits blood [bullet] 
has bloody or black stools [bullet] has stomach pain that does not get 
better''].
    (B) Directions. The labeling of the product contains the following 
information under the heading ``Directions'': ``this product does not 
contain directions or complete warnings for adult use'' [in bold type].
    (v) For products labeled for adults and children under 12 years of 
age. The labeling of the product states all of the warnings in 
paragraphs (a)(2)(iii)(A) through (a)(2)(iii)(C) of this section with 
the following modifications:
    (A) The Stomach bleeding warning states ``Stomach bleeding warning 
[heading in bold type]: This product contains an NSAID, which may cause 
severe stomach bleeding. The chance is higher if the user [bullet] has 
had stomach ulcers or bleeding problems [bullet] takes a blood thinning 
(anticoagulant) or steroid drug [bullet] takes other drugs containing 
prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or 
others) [bullet] takes more or for a longer time than directed [bullet] 
is age 60 or older [bullet] has 3 or more alcoholic drinks everyday 
while using this product''. The ``Stomach bleeding'' warning must appear 
after the ``Reye's syndrome`` and ``Allergy alert'' warnings in Sec.  
201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). If there is an outer and 
immediate container of a retail package, this warning must appear on 
both the outer and immediate containers. If the immediate container is a 
blister card, the warning must appear on the blister card and remain 
intact and readable when drug product is removed from the blister card. 
The warning is not required to be included on each blister unit.
    (B) The labeling states ``Ask a doctor before use if [bullet] 
stomach bleeding warning applies to user [bullet] user has history of 
stomach problems, such as heartburn [bullet] user has high blood 
pressure, heart disease, liver cirrhosis, or kidney disease [bullet] 
user takes a diuretic [bullet] user has not been drinking fluids 
[bullet] user has lost a lot of fluid due to vomiting or diarrhea''.

[[Page 95]]

    (C) The labeling states ``Stop use and ask a doctor if [bullet] user 
experiences any of the following signs of stomach bleeding:'' [add the 
following as second level of statements: [bullet] feels faint [bullet] 
vomits blood [bullet] has bloody or black stools [bullet] has stomach 
pain that does not get better''].
    (b) New warnings information statement. The labeling of any drug 
product subject to this section that is initially introduced or 
initially delivered for introduction into interstate commerce before or 
on April 29, 2010, must bear on its PDP, as defined in Sec.  201.60, the 
statement ``See new warnings information''. This statement must appear 
highlighted (e.g., fluorescent or color contrast) or in bold type, be in 
lines generally parallel to the base on which the package rests as it is 
designed to be displayed, and be in one of the following sizes, 
whichever is greater:
    (1) At least one-quarter as large as the size of the most prominent 
printed matter on the PDP, or
    (2) At least as large as the size of the ``Drug Facts'' title, as 
required in Sec.  201.66(d)(2). The new warnings information statement 
must remain on the PDP of the drug product for at least 1 year from the 
date the product is initially introduced into interstate commerce.
    (c) Requirements to supplement approved application. Holders of 
approved applications for OTC drug products that contain internal 
analgesic/antipyretic active ingredients that are subject to the 
requirements of paragraph (a) of this section must submit supplements 
under Sec.  314.70(c) of this chapter to include the required 
information in the product's labeling. Such labeling may be put into use 
without advance approval of FDA provided it includes at least the exact 
information included in paragraph (a) of this section.

[74 FR 19407, Apr. 29, 2009, as amended at 74 FR 31180, June 30, 2009; 
74 FR 61514, Nov. 25, 2009]



Sec.  201.327  Over-the-counter sunscreen drug products; required
labeling based on effectiveness testing.

    The following provisions apply to sunscreen products containing 
aminobenzoic acid, avobenzone, cinoxate, dioxybenzone, ensulizole, 
homosalate, meradimate, octinoxate, octisalate, octocrylene, oxybenzone, 
padimate O, sulisobenzone, titanium dioxide, trolamine salicylate, or 
zinc oxide, alone or in combination. The provisions do not apply to 
sunscreen products marketed under approved new drug applications or 
abbreviated new drug applications.
    (a) Principal display panel. In addition to the statement of 
identity in paragraph (b) of this section, the following labeling shall 
be prominently placed on the principal display panel:
    (1) Effectiveness claim--(i) For products that pass the broad 
spectrum test in paragraph (j) of this section. (A) The labeling states 
``Broad Spectrum SPF [insert numerical SPF value resulting from testing 
under paragraph (i) of this section]''.
    (B) Prominence. The Broad Spectrum SPF statement shall appear as 
continuous text with no intervening text or graphic. The entire text 
shall appear in the same font style, size, and color with the same 
background color.
    (ii) For sunscreen products that do not pass the broad spectrum test 
in paragraph (j) of this section. The labeling states ``SPF [insert 
numerical SPF value resulting from testing under paragraph (i) of this 
section]''. The entire text shall appear in the same font style, size, 
and color with the same background color.
    (2) Water resistance statements--(i) For products that provide 40 
minutes of water resistance according to the test in paragraph (i)(7)(i) 
of this section. The labeling states ``Water Resistant (40 minutes)''.
    (ii) For products that provide 80 minutes of water resistance 
according to the test in paragraph (i)(7)(ii) of this section. The 
labeling states ``Water Resistant (80 minutes)''.
    (b) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the drug as a 
``sunscreen.''
    (c) Indications. The labeling of the product states, under the 
heading ``Uses,'' the phrases listed in this paragraph (c), as 
appropriate. Other truthful and nonmisleading statements, describing 
only the uses that have been established and listed in this paragraph

[[Page 96]]

(c), may also be used, as provided in Sec.  330.1(c)(2) of this chapter, 
subject to the provisions of section 502 of the Federal Food, Drug, and 
Cosmetic Act (the FD&C Act) relating to misbranding and the prohibition 
in section 301(d) of the FD&C Act against the introduction or delivery 
for introduction into interstate commerce of unapproved new drugs in 
violation of section 505(a) of the FD&C Act.
    (1) For all sunscreen products, the following indication statement 
must be included under the heading ``Uses'': ``[Bullet] helps prevent 
sunburn''. See Sec.  201.66(b)(4) of this chapter for definition of 
bullet.
    (2) For sunscreen products with a Broad Spectrum SPF value of 15 or 
higher according to the tests in paragraphs (i) and (j) of this section, 
the labeling may include the following statement in addition to the 
indication in Sec.  201.327(c)(1): ``[Bullet] if used as directed with 
other sun protection measures (see Directions [in bold italic font]), 
decreases the risk of skin cancer and early skin aging caused by the 
sun''.
    (3) Any labeling or promotional materials that suggest or imply that 
the use, alone, of any sunscreen reduces the risk of or prevents skin 
cancer or early skin aging will cause the product to be misbranded under 
section 502 of the FD&C Act (21 U.S.C. 352).
    (d) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings''.
    (1) For all sunscreen products. (i) The labeling states ``Do not use 
[bullet] on damaged or broken skin''.
    (ii) The labeling states ``When using this product [bullet] keep out 
of eyes. Rinse with water to remove.''
    (iii) The labeling states ``Stop use and ask a doctor if [bullet] 
rash occurs''.
    (2) For sunscreen products that are broad spectrum with SPF values 
of at least 2 but less than 15 according to the SPF test in paragraph 
(i) of this section or that do not pass the broad spectrum test in 
paragraph (j) of this section. The first statement under the heading 
``Warnings'' states ``Skin Cancer/Skin Aging Alert [in bold font]; 
Spending time in the sun increases your risk of skin cancer and early 
skin aging. This product has been shown only to help prevent sunburn, 
not [in bold font] skin cancer or early skin aging.''
    (e) Directions. The labeling of the product contains the following 
statements, as appropriate, under the heading ``Directions.'' More 
detailed directions applicable to a particular product formulation may 
also be included.
    (1) For all sunscreen products. (i) As an option, the labeling may 
state ``For sunscreen use:''.
    (ii) The labeling states ``[bullet] apply [select one of the 
following: `Liberally' or `generously'] [and, as an option: `And 
evenly'] 15 minutes before sun exposure''.
    (iii) As an option, the labeling may state ``[bullet] apply to all 
skin exposed to the sun''.
    (iv) The labeling states ``[bullet] children under 6 months of age: 
Ask a doctor''.
    (2) For sunscreen products with a Broad Spectrum SPF value of 15 or 
higher according to the tests in paragraphs (i) and (j) of this section. 
The labeling states ``[bullet] Sun Protection Measures. [in bold font] 
Spending time in the sun increases your risk of skin cancer and early 
skin aging. To decrease this risk, regularly use a sunscreen with a 
Broad Spectrum SPF value of 15 or higher and other sun protection 
measures including: [Bullet] limit time in the sun, especially from 10 
a.m.-2 p.m. [bullet] wear long-sleeved shirts, pants, hats, and 
sunglasses''.
    (3) For products that satisfy the water resistance test in paragraph 
(i)(7) of this section. The labeling states ``[bullet] reapply: [Bullet] 
after [select one of the following determined by water resistance test: 
`40 minutes of' or `80 minutes of'] swimming or sweating [bullet] 
immediately after towel drying [bullet] at least every 2 hours''.
    (4) For products that do not satisfy the water resistance test in 
paragraph (i)(7) of this section. The labeling states ``[bullet] reapply 
at least every 2 hours [bullet] use a water resistant sunscreen if 
swimming or sweating''.
    (f) Other information. The labeling of the product contains the 
following statement under the heading ``Other information:'' ``[bullet] 
protect the product in this container from excessive heat and direct 
sun''.

[[Page 97]]

    (g) False and misleading claims. There are claims that would be 
false and/or misleading on sunscreen products. These claims include but 
are not limited to the following: ``Sunblock,'' ``sweatproof,'' and 
``waterproof.'' These or similar claims will cause the product to be 
misbranded under section 502 of the FD&C Act (21 U.S.C. 352).
    (h) Labeling of products containing a combination of sunscreen and 
skin protectant active ingredients. Statements of identity, indications, 
warnings, and directions for use, respectively, applicable to each 
ingredient in the product may be combined to eliminate duplicative words 
or phrases so that the resulting information is clear and 
understandable. Labeling provisions in Sec.  347.50(e) of this chapter 
shall not apply to these products.
    (i) SPF test procedure--(1) UV source (solar simulator). (i) 
Emission spectrum. A single port or multiport solar simulator should be 
filtered so that it provides a continuous emission spectrum from 290 to 
400 nanometers (nm) with a limit of 1,500 Watts per square meter (W/
m\2\) on total irradiance for all wavelengths between 250 and 1,400 nm.
    (A) The solar simulator should have the following percentage of 
erythema-effective radiation in each specified range of wavelengths:

                    Solar Simulator Emission Spectrum
------------------------------------------------------------------------
                                                       Percent erythemal
                Wavelength range (nm)                   contribution \1\
------------------------------------------------------------------------
<290.................................................               <0.1
290-300..............................................            1.0-8.0
290-310..............................................          49.0-65.0
290-320..............................................          85.0-90.0
290-330..............................................          91.5-95.5
290-340..............................................          94.0-97.0
290-400..............................................         99.9-100.0
------------------------------------------------------------------------
\1\ Calculation of erythema action spectrum described in Sec.
  201.327(i)(1)(ii) of this section.

    (B) In addition, UVA II (320-340 nm) irradiance should equal or 
exceed 20 percent of the total UV (290-400 nm) irradiance. UVA I (340-
400 nm) irradiance should equal or exceed 60 percent of the total UV 
irradiance.
    (ii) Erythema action spectrum. (A) Calculate the erythema action 
spectrum weighting factor (Vi) at each wavelength [lambda]:
    (1) Vi ([lambda]) = 1.0 (250 <[lambda] <=298 nm)
    (2) Vi ([lambda]) = 10\0.094\* (\298\-[lambda]) 
(298 <[lambda] <=328 nm)
    (3) Vi ([lambda]) = 10\0.015\* (\140\-[lambda]) 
(328 <[lambda] <=400 nm)
    (B) Calculate the erythema-effective UV dose (E) delivered by a 
solar simulator as follows:
[GRAPHIC] [TIFF OMITTED] TR17JN11.002

Where Vi([lambda]) = erythema action spectrum weighting 
          factor at each wavelength [lambda]
I([lambda]) = irradiance (Watts per square meter) at each wavelength 
          [lambda]
t = exposure time (seconds)


Erythema-effective dose (E) is expressed as effective Joules per square 
meter (J/m\2\-eff).

    (C) The emission spectrum must be determined using a handheld 
radiometer with a response weighted to match the spectrum in ISO 17166 
CIE S 007/E entitled ``Erythemal reference action spectrum and standard 
erythema dose,'' dated 1999 (First edition, 1999-12-15; corrected and 
reprinted 2000-11-15), which is incorporated by reference in accordance 
with 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain a copy from the 
ISO Copyright Office, Case Postale 56, CH-1211, Geneva 20, Switzerland, 
telephone +41-22-749-01-11 or fax +41-22-74-09-47. http://www.iso.org. 
You may inspect a copy at the Center for Drug Evaluation and Research, 
10903 New Hampshire Ave., Bldg. 22, Silver Spring, MD 20993, call 301-
796-2090, or at the National Archives and Records Administration (NARA). 
For information on the availability of this material at NARA, call 202-
741-6030, or go to: http://www.archives.gov/federal_register/
code_of_federal_regulations/ibr_locations.html. The solar simulator 
output should be measured before and after each phototest or, at a 
minimum, at the beginning and end of each test day. This radiometer 
should be calibrated using side-by-side comparison with the 
spectroradiometer (using the weighting factors determined according to 
paragraph (i)(1)(ii)(A) of this section) at the time of the annual 
spectroradiometric measurement of the solar simulator as described in 
paragraph (i)(1)(iv) of this section.
    (iii) Operation. A solar simulator should have no significant time-
related fluctuations (within 20 percent) in radiation emissions after an 
appropriate warm-up time and demonstrate good

[[Page 98]]

beam uniformity (within 20 percent) in the exposure plane. The delivered 
dose to the UV exposure site must be within 10 percent of the expected 
dose.
    (iv) Periodic measurement. To ensure that the solar simulator 
delivers the appropriate spectrum of UV radiation, the emission spectrum 
of the solar simulator should be measured at least annually with an 
appropriate and accurately calibrated spectroradiometer system (results 
should be traceable to the National Institute for Standards and 
Technology). In addition, the solar simulator must be recalibrated if 
there is any change in the lamp bulb or the optical filtering components 
(i.e., filters, mirrors, lenses, collimating devices, or focusing 
devices). Daily solar simulator radiation intensity should be monitored 
with a broadband radiometer with a response weighted to match the 
erythema action spectrum in ISO 17166 CIE S 007/E entitled ``Erythemal 
reference action spectrum and standard erythema dose,'' which is 
incorporated by reference in paragraph (i)(1)(ii)(C) of this section. If 
a lamp must be replaced due to failure or aging during a phototest, 
broadband device readings consistent with those obtained for the 
original calibrated lamp will suffice until measurements can be 
performed with the spectroradiometer at the earliest possible 
opportunity.
    (2) SPF standard--(i) Preparation. The SPF standard should be a 
formulation containing 7-percent padimate O and 3-percent oxybenzone.

          Composition of the Padimate O/oxybenzone SPF Standard
------------------------------------------------------------------------
                                                              Percent by
                        Ingredients                             weight
------------------------------------------------------------------------
Part A:
  Lanolin..................................................         4.50
  Cocoa butter.............................................         2.00
  Glyceryl monostearate....................................         3.00
  Stearic acid.............................................         2.00
  Padimate O...............................................         7.00
  Oxybenzone...............................................         3.00
Part B:
  Purified water USP.......................................        71.60
  Sorbitol solution........................................         5.00
  Triethanolamine, 99 percent..............................         1.00
  Methylparaben............................................         0.30
  Propylparaben............................................         0.10
Part C:
  Benzyl alcohol...........................................         0.50
Part D:
  Purified water USP.......................................       QS \1\
------------------------------------------------------------------------
\1\ Quantity sufficient to make 100 grams.

    Step 1. Add the ingredients of Part A into a suitable stainless 
steel kettle equipped with a propeller agitator. Mix at 77 to 82 [deg]C 
until uniform.
    Step 2. Add the water of Part B into a suitable stainless steel 
kettle equipped with a propeller agitator and begin mixing at 77 to 82 
[deg]C. Add the remaining ingredients of Part B and mix until uniform.
    Step 3. Add the batch of Step 1 to the batch of Step 2 and mix at 77 
to 82 [deg]C until smooth and uniform. Slowly cool the batch to 49 to 54 
[deg]C.
    Step 4. Add the benzyl alcohol of Part C to the batch of Step 3 at 
49 to 54 [deg]C. Mix until uniform. Continue to cool batch to 35 to 41 
[deg]C.
    Step 5. Add sufficient water of Part D to the batch of Step 4 at 35 
to 41 [deg]C to obtain 100 grams of SPF standard. Mix until uniform. 
Cool batch to 27 to 32 [deg]C.
    (ii) HPLC assay. Use the following high performance liquid 
chromatography (HPLC) procedure to verify the concentrations of padimate 
O and oxybenzone in the SPF standard:
    (A) Instrumentation. (1) Equilibrate a suitable liquid chromatograph 
to the following or equivalent conditions:

------------------------------------------------------------------------
 
------------------------------------------------------------------------
(i) Column................................  C-18, 250 millimeters (mm)
                                             length, 4.6 mm inner
                                             diameter (5 microns)
(ii) Mobile Phase.........................  85:15:0.5 methanol: water:
                                             acetic acid
(iii) Flow Rate...........................  1.5 milliliters (mL) per
                                             minute
(iv) Temperature..........................  Ambient
(v) Detector..............................  UV spectrophotometer at 308
                                             nanometers
(vi) Attenuation..........................  As needed
------------------------------------------------------------------------

    (2) Use HPLC grade reagents for mobile phase.
    (B) Preparation of the HPLC reference standard. (1) Weigh 0.50 gram 
(g) of oxybenzone USP reference standard into a 250-mL volumetric flask. 
Dissolve and dilute to volume with isopropanol. Mix well.
    (2) Weigh 0.50 g of padimate O USP reference standard into a 250-mL 
volumetric flask. Dissolve and dilute to volume with isopropanol. Mix 
well.

[[Page 99]]

    (3) Pipet 3.0 mL of the oxybenzone solution and 7.0 mL of the 
padimate O solution into a 100-mL volumetric flask. Dilute to volume 
with isopropanol and mix well.
    (C) HPLC system suitability. (1) Make three replicate 10-microliter 
injections of the HPLC reference standard (described in paragraph 
(i)(2)(ii)(B) of this section). The relative standard deviation in peak 
areas should not be more than 2.0 percent for either oxybenzone or 
padimate O.
    (2) Calculate the resolution (R) between the oxybenzone and padimate 
O peaks from one chromatogram as follows:
[GRAPHIC] [TIFF OMITTED] TR17JN11.003

Where to = retention time for oxybenzone
tp = retention time for padimate O
Wo = oxybenzone peak width at baseline
Wp = padimate O peak width at baseline


If the resolution (R) is less than 3.0, adjust the mobile phase or 
replace the column.
    (D) SPF standard assay--(1) The SPF standard is diluted to the same 
concentration as the HPLC reference standard according to the following 
steps:
    (i) Step 1. Weigh 1.0 g of the SPF standard (described in paragraph 
(i)(2)(i) of this section) into a 50-mL volumetric flask.
    (ii) Step 2. Add approximately 30 mL of isopropanol and heat with 
swirling until contents are evenly dispersed.
    (iii) Step 3. Cool to room temperature (15 to 30 [deg]C) and dilute 
to volume with isopropanol. Mix well.
    (iv) Step 4. Pipet 5.0 mL of the preparation into a 50-mL volumetric 
flask and dilute to volume with isopropanol. Mix well.
    (2)(i) Inject 10-microliter of diluted SPF standard from paragraph 
(i)(2)(D)(1) of this section and calculate the amount of oxybenzone and 
padimate O as follows:
[GRAPHIC] [TIFF OMITTED] TR17JN11.004

    (ii) The percent of oxybenzone and padimate O in the SPF standard 
should be between 95 and 105.
    (3) Test subjects--(i) Number of subjects. A test panel should 
include enough subjects to produce a minimum of 10 valid test results. A 
maximum of three subjects may be rejected from this panel based on 
paragraph (i)(5)(v)) of this section.
    (ii) Medical history. (A) Obtain a medical history from each subject 
with emphasis on the effects of sunlight on the subject's skin. 
Determine that each subject is in good general health with skin type I, 
II, or III as follows:
    (1) Always burns easily; never tans (sensitive).
    (2) Always burns easily; tans minimally (sensitive).
    (3) Burns moderately; tans gradually (light brown) (normal).
    (4) Burns minimally; always tans well (moderate brown) (normal).
    (5) Rarely burns; tans profusely (dark brown) (insensitive).
    (6) Never burns; deeply pigmented (insensitive).
    (B) Skin type is based on first 30 to 45 minutes of sun exposure 
after a winter season of no sun exposure. Determine that each subject is 
not taking topical or systemic medication that is known to alter 
responses to UV radiation. Determine that each subject has no history of 
sensitivities to topical products and/or abnormal responses to sunlight, 
such as a phototoxic or photoallergic response.
    (iii) Physical examination. Conduct a physical examination to 
determine the

[[Page 100]]

presence of sunburn, suntan, scars, active dermal lesions, and uneven 
skin tones on the areas of the back to be tested. A suitable source of 
low power UVA, such as a Woods lamp, is helpful in this process. If any 
of these conditions are present, the subject is not qualified to 
participate in the study. The presence of nevi, blemishes, or moles will 
be acceptable if, in the physician's judgment, they will neither 
compromise the study nor jeopardize a subject's safety. Subjects with 
dysplastic nevi should not be enrolled. Excess hair on the back is 
acceptable if the hair is clipped. Shaving is unacceptable because it 
may remove a significant portion of the stratum corneum and temporarily 
alter the skin's response to UV radiation.
    (iv) Informed consent. Obtain legally effective written informed 
consent from all test subjects.
    (4) Sunscreen application. (i) Test site. Test sites are locations 
on each subject's back, between the beltline and the shoulder blades 
(scapulae) and lateral to the midline, where skin responses to UV 
radiation are determined. Responses on unprotected skin (no test 
material applied) and protected skin (sunscreen test product(s) or SPF 
standard applied) are determined at separate unprotected and protected 
test sites, respectively. Test sites should be randomly located in a 
blinded manner. Each test site should be a minimum of 30 square 
centimeters and outlined with indelible ink.
    (ii) Test subsite. Test subsites are the locations to which UV 
radiation is administered within a test site. At least five test 
subsites should receive UV doses within each test site. Test subsites 
should be at least 0.5 square centimeters (cm\2\) in area and should be 
separated from each other by at least 0.8 cm. Each test subsite should 
be outlined with indelible ink.
    (iii) Applying test materials. Apply the sunscreen test product and 
the SPF standard at 2 milligrams per square centimeter (mg/cm\2\) to 
their respective test sites. Use a finger cot compatible with the 
sunscreen to spread the product as evenly as possible.
    (iv) Waiting period. Wait at least 15 minutes after applying a 
sunscreen product before exposing the test sites to UV radiation as 
described in paragraph (i)(5)) of this section. For water resistant 
sunscreen products, proceed with the water resistance testing procedure 
described in paragraph (i)(7) of this section after waiting at least 15 
minutes.
    (5) UV exposure--(i) Definition of minimal erythema dose (MED). The 
minimal erythema dose (MED) is the smallest UV dose that produces 
perceptible redness of the skin (erythema) with clearly defined borders 
at 16 to 24 hours after UV exposure. The MED for unprotected skin 
(MEDu) is determined on a test site that does not have 
sunscreen applied. The MED for protected skin (MEDp) is 
determined on a test site that has sunscreen applied. An MEDp 
is determined for the SPF standard (ssMEDp). An 
MEDp is determined for the sunscreen test product 
(tpMEDp).
    (ii) UV exposure for initial MEDu. For each test subject, 
administer a series of UV radiation doses expressed as J/m\2\-eff (as 
determined according to paragraph (a)(2) of this section) to the test 
subsites within an unprotected test site using an accurately calibrated 
solar simulator. Select doses that are a geometric series represented by 
1.25\n\ (i.e., each dose is 25 percent greater than the previous dose).
    (iii) UV exposure for final MEDu, ssMEDp, and 
tpMEDp. For each subject, determine the final 
MEDu, ssMEDp, and tpMEDp by 
administering a series of five UV doses to the appropriate test sites. 
The middle dose (X) in each of these dose series (i.e., the third dose) 
should equal the initial MEDu times the expected SPF. Note 
that the expected SPF equals 1 and 16.3 for the final MEDu 
and ssMEDp, respectively. The remaining UV doses in the 
series depend upon the expected SPF value of the sunscreen test 
product(s).
    For products with an expected SPF less than 8, administer UV doses 
that increase by 25 percent with each successive dose (i.e., 0.64X, 
0.80X, 1.00X, 1.25X, and 1.56X). For products with an expected SPF from 
8 to 15, administer UV doses that increase by 20 percent with each 
successive dose (i.e., 0.69X, 0.83X, 1.00X, 1.20X, and 1.44X). For 
products with an expected SPF higher than 15, administer UV doses that 
increase by 15 percent with each successive dose

[[Page 101]]

(i.e., 0.76X, 0.87X, 1.00X, 1.15X, and 1.32X).
    (iv) Evaluation of test subsites. In order that the person who 
evaluates the test subsites is not biased, he/she should not be the same 
person who applied the sunscreen drug product to the test site or 
administered the UV doses. After UV doses are administered, all 
immediate responses should be recorded. These may include an immediate 
darkening or tanning, typically grayish or purplish in color, which 
fades in 30 to 60 minutes; an immediate reddening at the subsite, due to 
heating of the skin, which fades rapidly; and an immediate generalized 
heat response, spreading beyond the subsite, which fades in 30 to 60 
minutes. After the immediate responses are noted, each subject should 
shield the exposed area from further UV radiation until the MED is 
determined. Determine the MED 16 to 24 hours after UV exposure. Because 
erythema is evaluated 16 to 24 hours after UV exposure, the final 
MEDu, ssMEDp, and tpMEDp are typically 
determined the day following determination of the initial 
MEDu. Evaluate the erythema responses of each test subsite 
using either tungsten or warm white fluorescent lighting that provides 
at least 450 lux of illumination at the test site. For the evaluation, 
the test subject should be in the same position as when the test site 
was irradiated.
    (v) Invalid test data. Reject test data for a test subject if 
erythema is not present on either the unprotected or protected test 
sites; or erythema is present at all subsites; or the responses are 
inconsistent with the series of UV doses administered; or the subject 
was noncompliant (e.g., the subject withdraws from the test due to 
illness or work conflicts or does not shield the exposed testing sites 
from further UV radiation until the MED is determined).
    (6) Determination of SPF. (i) Calculate an SPF value for each test 
subject (SPFi) as follows:
[GRAPHIC] [TIFF OMITTED] TR17JN11.005

    (ii) Calculate the mean
    [GRAPHIC] [TIFF OMITTED] TR17JN11.009
    

and the standard deviation (s) from the SPFi values. 
Calculate the standard error (SE), which equals s/[radic]n (where n 
equals the number of subjects who provided valid test results). Obtain 
the t value from Student's t distribution table corresponding to the 
upper 5-percent point with n--1 degrees of freedom. Determine the 
labeled SPF value, which equals the largest whole number less than
[GRAPHIC] [TIFF OMITTED] TR17JN11.012


In order for the SPF determination of a test product to be considered 
valid, the SPF value of the SPF standard should fall within the standard 
deviation range of the expected SPF (i.e., 16.3 3.43).
    (7) Determination of water resistance. The following procedure 
should be performed in an indoor fresh water pool, whirlpool, and/or hot 
tub maintained at 23 to 32 [deg]C. Fresh water is clean drinking water 
that meets the standards in 40 CFR part 141. The pool and air 
temperature and the relative humidity should be recorded.
    (i) Water resistance (40 minutes). The labeled SPF should be 
determined after 40 minutes of water immersion using the following 
procedure:
    (A) Step 1: Apply the sunscreen as described in paragraph (d) of 
this section.
    (B) Step 2: Perform moderate activity in water for 20 minutes.
    (C) Step 3: Rest out of water for 15 minutes. Do not towel test 
site(s).
    (D) Step 4: Perform moderate activity in water for 20 minutes.
    (E) Step 5: Allow test sites to dry completely without toweling.
    (F) Step 6: Apply the SPF standard as described in paragraph (d) of 
this section.
    Step 1. Expose test sites to UV doses as described in paragraph (e) 
of this section.
    (ii) Water resistance (80 minutes). The labeled SPF should be 
determined after 80 minutes of water immersion using the following 
procedure:
    (A) Step 1: Apply the sunscreen as described in paragraph (d) of 
this section.
    (B) Step 2: Perform moderate activity in water for 20 minutes.

[[Page 102]]

    (C) Step 3: Rest out of water for 15 minutes. Do not towel test 
site(s).
    (D) Step 4: Perform moderate activity in water for 20 minutes.
    (E) Step 5: Rest out of water for 15 minutes. Do not towel test 
site(s).
    (F) Step 6: Perform moderate activity in water for 20 minutes.
    (G) Step 7: Rest out of water for 15 minutes. Do not towel test 
site(s).
    (H) Step 8: Perform moderate activity in water for 20 minutes.
    (I) Step 9: Allow test sites to dry completely without toweling.
    (J) Step 10: Apply the SPF standard as described in paragraph (d) of 
this section.
    (K) Step 11: Expose test sites to UV doses as described in paragraph 
(e) of this section.
    (j) Broad spectrum test procedure--(1) UV Spectrometry. (i) Plate. 
Use optical-grade polymethylmethacrylate (PMMA) plates suitable for UV 
transmittance measurements. The plate should be roughened on one side to 
a three dimensional surface topography measure (Sa) between 2 and 7 
micrometers and must have a rectangular application area of at least 16 
square centimeters (with no side shorter than 4 cm).
    (ii) Sample holder. The sample holder should hold the PMMA plate in 
a horizontal position to avoid flowing of the sunscreen drug product 
from one edge of the PMMA plate to the other. It should be mounted as 
close as possible to the input optics of the spectrometer to maximize 
capture of forward scattered radiation. The sample holder should be a 
thin, flat plate with a suitable aperture through which UV radiation can 
pass. The PMMA plate should be placed on the upper surface of the sample 
holder with the roughened side facing up.
    (iii) Light source. The light source should produce a continuous 
spectral distribution of UV radiation from 290 to 400 nanometers.
    (iv) Input optics. Unless the spectrometer is equipped with an 
integrating sphere, an ultraviolet radiation diffuser should be placed 
between the sample and the input optics of the spectrometer. The 
diffuser will be constructed from any UV radiation transparent material 
(e.g., Teflon [supreg] or quartz). The diffuser ensures that the 
radiation received by the spectrometer is not collimated. The 
spectrometer input slits should be set to provide a bandwidth that is 
less than or equal to 1 nanometer.
    (v) Dynamic range of the spectrometer. The dynamic range of the 
spectrometer should be sufficient to measure transmittance accurately 
through a highly absorbing sunscreen product at all terrestrial solar UV 
wavelengths (290 to 400 nm).
    (2) Sunscreen product application to PMMA plate. The accuracy of the 
test depends upon the application of a precisely controlled amount of 
sunscreen product with a uniform distribution over the PMMA plate. The 
product is applied at 0.75 mg per square centimeter to the roughened 
side of the PMMA plate. The sunscreen product should be applied in a 
series of small dots over the entire PMMA plate and then spread evenly 
using a gloved finger. Spreading should be done with a very light 
spreading action for approximately 30 seconds followed by spreading with 
greater pressure for approximately 30 seconds. The plate should then be 
allowed to equilibrate for 15 minutes in the dark before the pre-
irradiation described in paragraph (c) of this section.
    (3) Sunscreen product pre-irradiation. To account for lack of 
photostability, apply the sunscreen product to the PMMA plate as 
described in paragraph (b) of this section and then irradiate with a 
solar simulator described in section 352.70(b) of this chapter. The 
irradiation dose should be 4 MEDs which is equivalent to an erythemal 
effective dose of 800 J/m\2\ (i.e., 800 J/m\2\-eff).
    (4) Calculation of mean transmittance values. After pre-irradiation 
described in paragraph (c) of this section, mean transmittance values 
should be determined for each wavelength [lambda] over the full UV 
spectrum (290 to 400 nanometers). The transmittance values should be 
measured at 1 nanometer intervals. Measurements of spectral irradiance 
transmitted for each wavelength [lambda] through control PMMA plates 
coated with 15 microliters of glycerin (no sunscreen product) should be 
obtained from at least 5 different locations on the PMMA plate 
[C1([lambda]), C2([lambda]),

[[Page 103]]

C3([lambda]), C4([lambda]), and C5([lambda])]. In addition, a minimum of 
5 measurements of spectral irradiance transmitted for each wavelength 
[lambda] through the PMMA plate covered with the sunscreen product will 
be similarly obtained after pre-irradiation of the sunscreen product 
[P1([lambda]), P2([lambda]), P3([lambda]), P4([lambda]), and 
P5([lambda])].
    The mean transmittance for each wavelength,
    [GRAPHIC] [TIFF OMITTED] TR17JN11.010
    

is the ratio of the mean of the C([lambda]) values to the mean of the 
P([lambda]) values, as follows:
[GRAPHIC] [TIFF OMITTED] TR17JN11.006


Where n =5

    (5) Calculation of mean absorbance values. (i) Mean transmittance 
values,
[GRAPHIC] [TIFF OMITTED] TR17JN11.010


are converted into mean absorbance values,
[GRAPHIC] [TIFF OMITTED] TR17JN11.011


at each wavelength by taking the negative logarithm of the mean 
transmittance value as follows:
[GRAPHIC] [TIFF OMITTED] TR17JN11.008

    (ii) The calculation yields 111 monochromatic absorbance values in 1 
nanometer increments from 290 to 400 nanometers.
    (6) Number of plates. For each sunscreen product, mean absorbance 
values should be determined from at least three individual PMMA plates. 
Because paragraph (d) of this section requires at least 5 measurements 
per plate, there should be a total of at least 15 measurements.
    (7) Calculation of the critical wavelength. The critical wavelength 
is identified as the wavelength at which the integral of the spectral 
absorbance curve reaches 90 percent of the integral over the UV spectrum 
from 290 to 400 nm. The following equation defines the critical 
wavelength:
[GRAPHIC] [TIFF OMITTED] TR17JN11.007


Where [lambda]c = critical wavelength
A([lambda]) = mean absorbance at each wavelength
d[lambda] = wavelength interval between measurements


A mean critical wavelength of 370 nm or greater is classified as broad 
spectrum protection.

[76 FR 35660, June 17, 2011, as amended at 76 FR 38975, July 5, 2011]



Sec.  201.328  Labeling of medical gas containers.

    (a) Portable cryogenic medical gas containers. For the purposes of 
this section a ``portable cryogenic medical gas container'' is one that 
is capable of being transported and is intended to be attached to a 
medical gas supply system within a hospital, health care entity, nursing 
home, other facility, or home health care setting, or is a base unit 
used to fill small cryogenic gas containers for use by individual 
patients. The term does not include cryogenic containers that are not 
designed to be connected to a medical gas supply system, e.g., tank 
trucks, trailers, rail cars, or small cryogenic gas containers for use 
by individual patients (including portable liquid oxygen units as 
defined at Sec.  868.5655 of this chapter).
    (1) Each portable cryogenic medical gas container must be 
conspicuously marked with a 360[deg] wraparound label identifying its 
contents. Such label must meet the requirements of Sec.  211.94(e)(2) of 
this chapter and the following additional requirements.
    (i) If the container holds a single gas, the name of the gas held in 
the container must be printed on the label in one of the following ways:
    (A) Using lettering that appears in the color designated for the gas 
in paragraph (c) of this section and that is printed against a white 
background, or
    (B) Using lettering that appears in white against a background that 
is painted in the color for the gas designated in paragraph (c) of this 
section.
    (ii) The lettering for the name of the gas on the label must be at 
least 2 inches high.

[[Page 104]]

    (iii) The name of the gas must be printed continuously around the 
label and be capable of being read around the entire container.
    (iv) The label must be on the sidewall of the container, as close to 
the top of the container as possible but below the top weld seam.
    (v) A portable cryogenic medical gas container may only be colored 
in the color or colors designated in paragraph (c) of this section if 
the gas or gases held within the container correspond to that color or 
those colors.
    (2) A label on the container (either the 360[deg] wraparound label 
required in paragraph (a)(1) of this section or a separate label) must 
include, in conspicuous lettering, the phrase ``For Medical Use'', 
``Medical Gas,'' or some similar phrase that indicates the gas is for 
medical use.
    (b) High-pressure medical gas cylinders. Each high-pressure medical 
gas cylinder must be colored on the shoulder portion of the cylinder in 
the color or colors designated in paragraph (c) of this section. The 
color or colors must be visible when viewed from the top of cylinder.
    (c) Medical gas colors. The colors required to identify medical 
gases under paragraph (a) and (b) of this section are:

------------------------------------------------------------------------
                Medical gas                             Color
------------------------------------------------------------------------
Medical Air...............................  Yellow.
Carbon Dioxide............................  Gray.
Helium....................................  Brown.
Nitrogen..................................  Black.
Nitrous Oxide.............................  Blue.
Oxygen....................................  Green.
Mixture or Blend..........................  Colors corresponding to each
                                             component gas.
------------------------------------------------------------------------


[81 FR 81696, Nov. 18, 2016]



 Sec. Appendix A to Part 201--Examples of Graphic Enhancements Used by 
                                   FDA

               I. Section 201.66 Standard Labeling Format

                               A. Overall

    1. The ``Drug Facts'' labeling is set off in a box or similar 
enclosure by the use of a barline with all black type printed on a 
white, color contrasting background.

                          B. Typeface and size

    1. ``Drug Facts'' is set in 14 point Helvetica Bold Italic, left 
justified.
    2. ``Drug Facts (continued)'' is set in 8 point Helvetica Bold 
Italic for the words ``Drug Facts'' and 8 point Helvetica Regular for 
the word ``(continued)'' and is left justified.
    3. The headings (e.g., ``Directions'') are set in 8 point Helvetica 
Bold Italic, left justified.
    4. The subheadings (e.g., ``Ask a doctor or pharmacist before use if 
you are'') are set in 6 point Helvetica Bold, left justified.
    5. The information is set in 6 point Helvetica Regular with 6.5 
point leading, left justified.
    6. The heading ``Purpose'' is right justified.
    7. The bullet is a 5-point solid square.
    8. Two em spacing separates bullets when more than one bullet is on 
the same line.
    9. A table format is used for 3 or more dosage directions.
    10. A graphic appears at the bottom of the first panel leading the 
reader to the next panel.

                        C. Barlines and hairlines

    1. A 2.5-point horizontal barline extends to each end of the ``Drug 
Facts'' box (or similar enclosure), providing separation between each of 
the headings.
    2. A 0.5-point horizontal hairline extends within 2 spaces on either 
side of the ``Drug Facts'' box (or similar enclosure), immediately 
following the title and immediately preceding the subheadings.
    3. A 0.5-point horizontal hairline follows the title, immediately 
preceding the heading, when a heading appears on a subsequent panel 
immediately after the ``Drug Facts (continued)'' title.

                           D. Box or Enclosure

    1. All information is enclosed by a 2.5-point barline.

               II. Section 201.66 Modified Labeling Format

                               A. Overall

    1. The ``Drug Facts'' labeling is presented in all black type 
printed on a white color contrasting background.

                          B. Typeface and size

    1. ``Drug Facts'' is set in 9 point Helvetica Bold Italic, left 
justified.
    2. The headings (e.g., ``Directions'') are set in 8 point Helvetica 
Bold Italic, left justified.
    3. The subheadings (e.g., ``Ask a doctor or pharmacist before use if 
you are'') are set in 6 point Helvetica Bold, left justified.
    4. The information is set in 6 point Helvetica Regular with 6.5 
point leading, left justified.
    5. The heading ``Purpose'' is right justified.
    6. The bullet is a 5-point solid square.
    7. Bulleted information may start on same line as headings (except 
for the ``Warnings''

[[Page 105]]

heading) and subheadings, with 2 em spacing separating bullets, and need 
not be vertically aligned.

                        C. Barlines and hairlines

    1. A 2.5-point horizontal barline extends to each end of the ``Drug 
Facts'' box (or similar enclosure), providing separation between each of 
the headings.
    2. A 0.5-point horizontal hairline extends within 2 spaces on either 
side of the ``Drug Facts'' box (or similar enclosure), immediately 
following the title and immediately preceding the subheadings.

                           D. Box or Enclosure

    1. All information is set off by color contrast. No barline is used.

 III. Examples of Sec.  201.66 Standard Labeling and Modified Labeling 
                                 Formats

               A. Section 201.66 Standard Labeling Format
[GRAPHIC] [TIFF OMITTED] TR17MR99.007


[[Page 106]]



               B. Section 201.66 Modified Labeling Format
[GRAPHIC] [TIFF OMITTED] TR17MR99.008



PART 202_PRESCRIPTION DRUG ADVERTISING--Table of Contents



    Authority: 21 U.S.C. 321, 331, 352, 355, 360b, 371.



Sec.  202.1  Prescription-drug advertisements.

    (a)(1) The ingredient information required by section 502(n) of the 
Federal Food, Drug, and Cosmetic Act shall appear together, without any 
intervening written, printed, or graphic matter, except the proprietary 
names of ingredients, which may be included with the listing of 
established names.
    (2) The order of listing of ingredients in the advertisement shall 
be the same as the order of listing of ingredients on the label of the 
product, and the information presented in the advertisement concerning 
the quantity of each such ingredient shall be the same as the 
corresponding information on the label of the product.
    (3) The advertisement shall not employ a fanciful proprietary name 
for the drug or any ingredient in such a manner as to imply that the 
drug or ingredient has some unique effectiveness or composition, when, 
in fact, the drug or ingredient is a common substance, the limitations 
of which are readily recognized when the drug or ingredient is listed by 
its established name.
    (4) The advertisement shall not feature inert or inactive 
ingredients in a manner that creates an impression of value greater than 
their true functional role in the formulation.
    (5) The advertisement shall not designate a drug or ingredient by a 
proprietary name that, because of similarity in spelling or 
pronunciation, may be confused with the proprietary name or the 
established name of a different drug or ingredient.
    (b)(1) If an advertisement for a prescription drug bears a 
proprietary name or designation for the drug or any ingredient thereof, 
the established name, if such there be, corresponding to such 
proprietary name or designation shall accompany such proprietary name or 
designation each time it is featured in the advertisement for the drug; 
but, except as provided below in this subparagraph, the established name 
need not be used with the proprietary name or designation in the running 
text of the advertisement. On any page of an advertisement in which the 
proprietary name or designation is not featured but is used in the 
running text, the established name shall be used at least once in the 
running text in association with such proprietary name or designation 
and in the same type size used in the running text: Provided, however, 
That if the proprietary

[[Page 107]]

name or designation is used in the running text in larger size type, the 
established name shall be used at least once in association with, and in 
type at least half as large as the type used for, the most prominent 
presentation of the proprietary name or designation in such running 
text. If any advertisement includes a column with running text 
containing detailed information as to composition, prescribing, side 
effects, or contraindications and the proprietary name or designation is 
used in such column but is not featured above or below the column, the 
established name shall be used at least once in such column of running 
text in association with such proprietary name or designation and in the 
same type size used in such column of running text: Provided, however, 
That if the proprietary name or designation is used in such column of 
running text in larger size type, the established name shall be used at 
least once in association with, and in type at least half as large as 
the type used for, the most prominent presentation of the proprietary 
name or designation in such column of running text. Where the 
established name is required to accompany or to be used in association 
with the proprietary name or designation, the established name shall be 
placed in direct conjunction with the proprietary name or designation, 
and the relationship between the proprietary name or designation and the 
established name shall be made clear by use of a phrase such as ``brand 
of'' preceding the established name, by brackets surrounding the 
established name, or by other suitable means.
    (2) The established name shall be printed in letters that are at 
least half as large as the letters comprising the proprietary name or 
designation with which it is joined, and the established name shall have 
a prominence commensurate with the prominence with which such 
proprietary name or designation appears, taking into account all 
pertinent factors, including typography, layout, contrast, and other 
printing features.
    (c) In the case of a prescription drug containing two or more active 
ingredients, if the advertisement bears a proprietary name or 
designation for such mixture and there is no established name 
corresponding to such proprietary name or designation, the quantitative 
ingredient information required in the advertisement by section 502(n) 
of the act shall be placed in direct conjunction with the most prominent 
display of the proprietary name or designation. The prominence of the 
quantitative ingredient information shall bear a reasonable relationship 
to the prominence of the proprietary name.
    (d)(1) If the advertisement employs one proprietary name or 
designation to refer to a combination of active ingredients present in 
more than one preparation (the individual preparations differing from 
each other as to quantities of active ingredients and/or the form of the 
finished preparation) and there is no established name corresponding to 
such proprietary name or designation, a listing showing the established 
names of the active ingredients shall be placed in direct conjunction 
with the most prominent display of such proprietary name or designation. 
The prominence of this listing of active ingredients shall bear a 
reasonable relationship to the prominence of the proprietary name and 
the relationship between such proprietary name or designation, and the 
listing of active ingredients shall be made clear by use of such phrase 
as ``brand of'', preceding the listing of active ingredients.
    (2) The advertisement shall prominently display the name of at least 
one specific dosage form and shall have the quantitative ingredient 
information required by section 502(n) of the act in direct conjunction 
with such display. If other dosage forms are listed in the 
advertisement, the quantitative ingredient information for such dosage 
forms shall appear in direct conjunction and in equal prominence with 
the most prominent listing of the names of such dosage forms.
    (e) True statement of information in brief summary relating to side 
effects, contraindications, and effectiveness:
    (1) When required. All advertisements for any prescription drug 
(``prescription drug'' as used in this section means drugs defined in 
section 503(b)(1) of the act and Sec.  201.105, applicable to drugs for 
use by man and veterinary

[[Page 108]]

drugs, respectively), except advertisements described in paragraph 
(e)(2) of this section, shall present a true statement of information in 
brief summary relating to side effects, contraindications (when used in 
this section ``side effects, contraindications'' include side effects, 
warnings, precautions, and contraindications and include any such 
information under such headings as cautions, special considerations, 
important notes, etc.) and effectiveness. Advertisements broadcast 
through media such as radio, television, or telephone communications 
systems shall include information relating to the major side effects and 
contraindications of the advertised drugs in the audio or audio and 
visual parts of the presentation and unless adequate provision is made 
for dissemination of the approved or permitted package labeling in 
connection with the broadcast presentation shall contain a brief summary 
of all necessary information related to side effects and 
contraindications.
    (2) Exempt advertisements. The following advertisements are exempt 
from the requirements of paragraph (e)(1) of this section under the 
conditions specified:
    (i) Reminder advertisements. Reminder advertisements are those which 
call attention to the name of the drug product but do not include 
indications or dosage recommendations for use of the drug product. These 
reminder advertisements shall contain only the proprietary name of the 
drug product, if any; the established name of the drug product, if any; 
the established name of each active ingredient in the drug product; and, 
optionally, information relating to quantitative ingredient statements, 
dosage form, quantity of package contents, price, the name and address 
of the manufacturer, packer, or distributor or other written, printed, 
or graphic matter containing no representation or suggestion relating to 
the advertised drug product. If the Commissioner finds that there is 
evidence of significant incidence of fatalities or serious injury 
associated with the use of a particular prescription drug, he may 
withdraw this exemption by so notifying the manufacturer, packer, or 
distributor of the drug by letter. Reminder advertisements, other than 
those solely intended to convey price information including, but not 
limited to, those subject to the requirements of Sec.  200.200 of this 
chapter, are not permitted for a prescription drug product whose 
labeling contains a boxed warning relating to a serious hazard 
associated with the use of the drug product. Reminder advertisements 
which are intended to provide consumers with information concerning the 
price charged for a prescription for a drug product are exempt from the 
requirements of this section if they meet all of the conditions 
contained in Sec.  200.200 of this chapter. Reminder advertisements, 
other than those subject to the requirements of Sec.  200.200 of this 
chapter, are not permitted for a drug for which an announcement has been 
published pursuant to a review on the labeling claims for the drug by 
the National Academy of Sciences/National Research Council (NAS/NRC), 
Drug Efficacy Study Group, and for which no claim has been evaluated as 
higher than ``possibly effective.'' If the Commissioner finds the 
circumstances are such that a reminder advertisement may be misleading 
to prescribers of drugs subject to NAS/NRC evaluation, such 
advertisements will not be allowed and the manufacturer, packer, or 
distributor will be notified either in the publication of the 
conclusions on the effectiveness of the drug or by letter.
    (ii) Advertisements of bulk-sale drugs. Advertisements of bulk-sale 
drugs that promote sale of the drug in bulk packages in accordance with 
the practice of the trade solely to be processed, manufactured, labeled, 
or repackaged in substantial quantities and that contain no claims for 
the therapeutic safety or effectiveness of the drug.
    (iii) Advertisements of prescription-compounding drugs. 
Advertisements of prescription-compounding drugs that promote sale of a 
drug for use as a prescription chemical or other compound for use by 
registered pharmacists in compounding prescriptions if the drug 
otherwise complies with the conditions for the labeling exemption 
contained in Sec.  201.120 and the advertisement contains no claims for 
the therapeutic safety or effectiveness of the drug.

[[Page 109]]

    (3) Scope of information to be included; applicability to the entire 
advertisement. (i) The requirement of a true statement of information 
relating to side effects, contraindications, and effectiveness applies 
to the entire advertisement. Untrue or misleading information in any 
part of the advertisement will not be corrected by the inclusion in 
another distinct part of the advertisement of a brief statement 
containing true information relating to side effects, contraindications, 
and effectiveness of the drug. If any part or theme of the advertisement 
would make the advertisement false or misleading by reason of the 
omission of appropriate qualification or pertinent information, that 
part or theme shall include the appropriate qualification or pertinent 
information, which may be concise if it is supplemented by a prominent 
reference on each page to the presence and location elsewhere in the 
advertisement of a more complete discussion of such qualification or 
information.
    (ii) The information relating to effectiveness is not required to 
include information relating to all purposes for which the drug is 
intended but may optionally be limited to a true statement of the 
effectiveness of the drug for the selected purpose(s) for which the drug 
is recommended or suggested in the advertisement. The information 
relating to effectiveness shall include specific indications for use of 
the drug for purposes claimed in the advertisement; for example, when an 
advertisement contains a broad claim that a drug is an antibacterial 
agent, the advertisement shall name a type or types of infections and 
microorganisms for which the drug is effective clinically as 
specifically as required, approved, or permitted in the drug package 
labeling.
    (iii) The information relating to side effects and contraindications 
shall disclose each specific side effect and contraindication (which 
include side effects, warnings, precautions, and contraindications and 
include any such information under such headings as cautions, special 
considerations, important notes, etc.; see paragraph (e)(1) of this 
section) contained in required, approved, or permitted labeling for the 
advertised drug dosage form(s): Provided, however,
    (a) The side effects and contraindications disclosed may be limited 
to those pertinent to the indications for which the drug is recommended 
or suggested in the advertisement to the extent that such limited 
disclosure has previously been approved or permitted in drug labeling 
conforming to the provisions of Sec. Sec.  201.100 or 201.105; and
    (b) The use of a single term for a group of side effects and 
contraindications (for example, ``blood dyscrasias'' for disclosure of 
``leukopenia,'' ``agranulocytosis,'' and ``neutropenia'') is permitted 
only to the extent that the use of such a single term in place of 
disclosure of each specific side effect and contraindication has been 
previously approved or permitted in drug labeling conforming to the 
provisions of Sec. Sec.  201.100 or 201.105.
    (4) Substance of information to be included in brief summary. (i)(a) 
An advertisement for a prescription drug covered by a new-drug 
application approved pursuant to section 505 of the act after October 
10, 1962, or a prescription drug covered by a new animal drug 
application approved pursuant to section 512 of the act after August 1, 
1969, or any approved supplement thereto, or for a prescription drug 
listed in the index pursuant to section 572 of the act, or any granted 
modification thereto, shall not recommend or suggest any use that is not 
in the labeling accepted in such approved new-drug application or 
supplement, new animal drug application or supplement, or new animal 
drug index listing or modification. The advertisement shall present 
information from labeling required, approved, permitted, or granted in a 
new-drug or new animal drug application or new animal drug index listing 
relating to each specific side effect and contraindication in such 
labeling that relates to the uses of the advertised drug dosage form(s) 
or shall otherwise conform to the provisions of paragraph (e)(3)(iii) of 
this section.
    (b) If a prescription drug was covered by a new-drug application or 
a supplement thereto that became effective prior to October 10, 1962, an 
advertisement may recommend or suggest:
    (1) Uses contained in the labeling accepted in such new-drug 
application

[[Page 110]]

and any effective, approved, or permitted supplement thereto.
    (2) Additional uses contained in labeling in commercial use on 
October 9, 1962, to the extent that such uses did not cause the drug to 
be an unapproved ``new drug'' as ``new drug'' was defined in section 
201(p) of the act as then in force, and to the extent that such uses 
would be permitted were the drug subject to paragraph (e)(4)(iii) of 
this section.
    (3) Additional uses contained in labeling in current commercial use 
to the extent that such uses do not cause the drug to be an unapproved 
``new drug'' as defined in section 201(p) of the act as amended or a 
``new animal drug'' as defined in section 201(v) of the act as amended.

The advertisement shall present information from labeling required, 
approved, or permitted in a new-drug application relating to each 
specific side effect and contraindication in such labeling that relates 
to the uses of the advertised drug dosage form(s) or shall otherwise 
conform to the provisions of paragraph (e)(3)(iii) of this section.
    (ii) In the case of an advertisement for a prescription drug other 
than a drug the labeling of which causes it to be an unapproved ``new 
drug'' and other than drugs covered by paragraph (e)(4)(i) of this 
section, an advertisement may recommend and suggest the drug only for 
those uses contained in the labeling thereof:
    (a) For which the drug is generally recognized as safe and effective 
among experts qualified by scientific training and experience to 
evaluate the safety and effectiveness of such drugs; or
    (b) For which there exists substantial evidence of safety and 
effectiveness, consisting of adequate and well-controlled 
investigations, including clinical investigations (as used in this 
section ``clinical investigations,'' ``clinical experience,'' and 
``clinical significance'' mean in the case of drugs intended for 
administration to man, investigations, experience, or significance in 
humans, and in the case of drugs intended for administration to other 
animals, investigations, experience, or significance in the specie or 
species for which the drug is advertised), by experts qualified by 
scientific training and experience to evaluate the safety and 
effectiveness of the drug involved, on the basis of which it can fairly 
and responsibly be concluded by such experts that the drug is safe and 
effective for such uses; or
    (c) For which there exists substantial clinical experience (as used 
in this section this means substantial clinical experience adequately 
documented in medical literature or by other data (to be supplied to the 
Food and Drug Administration, if requested)), on the basis of which it 
can fairly and responsibly be concluded by qualified experts that the 
drug is safe and effective for such uses; or
    (d) For which safety is supported under any of the preceding clauses 
in paragraphs (e)(4)(iii) (a), (b), and (c) of this section and 
effectiveness is supported under any other of such clauses.

The advertisement shall present information relating to each specific 
side effect and contraindication that is required, approved, or 
permitted in the package labeling by Sec. Sec.  201.100 or 201.105 of 
this chapter of the drug dosage form(s) or shall otherwise conform to 
the provisions of paragraph (e)(3)(iii) of this section.
    (5) ``True statement'' of information. An advertisement does not 
satisfy the requirement that it present a ``true statement'' of 
information in brief summary relating to side effects, 
contraindications, and effectiveness if:
    (i) It is false or misleading with respect to side effects, 
contraindications, or effectiveness; or
    (ii) It fails to present a fair balance between information relating 
to side effects and contraindications and information relating to 
effectiveness of the drug in that the information relating to 
effectiveness is presented in greater scope, depth, or detail than is 
required by section 502(n) of the act and this information is not fairly 
balanced by a presentation of a summary of true information relating to 
side effects and contraindications of the drug; Provided, however, That 
no advertisement shall be considered to be in violation of this section 
if the presentation of true information relating to side effects and 
contraindications is comparable in depth and detail with the claims for 
effectiveness or safety.

[[Page 111]]

    (iii) It fails to reveal facts material in the light of its 
representations or material with respect to consequences that may result 
from the use of the drug as recommended or suggested in the 
advertisement.
    (6) Advertisements that are false, lacking in fair balance, or 
otherwise misleading. An advertisement for a prescription drug is false, 
lacking in fair balance, or otherwise misleading, or otherwise violative 
of section 502(n) of the act, among other reasons, if it:
    (i) Contains a representation or suggestion, not approved or 
permitted for use in the labeling, that a drug is better, more 
effective, useful in a broader range of conditions or patients (as used 
in this section patients means humans and in the case of veterinary 
drugs, other animals), safer, has fewer, or less incidence of, or less 
serious side effects or contraindications than has been demonstrated by 
substantial evidence or substantial clinical experience (as described in 
paragraphs (e)(4)(ii) (b) and (c) of this section) whether or not such 
representations are made by comparison with other drugs or treatments, 
and whether or not such a representation or suggestion is made directly 
or through use of published or unpublished literature, quotations, or 
other references.
    (ii) Contains a drug comparison that represents or suggests that a 
drug is safer or more effective than another drug in some particular 
when it has not been demonstrated to be safer or more effective in such 
particular by substantial evidence or substantial clinical experience.
    (iii) Contains favorable information or opinions about a drug 
previously regarded as valid but which have been rendered invalid by 
contrary and more credible recent information, or contains literature 
references or quotations that are significantly more favorable to the 
drug than has been demonstrated by substantial evidence or substantial 
clinical experience.
    (iv) Contains a representation or suggestion that a drug is safer 
than it has been demonstrated to be by substantial evidence or 
substantial clinical experience, by selective presentation of 
information from published articles or other references that report no 
side effects or minimal side effects with the drug or otherwise selects 
information from any source in a way that makes a drug appear to be 
safer than has been demonstrated.
    (v) Presents information from a study in a way that implies that the 
study represents larger or more general experience with the drug than it 
actually does.
    (vi) Contains references to literature or studies that misrepresent 
the effectiveness of a drug by failure to disclose that claimed results 
may be due to concomitant therapy, or by failure to disclose the 
credible information available concerning the extent to which claimed 
results may be due to placebo effect (information concerning placebo 
effect is not required unless the advertisement promotes the drug for 
use by man).
    (vii) Contains favorable data or conclusions from nonclinical 
studies of a drug, such as in laboratory animals or in vitro, in a way 
that suggests they have clinical significance when in fact no such 
clinical significance has been demonstrated.
    (viii) Uses a statement by a recognized authority that is apparently 
favorable about a drug but fails to refer to concurrent or more recent 
unfavorable data or statements from the same authority on the same 
subject or subjects.
    (ix) Uses a quote or paraphrase out of context to convey a false or 
misleading idea.
    (x) Uses literature, quotations, or references that purport to 
support an advertising claim but in fact do not support the claim or 
have relevance to the claim.
    (xi) Uses literature, quotations, or references for the purpose of 
recommending or suggesting conditions of drug use that are not approved 
or permitted in the drug package labeling.
    (xii) Offers a combination of drugs for the treatment of patients 
suffering from a condition amenable to treatment by any of the 
components rather than limiting the indications for use to patients for 
whom concomitant therapy as provided by the fixed combination drug is 
indicated, unless such condition is included in the uses permitted under 
paragraph (e)(4) of this section.

[[Page 112]]

    (xiii) Uses a study on normal individuals without disclosing that 
the subjects were normal, unless the drug is intended for use on normal 
individuals.
    (xiv) Uses ``statistics'' on numbers of patients, or counts of 
favorable results or side effects, derived from pooling data from 
various insignificant or dissimilar studies in a way that suggests 
either that such ``statistics'' are valid if they are not or that they 
are derived from large or significant studies supporting favorable 
conclusions when such is not the case.
    (xv) Uses erroneously a statistical finding of ``no significant 
difference'' to claim clinical equivalence or to deny or conceal the 
potential existence of a real clinical difference.
    (xvi) Uses statements or representations that a drug differs from or 
does not contain a named drug or category of drugs, or that it has a 
greater potency per unit of weight, in a way that suggests falsely or 
misleadingly or without substantial evidence or substantial clinical 
experience that the advertised drug is safer or more effective than such 
other drug or drugs.
    (xvii) Uses data favorable to a drug derived from patients treated 
with dosages different from those recommended in approved or permitted 
labeling if the drug advertised is subject to section 505 of the act, 
or, in the case of other drugs, if the dosages employed were different 
from those recommended in the labeling and generally recognized as safe 
and effective. This provision is not intended to prevent citation of 
reports of studies that include some patients treated with dosages 
different from those authorized, if the results in such patients are not 
used.
    (xviii) Uses headline, subheadline, or pictorial or other graphic 
matter in a way that is misleading.
    (xix) Represents or suggests that drug dosages properly recommended 
for use in the treatment of certain classes of patients or disease 
conditions are safe and effective for the treatment of other classes of 
patients or disease conditions when such is not the case.
    (xx) Presents required information relating to side effects or 
contraindications by means of a general term for a group in place of 
disclosing each specific side effect and contraindication (for example 
employs the term blood dyscrasias instead of ``leukopenia,'' 
``agranulocytosis,'' ``neutropenia,'' etc.) unless the use of such 
general term conforms to the provisions of paragraph (e)(3)(iii) of this 
section.

Provided, however, That any provision of this paragraph shall be waived 
with respect to a specified advertisement as set forth in a written 
communication from the Food and Drug Administration on a petition for 
such a waiver from a person who would be adversely affected by the 
enforcement of such provision on the basis of a showing that the 
advertisement is not false, lacking in fair balance, or otherwise 
misleading, or otherwise violative of section 502(n) of the act. A 
petition for such a waiver shall set forth clearly and concisely the 
petitioner's interest in the advertisement, the specific provision of 
this paragraph from which a waiver is sought, a complete copy of the 
advertisement, and a showing that the advertisement is not false, 
lacking in fair balance, or otherwise misleading, or otherwise violative 
of section 502(n) of the act.
    (7) Advertisements that may be false, lacking in fair balance, or 
otherwise misleading. An advertisement may be false, lacking in fair 
balance, or otherwise misleading or otherwise violative of section 
502(n) of the act if it:
    (i) Contains favorable information or conclusions from a study that 
is inadequate in design, scope, or conduct to furnish significant 
support for such information or conclusions.
    (ii) Uses the concept of ``statistical significance'' to support a 
claim that has not been demonstrated to have clinical significance or 
validity, or fails to reveal the range of variations around the quoted 
average results.
    (iii) Uses statistical analyses and techniques on a retrospective 
basis to discover and cite findings not soundly supported by the study, 
or to suggest scientific validity and rigor for data from studies the 
design or protocol of which are not amenable to formal statistical 
evaluations.
    (iv) Uses tables or graphs to distort or misrepresent the 
relationships, trends, differences, or changes among the variables or 
products studied; for example, by failing to label abscissa

[[Page 113]]

and ordinate so that the graph creates a misleading impression.
    (v) Uses reports or statements represented to be statistical 
analyses, interpretations, or evaluations that are inconsistent with or 
violate the established principles of statistical theory, methodology, 
applied practice, and inference, or that are derived from clinical 
studies the design, data, or conduct of which substantially invalidate 
the application of statistical analyses, interpretations, or 
evaluations.
    (vi) Contains claims concerning the mechanism or site of drug action 
that are not generally regarded as established by scientific evidence by 
experts qualified by scientific training and experience without 
disclosing that the claims are not established and the limitations of 
the supporting evidence.
    (vii) Fails to provide sufficient emphasis for the information 
relating to side effects and contraindications, when such information is 
contained in a distinct part of an advertisement, because of repetition 
or other emphasis in that part of the advertisement of claims for 
effectiveness or safety of the drug.
    (viii) Fails to present information relating to side effects and 
contraindications with a prominence and readability reasonably 
comparable with the presentation of information relating to 
effectiveness of the drug, taking into account all implementing factors 
such as typography, layout, contrast, headlines, paragraphing, white 
space, and any other techniques apt to achieve emphasis.
    (ix) Fails to provide adequate emphasis (for example, by the use of 
color scheme, borders, headlines, or copy that extends across the 
gutter) for the fact that two facing pages are part of the same 
advertisement when one page contains information relating to side 
effects and contraindications.
    (x) In an advertisement promoting use of the drug in a selected 
class of patients (for example, geriatric patients or depressed 
patients), fails to present with adequate emphasis the significant side 
effects and contraindications or the significant dosage considerations, 
when dosage recommendations are included in an advertisement, especially 
applicable to that selected class of patients.
    (xi) Fails to present on a page facing another page (or on another 
full page) of an advertisement on more than one page, information 
relating to side effects and contraindications when such information is 
in a distinct part of the advertisement.
    (xii) Fails to include on each page or spread of an advertisement 
the information relating to side effects and contraindications or a 
prominent reference to its presence and location when it is presented as 
a distinct part of an advertisement.
    (xiii) Contains information from published or unpublished reports or 
opinions falsely or misleadingly represented or suggested to be 
authentic or authoritative.
    (f)-(i) [Reserved]
    (j)(1) No advertisement concerning a particular prescription drug 
may be disseminated without prior approval by the Food and Drug 
Administration if:
    (i) The sponsor or the Food and Drug Administration has received 
information that has not been widely publicized in medical literature 
that the use of the drug may cause fatalities or serious damage;
    (ii) The Commissioner (or in his absence the officer acting as 
Commissioner), after evaluating the reliability of such information, has 
notified the sponsor that the information must be a part of the 
advertisements for the drug; and
    (iii) The sponsor has failed within a reasonable time as specified 
in such notification to present to the Food and Drug Administration a 
program, adequate in light of the nature of the information, for 
assuring that such information will be publicized promptly and 
adequately to the medical profession in subsequent advertisements.

If the Commissioner finds that the program presented is not being 
followed, he will notify the sponsor that prior approval of all 
advertisements for the particular drug will be required. Nothing in this 
paragraph is to be construed as limiting the Commissioner's or the 
Secretary's rights, as authorized by law, to issue publicity, to suspend 
any new-drug application, to decertify any

[[Page 114]]

antibiotic, or to recommend any regulatory action.
    (2) Within a reasonable time after information concerning the 
possibility that a drug may cause fatalities or serious damage has been 
widely publicized in medical literature, the Food and Drug 
Administration shall notify the sponsor of the drug by mail that prior 
approval of advertisements for the drug is no longer necessary.
    (3) Dissemination of an advertisement not in compliance with this 
paragraph shall be deemed to be an act that causes the drug to be 
misbranded under section 502(n) of the act.
    (4) Any advertisement may be submitted to the Food and Drug 
Administration prior to publication for comment. If the advertiser is 
notified that the submitted advertisement is not in violation and, at 
some subsequent time, the Food and Drug Administration changes its 
opinion, the advertiser will be so notified and will be given a 
reasonable time for correction before any regulatory action is taken 
under this section. Notification to the advertiser that a proposed 
advertisement is or is not considered to be in violation shall be in 
written form.
    (5) The sponsor shall have an opportunity for a regulatory hearing 
before the Food and Drug Administration pursuant to part 16 of this 
chapter with respect to any determination that prior approval is 
required for advertisements concerning a particular prescription drug, 
or that a particular advertisement is not approvable.
    (k) An advertisement issued or caused to be issued by the 
manufacturer, packer, or distributor of the drug promoted by the 
advertisement and which is not in compliance with section 502(n) of the 
act and the applicable regulations thereunder shall cause stocks of such 
drug in possession of the person responsible for issuing or causing the 
issuance of the advertisement, and stocks of the drug distributed by 
such person and still in the channels of commerce, to be misbranded 
under section 502(n) of the act.
    (l)(1) Advertisements subject to section 502(n) of the act include 
advertisements in published journals, magazines, other periodicals, and 
newspapers, and advertisements broadcast through media such as radio, 
television, and telephone communication systems.
    (2) Brochures, booklets, mailing pieces, detailing pieces, file 
cards, bulletins, calendars, price lists, catalogs, house organs, 
letters, motion picture films, film strips, lantern slides, sound 
recordings, exhibits, literature, and reprints and similar pieces of 
printed, audio, or visual matter descriptive of a drug and references 
published (for example, the ``Physicians Desk Reference'') for use by 
medical practitioners, pharmacists, or nurses, containing drug 
information supplied by the manufacturer, packer, or distributor of the 
drug and which are disseminated by or on behalf of its manufacturer, 
packer, or distributor are hereby determined to be labeling as defined 
in section 201(m) of the act.

[40 FR 14016, Mar. 27, 1975, as amended at 40 FR 58799, Dec. 18, 1975; 
41 FR 48266, Nov. 2, 1976; 42 FR 15674, Mar. 22, 1977; 60 FR 38480, July 
27, 1995; 72 FR 69119, Dec. 6, 2007]

    Effective Date Notes: 1. At 44 FR 37467, June 26, 1979, Sec.  
202.1(e)(6) (ii) and (vii) were revised. At 44 FR 74817, Dec. 18, 1979, 
paragraphs (e)(6) (ii) and (vii) were stayed indefinitely. At 64 FR 400, 
Jan. 5, 1999, these paragraphs were amended. For the convenience of the 
user, paragraphs (e)(6) (ii) and (vii), published at 44 FR 37467, are 
set forth below:



Sec.  202.1  Prescription-drug advertisements.

                                * * * * *

    (e) * * *
    (6) * * *
    (ii) Represents or suggests that a prescription drug is safer or 
more effective than another drug in some particular when the difference 
has not been demonstrated by substantial evidence. An advertisement for 
a prescription drug may not, either directly or by implication, e.g., by 
use of comparative test data or reference to published reports, 
represent that the drug is safer or more effective than another drug, 
nor may an advertisement contain a quantitative statement of safety or 
effectiveness (a) unless the representation has been approved as part of 
the labeling in a new drug application or biologic license, or (b) if 
the drug is not a new drug or biologic, unless the representation of 
safety or effectiveness is supported by substantial evidence derived 
from adequate and well-controlled studies as defined in Sec.  
314.111(a)(5)(ii) of this chapter, or unless the

[[Page 115]]

requirement for adequate and well-controlled studies is waived as 
provided in Sec.  314.111(a)(5)(ii) of this chapter.

                                * * * * *

    (vii) Suggests, on the basis of favorable data or conclusions from 
nonclinical studies of a prescription drug, such as studies in 
laboratory animals or in vitro, that the studies have clinical 
significance, if clinical significance has not been demonstrated. Data 
that demonstrate activity or effectiveness for a prescription drug in 
animal or in vitro tests and have not been shown by adequate and well-
controlled clinical studies to pertain to clinical use may be used in 
advertising except that (a), in the case of anti-infective drugs, in 
vitro data may be included in the advertisement, if data are immediately 
preceded by the statement ``The following in vitro data are available 
but their clinical significance is unknown'' and (b), in the case of 
other drug classes, in vitro and animal data that have not been shown to 
pertain to clinical use by adequate and well-controlled clinical studies 
as defined in Sec.  314.111(a)(5)(ii) of this chapter may not be used 
unless the requirement for adequate and well-controlled studies is 
waived as provided in Sec.  314.111(a)(5)(ii) of this chapter.

                                * * * * *

    2. At 88 FR 80983, Nov. 21, 2023, Sec.  202.1 was amended by adding 
introductory text and revising paragraph (e)(1), effective May 20, 2024. 
For the convenience of the user, the added and revised text is set forth 
as follows:



Sec.  202.1  Prescription-drug advertisements.

    Prescription drug as used in this section means any drug defined in 
section 503(b)(1) of the Federal Food, Drug, and Cosmetic Act or Sec.  
201.105 of this chapter, applicable to drugs intended for use by humans 
and to veterinary drugs, respectively.

                                * * * * *

    (e) * * *
    (1) When required. All advertisements for any prescription drug, 
except advertisements described in paragraph (e)(2) of this section, 
must present a true statement of information in brief summary relating 
to side effects, contraindications (when used in this section, ``side 
effects, contraindications'' include side effects, warnings, 
precautions, and contraindications and include any such information 
under such headings as cautions, special considerations, important 
notes, etc.), and effectiveness.
    (i) Broadcast advertisements. Advertisements broadcast through media 
such as radio, television, or telephone communications systems must:
    (A) Include information relating to the major side effects and 
contraindications (``major statement'') of the advertised drugs in the 
audio or audio and visual parts of the presentation, unless required by 
paragraph (e)(1)(ii)(C) of this section to present the major statement 
using audio and text; and
    (B) Contain a brief summary of all necessary information related to 
side effects and contraindications, unless adequate provision is made 
for dissemination of the approved or permitted product labeling in 
connection with the broadcast presentation.
    (ii) Human drug advertisements in television or radio format--Clear, 
conspicuous, and neutral manner. For advertisements for prescription 
drugs intended for use by humans presented directly to consumers in 
television or radio format, the major statement must be presented in a 
clear, conspicuous, and neutral manner. The major statement is presented 
in a clear, conspicuous, and neutral manner if the following are met:
    (A) It is presented in consumer-friendly language and terminology 
that is readily understandable.
    (B) Its audio information, in terms of the volume, articulation, and 
pacing used, is at least as understandable as the audio information 
presented in the rest of the advertisement.
    (C) In advertisements in television format, it is presented 
concurrently using both audio and text (dual modality). To achieve dual 
modality:
    (1) Either the text displays the verbatim key terms or phrases from 
the corresponding audio, or the text displays the verbatim complete 
transcript of the corresponding audio; and
    (2) The text is displayed for a sufficient duration to allow it to 
be read easily. For purposes of the standard in this paragraph 
(e)(1)(ii)(C)(2), the duration is considered sufficient if the text 
display begins at the same time and ends at approximately the same time 
as the corresponding audio.
    (D) In advertisements in television format, for the text portion of 
the major statement, the size and style of font, the contrast with the 
background, and the placement on the screen allow the information to be 
read easily.
    (E) During the presentation of the major statement, the 
advertisement does not include audio or visual elements, alone or in 
combination, that are likely to interfere with comprehension of the 
major statement.

                                * * * * *

[[Page 116]]



PART 203_PRESCRIPTION DRUG MARKETING--Table of Contents



                      Subpart A_General Provisions

Sec.
203.1 Scope.
203.2 Purpose.
203.3 Definitions.

                         Subpart B_Reimportation

203.10 Restrictions on reimportation.
203.11 Applications for reimportation to provide emergency medical care.
203.12 An appeal from an adverse decision by the district office.

                      Subpart C_Sales Restrictions

203.20 Sales restrictions.
203.22 Exclusions.
203.23 Returns.

                            Subpart D_Samples

203.30 Sample distribution by mail or common carrier.
203.31 Sample distribution by means other than mail or common carrier 
          (direct delivery by a representative or detailer).
203.32 Drug sample storage and handling requirements.
203.33 Drug sample forms.
203.34 Policies and procedures; administrative systems.
203.35 Standing requests.
203.36 Fulfillment houses, shipping and mailing services, comarketing 
          agreements, and third-party recordkeeping.
203.37 Investigation and notification requirements.
203.38 Sample lot or control numbers; labeling of sample units.
203.39 Donation of drug samples to charitable institutions.

                    Subpart E_Wholesale Distribution

203.50 Requirements for wholesale distribution of prescription drugs.

        Subpart F_Request and Receipt Forms, Reports, and Records

203.60 Request and receipt forms, reports, and records.

                            Subpart G_Rewards

203.70 Application for a reward.

    Authority: 21 U.S.C. 331, 333, 351, 352, 353, 360, 371, 374, 381.

    Source: 64 FR 67756, Dec. 3, 1999, unless otherwise noted.



                      Subpart A_General Provisions



Sec.  203.1  Scope.

    This part sets forth procedures and requirements pertaining to the 
reimportation and wholesale distribution of prescription drugs, 
including both bulk drug substances and finished dosage forms; the sale, 
purchase, or trade of (or the offer to sell, purchase, or trade) 
prescription drugs, including bulk drug substances, that were purchased 
by hospitals or health care entities, or donated to charitable 
organizations; and the distribution of prescription drug samples. Blood 
and blood components intended for transfusion are excluded from the 
restrictions in and the requirements of the Prescription Drug Marketing 
Act of 1987 and the Prescription Drug Amendments of 1992.



Sec.  203.2  Purpose.

    The purpose of this part is to implement the Prescription Drug 
Marketing Act of 1987 and the Prescription Drug Amendments of 1992, 
except for those sections relating to State licensing of wholesale 
distributors (see part 205 of this chapter), to protect the public 
health, and to protect the public against drug diversion by establishing 
procedures, requirements, and minimum standards for the distribution of 
prescription drugs and prescription drug samples.



Sec.  203.3  Definitions.

    (a) The act means the Federal Food, Drug, and Cosmetic Act, as 
amended (21 U.S.C. 301 et seq.).
    (b) Authorized distributor of record means a distributor with whom a 
manufacturer has established an ongoing relationship to distribute such 
manufacturer's products.
    (c) Blood means whole blood collected from a single donor and 
processed either for transfusion or further manufacturing.
    (d) Blood component means that part of a single-donor unit of blood 
separated by physical or mechanical means.
    (e) Bulk drug substance means any substance that is represented for 
use in a drug and that, when used in the manufacturing, processing, or 
packaging of a drug, becomes an active ingredient or

[[Page 117]]

a finished dosage form of the drug, but the term does not include 
intermediates used in the synthesis of such substances.
    (f) Charitable institution or charitable organization means a 
nonprofit hospital, health care entity, organization, institution, 
foundation, association, or corporation that has been granted an 
exemption under section 501(c)(3) of the Internal Revenue Code of 1954, 
as amended.
    (g) Common control means the power to direct or cause the direction 
of the management and policies of a person or an organization, whether 
by ownership of stock, voting rights, by contract, or otherwise.
    (h) Distribute means to sell, offer to sell, deliver, or offer to 
deliver a drug to a recipient, except that the term ``distribute'' does 
not include:
    (1) Delivering or offering to deliver a drug by a common carrier in 
the usual course of business as a common carrier; or
    (2) Providing of a drug sample to a patient by:
    (i) A practitioner licensed to prescribe such drug;
    (ii) A health care professional acting at the direction and under 
the supervision of such a practitioner; or
    (iii) The pharmacy of a hospital or of another health care entity 
that is acting at the direction of such a practitioner and that received 
such sample in accordance with the act and regulations.
    (i) Drug sample means a unit of a prescription drug that is not 
intended to be sold and is intended to promote the sale of the drug.
    (j) Drug coupon means a form that may be redeemed, at no cost or at 
reduced cost, for a drug that is prescribed in accordance with section 
503(b) of the act.
    (k) Electronic record means any combination of text, graphics, data, 
audio, pictorial, or other information representation in digital form 
that is created, modified, maintained, archived, retrieved, or 
distributed by a computer system.
    (l) Electronic signature means any computer data compilation of any 
symbol or series of symbols executed, adopted, or authorized by an 
individual to be the legally binding equivalent of the individual's 
handwritten signature.
    (m) Emergency medical reasons include, but are not limited to, 
transfers of a prescription drug between health care entities or from a 
health care entity to a retail pharmacy to alleviate a temporary 
shortage of a prescription drug arising from delays in or interruption 
of regular distribution schedules; sales to nearby emergency medical 
services, i.e., ambulance companies and fire fighting organizations in 
the same State or same marketing or service area, or nearby licensed 
practitioners, of drugs for use in the treatment of acutely ill or 
injured persons; provision of minimal emergency supplies of drugs to 
nearby nursing homes for use in emergencies or during hours of the day 
when necessary drugs cannot be obtained; and transfers of prescription 
drugs by a retail pharmacy to another retail pharmacy to alleviate a 
temporary shortage; but do not include regular and systematic sales to 
licensed practitioners of prescription drugs that will be used for 
routine office procedures.
    (n) FDA means the U.S. Food and Drug Administration.
    (o) Group purchasing organization means any entity established, 
maintained, and operated for the purchase of prescription drugs for 
distribution exclusively to its members with such membership consisting 
solely of hospitals and health care entities bound by written contract 
with the entity.
    (p) Handwritten signature means the scripted name or legal mark of 
an individual handwritten by that individual and executed or adopted 
with the present intention to authenticate a writing in a permanent 
form. The act of signing with a writing or marking instrument such as a 
pen or stylus is preserved. The scripted name or legal mark, while 
conventionally applied to paper, may also be applied to other devices 
that capture the name or mark.
    (q) Health care entity means any person that provides diagnostic, 
medical, surgical, or dental treatment, or chronic or rehabilitative 
care, but does not include any retail pharmacy or any wholesale 
distributor. Except as provided in Sec.  203.22(h) and (i), a person 
cannot simultaneously be a ``health care

[[Page 118]]

entity'' and a retail pharmacy or wholesale distributor.
    (r) Licensed practitioner means any person licensed or authorized by 
State law to prescribe drugs.
    (s) Manufacturer means any person who is a manufacturer as defined 
by Sec.  201.1 of this chapter.
    (t) Nonprofit affiliate means any not-for-profit organization that 
is either associated with or a subsidiary of a charitable organization 
as defined in section 501(c)(3) of the Internal Revenue Code of 1954.
    (u) Ongoing relationship means an association that exists when a 
manufacturer and a distributor enter into a written agreement under 
which the distributor is authorized to distribute the manufacturer's 
products for a period of time or for a number of shipments. If the 
distributor is not authorized to distribute a manufacturer's entire 
product line, the agreement must identify the specific drug products 
that the distributor is authorized to distribute.
    (v) PDA means the Prescription Drug Amendments of 1992.
    (w) PDMA means the Prescription Drug Marketing Act of 1987.
    (x) Person includes any individual, partnership, corporation, or 
association.
    (y) Prescription drug means any drug (including any biological 
product, except for blood and blood components intended for transfusion 
or biological products that are also medical devices) required by 
Federal law (including Federal regulation) to be dispensed only by a 
prescription, including finished dosage forms and bulk drug substances 
subject to section 503(b) of the act.
    (z) Representative means an employee or agent of a drug manufacturer 
or distributor who promotes the sale of prescription drugs to licensed 
practitioners and who may solicit or receive written requests for the 
delivery of drug samples. A detailer is a representative.
    (aa) Sample unit means a packet, card, blister pack, bottle, 
container, or other single package comprised of one or more dosage units 
of a prescription drug sample, intended by the manufacturer or 
distributor to be provided by a licensed practitioner to a patient in an 
unbroken or unopened condition.
    (bb) Unauthorized distributor means a distributor who does not have 
an ongoing relationship with a manufacturer to sell or distribute its 
products.
    (cc) Wholesale distribution means distribution of prescription drugs 
to persons other than a consumer or patient, but does not include:
    (1) Intracompany sales;
    (2) The purchase or other acquisition by a hospital or other health 
care entity that is a member of a group purchasing organization of a 
drug for its own use from the group purchasing organization or from 
other hospitals or health care entities that are members of such 
organizations;
    (3) The sale, purchase, or trade of a drug or an offer to sell, 
purchase, or trade a drug by a charitable organization to a nonprofit 
affiliate of the organization to the extent otherwise permitted by law;
    (4) The sale, purchase, or trade of a drug or an offer to sell, 
purchase, or trade a drug among hospitals or other health care entities 
that are under common control;
    (5) The sale, purchase, or trade of a drug or an offer to sell, 
purchase, or trade a drug for emergency medical reasons;
    (6) The sale, purchase, or trade of a drug, an offer to sell, 
purchase, or trade a drug, or the dispensing of a drug under a 
prescription executed in accordance with section 503(b) of the act;
    (7) The distribution of drug samples by manufacturers' and 
authorized distributors' representatives;
    (8) The sale, purchase, or trade of blood or blood components 
intended for transfusion;
    (9) Drug returns, when conducted by a hospital, health care entity, 
or charitable institution in accordance with Sec.  203.23; or
    (10) The sale of minimal quantities of drugs by retail pharmacies to 
licensed practitioners for office use.
    (dd) Wholesale distributor means any person engaged in wholesale 
distribution of prescription drugs, including, but not limited to, 
manufacturers; repackers; own-label distributors; private-label 
distributors; jobbers; brokers; warehouses, including manufacturers' and 
distributors' warehouses,

[[Page 119]]

chain drug warehouses, and wholesale drug warehouses; independent 
wholesale drug traders; and retail pharmacies that conduct wholesale 
distributions.

[64 FR 67756, Dec. 3, 1999, as amended at 73 FR 59500, Oct. 9, 2008]



                         Subpart B_Reimportation



Sec.  203.10  Restrictions on reimportation.

    No prescription drug or drug composed wholly or partly of insulin 
that was manufactured in a State and exported from the United States may 
be reimported by anyone other than its manufacturer, except that FDA may 
grant permission to a person other than the manufacturer to reimport a 
prescription drug or insulin-containing drug if it determines that such 
reimportation is required for emergency medical care.



Sec.  203.11  Applications for reimportation to provide emergency medical care.

    (a) Applications for reimportation for emergency medical care shall 
be submitted to the director of the FDA District Office in the district 
where reimportation is sought (addresses found in part 5, subpart M of 
this chapter).
    (b) Applications for reimportation to provide emergency medical care 
shall be reviewed and approved or disapproved by each district office.

[64 FR 67756, Dec. 3, 1999, as amended at 69 FR 17292, Apr. 2, 2004]



Sec.  203.12  An appeal from an adverse decision by the district office.

    An appeal from an adverse decision by the district office involving 
insulin-containing drugs or human prescription drugs or biological 
products regulated by the Center for Drug Evaluation and Research may be 
made to the Office of Compliance, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver 
Spring, MD 20993-0002. An appeal from an adverse decision by the 
district office involving human prescription biological products 
regulated by the Center for Biologics Evaluation and Research may be 
made to the Food and Drug Administration, Center for Biologics 
Evaluation and Research, Document Control Center, 10903 New Hampshire 
Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002.

[80 FR 18090, Apr. 3, 2015]



                      Subpart C_Sales Restrictions



Sec.  203.20  Sales restrictions.

    Except as provided in Sec.  203.22 or Sec.  203.23, no person may 
sell, purchase, or trade, or offer to sell, purchase, or trade any 
prescription drug that was:
    (a) Purchased by a public or private hospital or other health care 
entity; or
    (b) Donated or supplied at a reduced price to a charitable 
organization.



Sec.  203.22  Exclusions.

    Section 203.20 does not apply to:
    (a) The purchase or other acquisition of a drug for its own use by a 
hospital or other health care entity that is a member of a group 
purchasing organization from the group purchasing organization or from 
other hospitals or health care entities that are members of the 
organization.
    (b) The sale, purchase, or trade of a drug or an offer to sell, 
purchase, or trade a drug by a charitable organization to a nonprofit 
affiliate of the organization to the extent otherwise permitted by law.
    (c) The sale, purchase, or trade of a drug or an offer to sell, 
purchase, or trade a drug among hospitals or other health care entities 
that are under common control.
    (d) The sale, purchase, or trade of a drug or an offer to sell, 
purchase, or trade a drug for emergency medical reasons.
    (e) The sale, purchase, or trade of a drug, an offer to sell, 
purchase, or trade a drug, or the dispensing of a drug under a valid 
prescription.
    (f) The sale, purchase, or trade of a drug or the offer to sell, 
purchase, or trade a drug by hospitals or health care entities owned or 
operated by Federal, State, or local governmental units to other 
hospitals or health care entities owned or operated by Federal, State, 
or local governmental units.
    (g) The sale, purchase, or trade of, or the offer to sell, purchase, 
or trade blood or blood components intended for transfusion.

[[Page 120]]

    (h) The sale, purchase, or trade of, or the offer to sell, purchase, 
or trade, by a registered blood establishment that qualifies as a health 
care entity any:
    (1) Drug indicated for a bleeding or clotting disorder, or anemia;
    (2) Blood collection container approved under section 505 of the 
act; or
    (3) Drug that is a blood derivative (or a recombinant or synthetic 
form of a blood derivative); as long as all of the health care services 
that the establishment provides are related to its activities as a 
registered blood establishment or the health care services consist of 
collecting, processing, storing, or administering human hematopoietic 
stem/progenitor cells or performing diagnostic testing of specimens 
provided that these specimens are tested together with specimens 
undergoing routine donor testing. Blood establishments relying on the 
exclusion in this paragraph must satisfy all other requirements of the 
act and this part applicable to a wholesale distributor or retail 
pharmacy.
    (i) The sale, purchase, or trade of, or the offer to sell, purchase, 
or trade, by a comprehensive hemophilia diagnostic treatment center that 
is receiving a grant under section 501(a)(2) of the Social Security Act 
and that qualifies as a health care entity, any drug indicated for a 
bleeding or clotting disorder, or anemia, or any drug that is a blood 
derivative (or a recombinant or synthetic form of a blood derivative). 
Comprehensive hemophilia diagnostic treatment centers relying on the 
exclusion in this paragraph must satisfy all other requirements of the 
act and this part applicable to a wholesale distributor or retail 
pharmacy.

[64 FR 67756, Dec. 3, 1999, as amended at 73 FR 59500, Oct. 9, 2008]



Sec.  203.23  Returns.

    The return of a prescription drug purchased by a hospital or health 
care entity or acquired at a reduced price by or donated to a charitable 
institution is exempt from the prohibitions in Sec.  203.20, provided 
that:
    (a) The hospital, health care entity, or charitable institution 
documents the return by filling out a credit memo specifying:
    (1) The name and address of the hospital, health care entity, or 
charitable institution;
    (2) The name and address of the manufacturer or wholesale 
distributor from which it was acquired;
    (3) The product name and lot or control number;
    (4) The quantity returned; and
    (5) The date of the return.
    (b) The hospital, health care entity, or charitable institution 
forwards a copy of each credit memo to the manufacturer and retains a 
copy of each credit memo for its records;
    (c) Any drugs returned to a manufacturer or wholesale distributor 
are kept under proper conditions for storage, handling, and shipping, 
and written documentation showing that proper conditions were maintained 
is provided to the manufacturer or wholesale distributor to which the 
drugs are returned.



                            Subpart D_Samples



Sec.  203.30  Sample distribution by mail or common carrier.

    (a) Requirements for drug sample distribution by mail or common 
carrier. A manufacturer or authorized distributor of record may 
distribute a drug sample to a practitioner licensed to prescribe the 
drug that is to be sampled or, at the written request of a licensed 
practitioner, to the pharmacy of a hospital or other health care entity, 
by mail or common carrier, provided that:
    (1) The licensed practitioner executes and submits a written request 
to the manufacturer or authorized distributor of record, as set forth in 
paragraph (b) of this section, before the delivery of the drug sample;
    (2) The manufacturer or authorized distributor of record verifies 
with the appropriate State authority that the practitioner requesting 
the drug sample is licensed or authorized under State law to prescribe 
the drug product;
    (3) The recipient executes a written receipt, as set forth in 
paragraph (c) of this section, when the drug sample is delivered; and
    (4) The receipt is returned to the manufacturer or distributor from 
which the drug sample was received.

[[Page 121]]

    (b) Contents of the written request form for delivery of samples by 
mail or common carrier. (1) A written request for a drug sample to be 
delivered by mail or common carrier to a licensed practitioner is 
required to contain the following:
    (i) The name, address, professional title, and signature of the 
practitioner making the request;
    (ii) The practitioner's State license or authorization number or, 
where a scheduled drug product is requested, the practitioner's Drug 
Enforcement Administration number.
    (iii) The proprietary or established name and the strength of the 
drug sample requested;
    (iv) The quantity requested;
    (v) The name of the manufacturer and the authorized distributor of 
record, if the drug sample is requested from an authorized distributor 
of record; and
    (vi) The date of the request.
    (2) A written request for a drug sample to be delivered by mail or 
common carrier to the pharmacy of a hospital or other health care entity 
is required to contain, in addition to all of the information in 
paragraph (b)(l) of this section, the name and address of the pharmacy 
of the hospital or other health care entity to which the drug sample is 
to be delivered.
    (c) Contents of the receipt to be completed upon delivery of a drug 
sample. The receipt is to be on a form designated by the manufacturer or 
distributor, and is required to contain the following:
    (1) If the drug sample is delivered to the licensed practitioner who 
requested it, the receipt is required to contain the name, address, 
professional title, and signature of the practitioner or the 
practitioner's designee who acknowledges delivery of the drug sample; 
the proprietary or established name and strength of the drug sample and 
the quantity of the drug sample delivered; and the date of the delivery.
    (2) If the drug sample is delivered to the pharmacy of a hospital or 
other health care entity at the request of a licensed practitioner, the 
receipt is required to contain the name and address of the requesting 
licensed practitioner; the name and address of the hospital or health 
care entity pharmacy designated to receive the drug sample; the name, 
address, professional title, and signature of the person acknowledging 
delivery of the drug sample; the proprietary or established name and 
strength of the drug sample; the quantity of the drug sample delivered; 
and the date of the delivery.



Sec.  203.31  Sample distribution by means other than mail or common
carrier (direct delivery by a representative or detailer).

    (a) Requirements for drug sample distribution by means other than 
mail or common carrier. A manufacturer or authorized distributor of 
record may distribute by means other than mail or common carrier, by a 
representative or detailer, a drug sample to a practitioner licensed to 
prescribe the drug to be sampled or, at the written request of such a 
licensed practitioner, to the pharmacy of a hospital or other health 
care entity, provided that:
    (1) The manufacturer or authorized distributor of record receives 
from the licensed practitioner a written request signed by the licensed 
practitioner before the delivery of the drug sample;
    (2) The manufacturer or authorized distributor of record verifies 
with the appropriate State authority that the practitioner requesting 
the drug sample is licensed or authorized under State law to prescribe 
the drug product;
    (3) A receipt is signed by the recipient, as set forth in paragraph 
(c) of this section, when the drug sample is delivered;
    (4) The receipt is returned to the manufacturer or distributor; and
    (5) The requirements of paragraphs (d) through (e) of this section 
are met.
    (b) Contents of the written request forms for delivery of samples by 
a representative. (1) A written request for delivery of a drug sample by 
a representative to a licensed practitioner is required to contain the 
following:
    (i) The name, address, professional title, and signature of the 
practitioner making the request;
    (ii) The practitioner's State license or authorization number, or, 
where a scheduled drug product is requested, the practitioner's Drug 
Enforcement Administration number;

[[Page 122]]

    (iii) The proprietary or established name and the strength of the 
drug sample requested;
    (iv) The quantity requested;
    (v) The name of the manufacturer and the authorized distributor of 
record, if the drug sample is requested from an authorized distributor 
of record; and
    (vi) The date of the request.
    (2) A written request for delivery of a drug sample by a 
representative to the pharmacy of a hospital or other health care entity 
is required to contain, in addition to all of the information in 
paragraph (b) of this section, the name and address of the pharmacy of 
the hospital or other health care entity to which the drug sample is to 
be delivered.
    (c) Contents of the receipt to be completed upon delivery of a drug 
sample. The receipt is to be on a form designated by the manufacturer or 
distributor, and is required to contain the following:
    (1) If the drug sample is received at the address of the licensed 
practitioner who requested it, the receipt is required to contain the 
name, address, professional title, and signature of the practitioner or 
the practitioner's designee who acknowledges delivery of the drug 
sample; the proprietary or established name and strength of the drug 
sample; the quantity of the drug sample delivered; and the date of the 
delivery.
    (2) If the drug sample is received by the pharmacy of a hospital or 
other health care entity at the request of a licensed practitioner, the 
receipt is required to contain the name and address of the requesting 
licensed practitioner; the name and address of the hospital or health 
care entity pharmacy designated to receive the drug sample; the name, 
address, professional title, and signature of the person acknowledging 
delivery of the drug sample; the proprietary or established name and 
strength of the drug sample; the quantity of the drug sample delivered; 
and the date of the delivery.
    (d) Inventory and reconciliation of drug samples of manufacturers' 
and distributors' representatives. Each drug manufacturer or authorized 
distributor of record that distributes drug samples by means of 
representatives shall conduct, at least annually, a complete and 
accurate physical inventory of all drug samples. All drug samples in the 
possession or control of each manufacturer's and distributor's 
representatives are required to be inventoried and the results of the 
inventory are required to be recorded in an inventory record, as 
specified in paragraph (d)(1) of this section. In addition, 
manufacturers and distributors shall reconcile the results of the 
physical inventory with the most recently completed prior physical 
inventory and create a report documenting the reconciliation process, as 
specified in paragraph (d)(2) of this section.
    (1) The inventory record is required to identify all drug samples in 
a representative's stock by the proprietary or established name, dosage 
strength, and number of units.
    (2) The reconciliation report is required to include:
    (i) The inventory record for the most recently completed prior 
inventory;
    (ii) A record of each drug sample shipment received since the most 
recently completed prior inventory, including the sender and date of the 
shipment, and the proprietary or established name, dosage strength, and 
number of sample units received;
    (iii) A record of drug sample distributions since the most recently 
completed inventory showing the name and address of each recipient of 
each sample unit shipped, the date of the shipment, and the proprietary 
or established name, dosage strength, and number of sample units 
shipped. For the purposes of this paragraph and paragraph (d)(2)(v) of 
this section, ``distributions'' includes distributions to health care 
practitioners or designated hospital or health care entity pharmacies, 
transfers or exchanges with other firm representatives, returns to the 
manufacturer or authorized distributor, destruction of drug samples by a 
sales representative, and other types of drug sample dispositions. The 
specific type of distribution must be specified in the record;
    (iv) A record of drug sample thefts or significant losses reported 
by the representative since the most recently completed prior inventory, 
including

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the approximate date of the occurrence and the proprietary or 
established name, dosage strength, and number of sample units stolen or 
lost; and
    (v) A record summarizing the information required by paragraphs 
(d)(2)(ii) through (d)(2)(iv) of this section. The record must show, for 
each type of sample unit (i.e., sample units having the same established 
or proprietary name and dosage strength), the total number of sample 
units received, distributed, lost, or stolen since the most recently 
completed prior inventory. For example, a typical entry in this record 
may read ``50 units risperidone (1 mg) returned to manufacturer'' or 
simply ``Risperidone (1 mg)/50/returned to manufacturer.''
    (3) Each drug manufacturer or authorized distributor of record shall 
take appropriate internal control measures to guard against error and 
possible fraud in the conduct of the physical inventory and 
reconciliation, and in the preparation of the inventory record and 
reconciliation report.
    (4) A manufacturer or authorized distributor of record shall 
carefully evaluate any apparent discrepancy or significant loss revealed 
through the inventory and reconciliation process and shall fully 
investigate any such discrepancy or significant loss that cannot be 
justified.
    (e) Lists of manufacturers' and distributors' representatives. Each 
drug manufacturer or authorized distributor of record who distributes 
drug samples by means of representatives shall maintain a list of the 
names and addresses of its representatives who distribute drug samples 
and of the sites where drug samples are stored.



Sec.  203.32  Drug sample storage and handling requirements.

    (a) Storage and handling conditions. Manufacturers, authorized 
distributors of record, and their representatives shall store and handle 
all drug samples under conditions that will maintain their stability, 
integrity, and effectiveness and ensure that the drug samples are free 
of contamination, deterioration, and adulteration.
    (b) Compliance with compendial and labeling requirements. 
Manufacturers, authorized distributors of record, and their 
representatives can generally comply with this section by following the 
compendial and labeling requirements for storage and handling of a 
particular prescription drug in handling samples of that drug.



Sec.  203.33  Drug sample forms.

    A sample request or receipt form may be delivered by mail, common 
carrier, or private courier or may be transmitted photographically or 
electronically (i.e., by telephoto, wirephoto, radiophoto, facsimile 
transmission (FAX), xerography, or electronic data transfer) or by any 
other system, provided that the method for transmission meets the 
security requirements set forth in Sec.  203.60(c).



Sec.  203.34  Policies and procedures; administrative systems.

    Each manufacturer or authorized distributor of record that 
distributes drug samples shall establish, maintain, and adhere to 
written policies and procedures describing its administrative systems 
for the following:
    (a) Distributing drug samples by mail or common carrier, including 
methodology for reconciliation of requests and receipts;
    (b) Distributing drug samples by means other than mail or common 
carrier including the methodology for:
    (1) Reconciling requests and receipts, identifying patterns of 
nonresponse, and the manufacturer's or distributor's response when such 
patterns are found;
    (2) Conducting the annual physical inventory and preparation of the 
reconciliation report;
    (3) Implementing a sample distribution security and audit system, 
including conducting random and for-cause audits of sales 
representatives by personnel independent of the sales force; and
    (4) Storage of drug samples by representatives;
    (c) Identifying any significant loss of drug samples and notifying 
FDA of the loss; and
    (d) Monitoring any loss or theft of drug samples.



Sec.  203.35  Standing requests.

    Manufacturers or authorized distributors of record shall not 
distribute

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drug samples on the basis of open-ended or standing requests, but shall 
require separate written requests for each drug sample or group of 
samples. An arrangement by which a licensed practitioner requests in 
writing that a specified number of drug samples be delivered over a 
period of not more than 6 months, with the actual delivery dates for 
parts of the order to be set by subsequent oral communication or 
electronic transmission, is not considered to be a standing request.



Sec.  203.36  Fulfillment houses, shipping and mailing services,
comarketing agreements, and third-party recordkeeping.

    (a) Responsibility for creating and maintaining forms, reports, and 
records. Any manufacturer or authorized distributor of record that uses 
a fulfillment house, shipping or mailing service, or other third party, 
or engages in a comarketing agreement with another manufacturer or 
distributor to distribute drug samples or to meet any of the 
requirements of PDMA, PDA, or this part, remains responsible for 
creating and maintaining all requests, receipts, forms, reports, and 
records required under PDMA, PDA, and this part.
    (b) Responsibility for producing requested forms, reports, or 
records. A manufacturer or authorized distributor of record that 
contracts with a third party to maintain some or all of its records 
shall produce requested forms, reports, records, or other required 
documents within 2 business days of a request by an authorized 
representative of FDA or another Federal, State, or local regulatory or 
law enforcement official.



Sec.  203.37  Investigation and notification requirements.

    (a) Investigation of falsification of drug sample records. A 
manufacturer or authorized distributor of record that has reason to 
believe that any person has falsified drug sample requests, receipts, or 
records, or is diverting drug samples, shall:
    (1) Notify FDA, by telephone or in writing, within 5 working days;
    (2) Immediately initiate an investigation; and
    (3) Provide FDA with a complete written report, including the reason 
for and the results of the investigation, not later than 30 days after 
the date of the initial notification in paragraph (a)(1) of this 
section.
    (b) Significant loss or known theft of drug samples. A manufacturer 
or authorized distributor of record that distributes drug samples or a 
charitable institution that receives donated drug samples from a 
licensed practitioner shall:
    (1) Notify FDA, by telephone or in writing, within 5 working days of 
becoming aware of a significant loss or known theft;
    (2) Immediately initiate an investigation into the significant loss 
or known theft; and
    (3) Provide FDA with a complete written report, including the reason 
for and the results of the investigation, not later than 30 days after 
the date of the initial notification in paragraph (b)(1) of this 
section.
    (c) Conviction of a representative. (1) A manufacturer or authorized 
distributor of record that distributes drug samples shall notify FDA, by 
telephone or in writing, within 30 days of becoming aware of the 
conviction of one or more of its representatives for a violation of 
section 503(c)(1) of the act or any State law involving the sale, 
purchase, or trade of a drug sample or the offer to sell, purchase, or 
trade a drug sample.
    (2) A manufacturer or authorized distributor of record shall provide 
FDA with a complete written report not later than 30 days after the date 
of the initial notification.
    (d) Selection of individual responsible for drug sample information. 
A manufacturer or authorized distributor of record that distributes drug 
samples shall inform FDA in writing within 30 days of selecting the 
individual responsible for responding to a request for information about 
drug samples of that individual's name, business address, and telephone 
number.
    (e) Whom to notify at FDA. Notifications and reports concerning 
human prescription drugs or biological products regulated by the Center 
for Drug Evaluation and Research shall be made to the Division of 
Compliance Risk Management and Surveillance, Office

[[Page 125]]

of Compliance, Center for Drug Evaluation and Research, Food and Drug 
Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002. 
Notifications and reports concerning human prescription biological 
products regulated by the Center for Biologics Evaluation and Research 
shall be made to the Food and Drug Administration, Center for Biologics 
Evaluation and Research, Document Control Center, 10903 New Hampshire 
Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002.

[64 FR 67756, Dec. 3, 1999, as amended at 69 FR 48775, Aug. 11, 2004; 70 
FR 14981, Mar. 24, 2005; 74 FR 13112, Mar. 26, 2009; 80 FR 18090, Apr. 
3, 2015]



Sec.  203.38  Sample lot or control numbers; labeling of sample units.

    (a) Lot or control number required on drug sample labeling and 
sample unit label. The manufacturer or authorized distributor of record 
of a drug sample shall include on the label of the sample unit and on 
the outside container or packaging of the sample unit, if any, an 
identifying lot or control number that will permit the tracking of the 
distribution of each drug sample unit.
    (b) Records containing lot or control numbers required for all drug 
samples distributed. A manufacturer or authorized distributor of record 
shall maintain for all samples distributed records of drug sample 
distribution containing lot or control numbers that are sufficient to 
permit the tracking of sample units to the point of the licensed 
practitioner.
    (c) Labels of sample units. Each sample unit shall bear a label that 
clearly denotes its status as a drug sample, e.g., ``sample,'' ``not for 
sale,'' ``professional courtesy package.''
    (1) A drug that is labeled as a drug sample is deemed to be a drug 
sample within the meaning of the act.
    (2) A drug product dosage unit that bears an imprint identifying the 
dosage form as a drug sample is deemed to be a drug sample within the 
meaning of the act.
    (3) Notwithstanding paragraphs (c)(1) and (c)(2) of this section, 
any article that is a drug sample as defined in section 503(c)(1) of the 
act and Sec.  203.3(i) that fails to bear the label required in this 
paragraph (c) is a drug sample.



Sec.  203.39  Donation of drug samples to charitable institutions.

    A charitable institution may receive a drug sample donated by a 
licensed practitioner or another charitable institution for dispensing 
to a patient of the charitable institution, or donate a drug sample to 
another charitable institution for dispensing to its patients, provided 
that the following requirements are met:
    (a) A drug sample donated by a licensed practitioner or donating 
charitable institution shall be received by a charitable institution in 
its original, unopened packaging with its labeling intact.
    (b) Delivery of a donated drug sample to a recipient charitable 
institution shall be completed by mail or common carrier, collection by 
an authorized agent or employee of the recipient charitable institution, 
or personal delivery by a licensed practitioner or an agent or employee 
of the donating charitable institution. Donated drug samples shall be 
placed by the donor in a sealed carton for delivery to or collection by 
the recipient charitable institution.
    (c) A donated drug sample shall not be dispensed to a patient or be 
distributed to another charitable institution until it has been examined 
by a licensed practitioner or registered pharmacist at the recipient 
charitable institution to confirm that the donation record accurately 
describes the drug sample delivered and that no drug sample is 
adulterated or misbranded for any reason, including, but not limited to, 
the following:
    (1) The drug sample is out of date;
    (2) The labeling has become mutilated, obscured, or detached from 
the drug sample packaging;
    (3) The drug sample shows evidence of having been stored or shipped 
under conditions that might adversely affect its stability, integrity, 
or effectiveness;
    (4) The drug sample is for a prescription drug product that has been 
recalled or is no longer marketed; or
    (5) The drug sample is otherwise possibly contaminated, 
deteriorated, or adulterated.
    (d) The recipient charitable institution shall dispose of any drug 
sample found to be unsuitable by destroying it

[[Page 126]]

or by returning it to the manufacturer. The charitable institution shall 
maintain complete records of the disposition of all destroyed or 
returned drug samples.
    (e) The recipient charitable institution shall prepare at the time 
of collection or delivery of a drug sample a complete and accurate 
donation record, a copy of which shall be retained by the recipient 
charitable institution for at least 3 years, containing the following 
information:
    (1) The name, address, and telephone number of the licensed 
practitioner (or donating charitable institution);
    (2) The manufacturer, brand name, quantity, and lot or control 
number of the drug sample donated; and
    (3) The date of the donation.
    (f) Each recipient charitable institution shall maintain complete 
and accurate records of donation, receipt, inspection, inventory, 
dispensing, redistribution, destruction, and returns sufficient for 
complete accountability and auditing of drug sample stocks.
    (g) Each recipient charitable institution shall conduct, at least 
annually, an inventory of prescription drug sample stocks and shall 
prepare a report reconciling the results of each inventory with the most 
recent prior inventory. Drug sample inventory discrepancies and 
reconciliation problems shall be investigated by the charitable 
institution and reported to FDA.
    (h) A recipient charitable institution shall store drug samples 
under conditions that will maintain the sample's stability, integrity, 
and effectiveness, and will ensure that the drug samples will be free of 
contamination, deterioration, and adulteration.
    (i) A charitable institution shall notify FDA within 5 working days 
of becoming aware of a significant loss or known theft of prescription 
drug samples.



                    Subpart E_Wholesale Distribution



Sec.  203.50  Requirements for wholesale distribution of prescription
drugs.

    (a) Identifying statement for sales by unauthorized distributors. 
Before the completion of any wholesale distribution by a wholesale 
distributor of a prescription drug for which the seller is not an 
authorized distributor of record to another wholesale distributor or 
retail pharmacy, the seller shall provide to the purchaser a statement 
identifying each prior sale, purchase, or trade of such drug. This 
identifying statement shall include:
    (1) The proprietary and established name of the drug;
    (2) Dosage;
    (3) Container size;
    (4) Number of containers;
    (5) The drug's lot or control number(s);
    (6) The business name and address of all parties to each prior 
transaction involving the drug, starting with the manufacturer; and
    (7) The date of each previous transaction.
    (b) The drug origin statement is subject to the record retention 
requirements of Sec.  203.60 and must be retained by all wholesale 
distributors involved in the distribution of the drug product, whether 
authorized or unauthorized, for 3 years.
    (c) Identifying statement not required when additional manufacturing 
processes are completed. A manufacturer that subjects a drug to any 
additional manufacturing processes to produce a different drug is not 
required to provide to a purchaser a statement identifying the previous 
sales of the component drug or drugs.
    (d) List of authorized distributors of record. Each manufacturer 
shall maintain at the corporate offices a current written list of all 
authorized distributors of record.
    (1) Each manufacturer's list of authorized distributors of record 
shall specify whether each distributor listed thereon is authorized to 
distribute the manufacturer's full product line or only particular, 
specified products.
    (2) Each manufacturer shall update its list of authorized 
distributors of record on a continuing basis.
    (3) Each manufacturer shall make its list of authorized distributors 
of record available on request to the public for inspection or copying. 
A manufacturer may impose reasonable copying charges for such requests 
from members of the public.

[[Page 127]]



        Subpart F_Request and Receipt Forms, Reports, and Records



Sec.  203.60  Request and receipt forms, reports, and records.

    (a) Use of electronic records, electronic signatures, and 
handwritten signatures executed to electronic records. (1) Provided the 
requirements of part 11 of this chapter are met, electronic records, 
electronic signatures, and handwritten signatures executed to electronic 
records may be used as an alternative to paper records and handwritten 
signatures executed on paper to meet any of the record and signature 
requirements of PDMA, PDA, or this part.
    (2) Combinations of paper records and electronic records, electronic 
records and handwritten signatures executed on paper, or paper records 
and electronic signatures or handwritten signatures executed to 
electronic records, may be used to meet any of the record and signature 
requirements of PDMA, PDA, or this part, provided that:
    (i) The requirements of part 11 of this chapter are met for the 
electronic records, electronic signatures, or handwritten signatures 
executed to electronic records; and
    (ii) A reasonably secure link between the paper-based and electronic 
components exists such that the combined records and signatures are 
trustworthy and reliable, and to ensure that the signer cannot readily 
repudiate the signed records as not genuine.
    (3) For the purposes of this paragraph (a), the phrase ``record and 
signature requirements of PDMA, PDA, or this part'' includes drug sample 
request and receipt forms, reports, records, and other documents, and 
their associated signatures required by PDMA, PDA, and this part.
    (b) Maintenance of request and receipt forms, reports, records, and 
other documents created on paper. Request and receipt forms, reports, 
records, and other documents created on paper may be maintained on paper 
or by photographic imaging (i.e., photocopies or microfiche), provided 
that the security and authentication requirements described in paragraph 
(c) of this section are followed. Where a required document is created 
on paper and electronically scanned into a computer, the resulting 
record is an electronic record that must meet the requirements of part 
11 of this chapter.
    (c) Security and authentication requirements for request and receipt 
forms, reports, records, and other documents created on paper. A request 
or receipt form, report, record, or other document, and any signature 
appearing thereon, that is created on paper and that is maintained by 
photographic imaging, or transmitted electronically (i.e., by facsimile) 
shall be maintained or transmitted in a form that provides reasonable 
assurance of being:
    (1) Resistant to tampering, revision, modification, fraud, 
unauthorized use, or alteration;
    (2) Preserved in accessible and retrievable fashion; and
    (3) Available to permit copying for purposes of review, analysis, 
verification, authentication, and reproduction by the person who 
executed the form or created the record, by the manufacturer or 
distributor, and by authorized personnel of FDA and other regulatory and 
law enforcement agencies.
    (d) Retention of request and receipt forms, reports, lists, records, 
and other documents. Any person required to create or maintain reports, 
lists, or other records under PDMA, PDA, or this part, including records 
relating to the distribution of drug samples, shall retain them for at 
least 3 years after the date of their creation.
    (e) Availability of request and receipt forms, reports, lists, and 
records. Any person required to create or maintain request and receipt 
forms, reports, lists, or other records under PDMA, PDA, or this part 
shall make them available, upon request, in a form that permits copying 
or other means of duplication, to FDA or other Federal, State, or local 
regulatory and law enforcement officials for review and reproduction. 
The records shall be made available within 2 business days of a request.



                            Subpart G_Rewards



Sec.  203.70  Application for a reward.

    (a) Reward for providing information leading to the institution of a 
criminal

[[Page 128]]

proceeding against, and conviction of, a person for the sale, purchase, 
or trade of a drug sample. A person who provides information leading to 
the institution of a criminal proceeding against, and conviction of, a 
person for the sale, purchase, or trade of a drug sample, or the offer 
to sell, purchase, or trade a drug sample, in violation of section 
503(c)(1) of the act, is entitled to one-half the criminal fine imposed 
and collected for such violation, but not more than $125,000.
    (b) Procedure for making application for a reward for providing 
information leading to the institution of a criminal proceeding against, 
and conviction of, a person for the sale, purchase, or trade of a drug 
sample. A person who provides information leading to the institution of 
a criminal proceeding against, and conviction of, a person for the sale, 
purchase, or trade of a drug sample, or the offer to sell, purchase, or 
trade a drug sample, in violation of section 503(c)(1) of the act, may 
apply for a reward by making written application to:
    (1) Director, Office of Compliance, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver 
Spring, MD 20993-0002; or
    (2) Food and Drug Administration, Center for Biologics Evaluation 
and Research, Office of Compliance and Biologics Quality (ATTN: 
Director), Document Control Center, 10903 New Hampshire Ave., Bldg. 71, 
Rm. G112, Silver Spring, MD 20993-0002, as appropriate.

[64 FR 67756, Dec. 3, 1999, as amended at 69 FR 48775, Aug. 11, 2004; 74 
FR 13112, Mar. 26, 2009; 80 FR 18091, Apr. 3, 2013]



PART 205_GUIDELINES FOR STATE LICENSING OF WHOLESALE PRESCRIPTION DRUG
DISTRIBUTORS--Table of Contents



Sec.
205.1 Scope.
205.2 Purpose.
205.3 Definitions.
205.4 Wholesale drug distributor licensing requirement.
205.5 Minimum required information for licensure.
205.6 Minimum qualifications.
205.7 Personnel.
205.8 Violations and penalties.
205.50 Minimum requirements for the storage and handling of prescription 
          drugs and for the establishment and maintenance of 
          prescription drug distribution records.

    Authority: 21 U.S.C. 351, 352, 353, 371, 374.

    Source: 55 FR 38023, Sept. 14, 1990, unless otherwise noted.



Sec.  205.1  Scope.

    This part applies to any person, partnership, corporation, or 
business firm in a State engaging in the wholesale distribution of human 
prescription drugs in interstate commerce.



Sec.  205.2  Purpose.

    The purpose of this part is to implement the Prescription Drug 
Marketing Act of 1987 by providing minimum standards, terms, and 
conditions for the licensing by State licensing authorities of persons 
who engage in wholesale distributions in interstate commerce of 
prescription drugs.



Sec.  205.3  Definitions.

    (a) Blood means whole blood collected from a single donor and 
processed either for transfusion or further manufacturing.
    (b) Blood component means that part of blood separated by physical 
or mechanical means.
    (c) Drug sample means a unit of a prescription drug that is not 
intended to be sold and is intended to promote the sale of the drug.
    (d) Manufacturer means anyone who is engaged in manufacturing, 
preparing, propagating, compounding, processing, packaging, repackaging, 
or labeling of a prescription drug.
    (e) Prescription drug means any human drug required by Federal law 
or regulation to be dispensed only by a prescription, including finished 
dosage forms and active ingredients subject to section 503(b) of the 
Federal Food, Drug, and Cosmetic Act.
    (f) Wholesale distribution and wholesale distribution means 
distribution of prescription drugs to persons other than a consumer or 
patient, but does not include:
    (1) Intracompany sales;

[[Page 129]]

    (2) The purchase or other acquisition by a hospital or other health 
care entity that is a member of a group purchasing organization of a 
drug for its own use from the group purchasing organization or from 
other hospitals or health care entities that are members of such 
organizations;
    (3) The sale, purchase, or trade of a drug or an offer to sell, 
purchase, or trade a drug by a charitable organization described in 
section 501(c)(3) of the Internal Revenue Code of 1954 to a nonprofit 
affiliate of the organization to the extent otherwise permitted by law;
    (4) The sale, purchase, or trade of a drug or an offer to sell, 
purchase, or trade a drug among hospitals or other health care entities 
that are under common control; for purposes of this section, common 
control means the power to direct or cause the direction of the 
management and policies of a person or an organization, whether by 
ownership of stock, voting rights, by contract, or otherwise;
    (5) The sale, purchase, or trade of a drug or an offer to sell, 
purchase, or trade a drug for emergency medical reasons; for purposes of 
this section, emergency medical reasons includes transfers of 
prescription drugs by a retail pharmacy to another retail pharmacy to 
alleviate a temporary shortage;
    (6) The sale, purchase, or trade of a drug, an offer to sell, 
purchase, or trade a drug, or the dispensing of a drug pursuant to a 
prescription;
    (7) The distribution of drug samples by manufacturers' 
representatives or distributors' representatives; or
    (8) The sale, purchase, or trade of blood and blood components 
intended for transfusion.
    (9) Drug returns, when conducted by a hospital, health care entity, 
or charitable institution in accordance with Sec.  203.23 of this 
chapter; or
    (10) The sale of minimal quantities of drugs by retail pharmacies to 
licensed practitioners for office use.
    (g) Wholesale distributor means any one engaged in wholesale 
distribution of prescription drugs, including, but not limited to, 
manufacturers; repackers; own-label distributors; private-label 
distributors; jobbers; brokers; warehouses, including manufacturers' and 
distributors' warehouses, chain drug warehouses, and wholesale drug 
warehouses; independent wholesale drug traders; and retail pharmacies 
that conduct wholesale distributions.
    (h) Health care entity means any person that provides diagnostic, 
medical, surgical, or dental treatment, or chronic or rehabilitative 
care, but does not include any retail pharmacy or any wholesale 
distributor. Except as provided in Sec.  203.22(h) and (i) of this 
chapter, a person cannot simultaneously be a ``health care entity'' and 
a retail pharmacy or wholesale distributor.

[55 FR 38023, Sept. 14, 1990, as amended at 64 FR 67762, Dec. 3, 1999, 
73 FR 59501, Oct. 9, 2008]



Sec.  205.4  Wholesale drug distributor licensing requirement.

    Every wholesale distributor in a State who engages in wholesale 
distributions of prescription drugs in interstate commerce must be 
licensed by the State licensing authority in accordance with this part 
before engaging in wholesale distributions of prescription drugs in 
interstate commerce.



Sec.  205.5  Minimum required information for licensure.

    (a) The State licensing authority shall require the following 
minimum information from each wholesale drug distributor as part of the 
license described in Sec.  205.4 and as part of any renewal of such 
license:
    (1) The name, full business address, and telephone number of the 
licensee;
    (2) All trade or business names used by the licensee;
    (3) Addresses, telephone numbers, and the names of contact persons 
for all facilities used by the licensee for the storage, handling, and 
distribution of prescription drugs;
    (4) The type of ownership or operation (i.e., partnership, 
corporation, or sole proprietorship); and
    (5) The name(s) of the owner and/or operator of the licensee, 
including:
    (i) If a person, the name of the person;
    (ii) If a partnership, the name of each partner, and the name of the 
partnership;

[[Page 130]]

    (iii) If a corporation, the name and title of each corporate officer 
and director, the corporate names, and the name of the State of 
incorporation; and
    (iv) If a sole proprietorship, the full name of the sole proprietor 
and the name of the business entity.
    (b) The State licensing authority may provide for a single license 
for a business entity operating more than one facility within that 
State, or for a parent entity with divisions, subsidiaries, and/or 
affiliate companies within that State when operations are conducted at 
more than one location and there exists joint ownership and control 
among all the entities.
    (c) Changes in any information in paragraph (a) of this section 
shall be submitted to the State licensing authority as required by such 
authority.

(Approved by the Office of Management and Budget under control number 
0910-0251)



Sec.  205.6  Minimum qualifications.

    (a) The State licensing authority shall consider, at a minimum, the 
following factors in reviewing the qualifications of persons who engage 
in wholesale distribution of prescription drugs within the State:
    (1) Any convictions of the applicant under any Federal, State, or 
local laws relating to drug samples, wholesale or retail drug 
distribution, or distribution of controlled substances;
    (2) Any felony convictions of the applicant under Federal, State, or 
local laws;
    (3) The applicant's past experience in the manufacture or 
distribution of prescription drugs, including controlled substances;
    (4) The furnishing by the applicant of false or fraudulent material 
in any application made in connection with drug manufacturing or 
distribution;
    (5) Suspension or revocation by Federal, State, or local government 
of any license currently or previously held by the applicant for the 
manufacture or distribution of any drugs, including controlled 
substances;
    (6) Compliance with licensing requirements under previously granted 
licenses, if any;
    (7) Compliance with requirements to maintain and/or make available 
to the State licensing authority or to Federal, State, or local law 
enforcement officials those records required under this section; and
    (8) Any other factors or qualifications the State licensing 
authority considers relevant to and consistent with the public health 
and safety.
    (b) The State licensing authority shall have the right to deny a 
license to an applicant if it determines that the granting of such a 
license would not be in the public interest.



Sec.  205.7  Personnel.

    The State licensing authority shall require that personnel employed 
in wholesale distribution have appropriate education and/or experience 
to assume responsibility for positions related to compliance with State 
licensing requirements.



Sec.  205.8  Violations and penalties.

    (a) State licensing laws shall provide for the suspension or 
revocation of licenses upon conviction of violations of Federal, State, 
or local drug laws or regulations, and may provide for fines, 
imprisonment, or civil penalties.
    (b) State licensing laws shall provide for suspension or revocation 
of licenses, where appropriate, for violations of its provisions.



Sec.  205.50  Minimum requirements for the storage and handling of
prescription drugs and for the establishment and maintenance of
prescription drug distribution records.

    The State licensing law shall include the following minimum 
requirements for the storage and handling of prescription drugs, and for 
the establishment and maintenance of prescription drug distribution 
records by wholesale drug distributors and their officers, agents, 
representatives, and employees:
    (a) Facilities. All facilities at which prescription drugs are 
stored, warehoused, handled, held, offered, marketed, or displayed 
shall:
    (1) Be of suitable size and construction to facilitate cleaning, 
maintenance, and proper operations;
    (2) Have storage areas designed to provide adequate lighting, 
ventilation, temperature, sanitation, humidity, space, equipment, and 
security conditions;

[[Page 131]]

    (3) Have a quarantine area for storage of prescription drugs that 
are outdated, damaged, deteriorated, misbranded, or adulterated, or that 
are in immediate or sealed, secondary containers that have been opened;
    (4) Be maintained in a clean and orderly condition; and
    (5) Be free from infestation by insects, rodents, birds, or vermin 
of any kind.
    (b) Security. (1) All facilities used for wholesale drug 
distribution shall be secure from unauthorized entry.
    (i) Access from outside the premises shall be kept to a minimum and 
be well-controlled.
    (ii) The outside perimeter of the premises shall be well-lighted.
    (iii) Entry into areas where prescription drugs are held shall be 
limited to authorized personnel.
    (2) All facilities shall be equipped with an alarm system to detect 
entry after hours.
    (3) All facilities shall be equipped with a security system that 
will provide suitable protection against theft and diversion. When 
appropriate, the security system shall provide protection against theft 
or diversion that is facilitated or hidden by tampering with computers 
or electronic records.
    (c) Storage. All prescription drugs shall be stored at appropriate 
temperatures and under appropriate conditions in accordance with 
requirements, if any, in the labeling of such drugs, or with 
requirements in the current edition of an official compendium, such as 
the United States Pharmacopeia/National Formulary (USP/NF).
    (1) If no storage requirements are established for a prescription 
drug, the drug may be held at ``controlled'' room temperature, as 
defined in an official compendium, to help ensure that its identity, 
strength, quality, and purity are not adversely affected.
    (2) Appropriate manual, electromechanical, or electronic temperature 
and humidity recording equipment, devices, and/or logs shall be utilized 
to document proper storage of prescription drugs.
    (3) The recordkeeping requirements in paragraph (f) of this section 
shall be followed for all stored drugs.
    (d) Examination of materials. (1) Upon receipt, each outside 
shipping container shall be visually examined for identity and to 
prevent the acceptance of contaminated prescription drugs or 
prescription drugs that are otherwise unfit for distribution. This 
examination shall be adequate to reveal container damage that would 
suggest possible contamination or other damage to the contents.
    (2) Each outgoing shipment shall be carefully inspected for identity 
of the prescription drug products and to ensure that there is no 
delivery of prescription drugs that have been damaged in storage or held 
under improper conditions.
    (3) The recordkeeping requirements in paragraph (f) of this section 
shall be followed for all incoming and outgoing prescription drugs.
    (e) Returned, damaged, and outdated prescription drugs. (1) 
Prescription drugs that are outdated, damaged, deteriorated, misbranded, 
or adulterated shall be quarantined and physically separated from other 
prescription drugs until they are destroyed or returned to their 
supplier.
    (2) Any prescription drugs whose immediate or sealed outer or sealed 
secondary containers have been opened or used shall be identified as 
such, and shall be quarantined and physically separated from other 
prescription drugs until they are either destroyed or returned to the 
supplier.
    (3) If the conditions under which a prescription drug has been 
returned cast doubt on the drug's safety, identity, strength, quality, 
or purity, then the drug shall be destroyed, or returned to the 
supplier, unless examination, testing, or other investigation proves 
that the drug meets appropriate standards of safety, identity, strength, 
quality, and purity. In determining whether the conditions under which a 
drug has been returned cast doubt on the drug's safety, identity, 
strength, quality, or purity, the wholesale drug distributor shall 
consider, among other things, the conditions under which the drug has 
been held, stored, or shipped before or during its return and the 
condition of the drug and its container, carton, or labeling, as a 
result of storage or shipping.

[[Page 132]]

    (4) The recordkeeping requirements in paragraph (f) of this section 
shall be followed for all outdated, damaged, deteriorated, misbranded, 
or adulterated prescription drugs.
    (f) Recordkeeping. (1) Wholesale drug distributors shall establish 
and maintain inventories and records of all transactions regarding the 
receipt and distribution or other disposition of prescription drugs. 
These records shall include the following information:
    (i) The source of the drugs, including the name and principal 
address of the seller or transferor, and the address of the location 
from which the drugs were shipped;
    (ii) The identity and quantity of the drugs received and distributed 
or disposed of; and
    (iii) The dates of receipt and distribution or other disposition of 
the drugs.
    (2) Inventories and records shall be made available for inspection 
and photocopying by authorized Federal, State, or local law enforcement 
agency officials for a period of 3 years after the date of their 
creation.
    (3) Records described in this section that are kept at the 
inspection site or that can be immediately retrieved by computer or 
other electronic means shall be readily available for authorized 
inspection during the retention period. Records kept at a central 
location apart from the inspection site and not electronically 
retrievable shall be made available for inspection within 2 working days 
of a request by an authorized official of a Federal, State, or local law 
enforcement agency.
    (g) Written policies and procedures. Wholesale drug distributors 
shall establish, maintain, and adhere to written policies and 
procedures, which shall be followed for the receipt, security, storage, 
inventory, and distribution of prescription drugs, including policies 
and procedures for identifying, recording, and reporting losses or 
thefts, and for correcting all errors and inaccuracies in inventories. 
Wholesale drug distributors shall include in their written policies and 
procedures the following:
    (1) A procedure whereby the oldest approved stock of a prescription 
drug product is distributed first. The procedure may permit deviation 
from this requirement, if such deviation is temporary and appropriate.
    (2) A procedure to be followed for handling recalls and withdrawals 
of prescription drugs. Such procedure shall be adequate to deal with 
recalls and withdrawals due to:
    (i) Any action initiated at the request of the Food and Drug 
Administration or other Federal, State, or local law enforcement or 
other government agency, including the State licensing agency;
    (ii) Any voluntary action by the manufacturer to remove defective or 
potentially defective drugs from the market; or
    (iii) Any action undertaken to promote public health and safety by 
replacing of existing merchandise with an improved product or new 
package design.
    (3) A procedure to ensure that wholesale drug distributors prepare 
for, protect against, and handle any crisis that affects security or 
operation of any facility in the event of strike, fire, flood, or other 
natural disaster, or other situations of local, State, or national 
emergency.
    (4) A procedure to ensure that any outdated prescription drugs shall 
be segregated from other drugs and either returned to the manufacturer 
or destroyed. This procedure shall provide for written documentation of 
the disposition of outdated prescription drugs. This documentation shall 
be maintained for 2 years after disposition of the outdated drugs.
    (h) Responsible persons. Wholesale drug distributors shall establish 
and maintain lists of officers, directors, managers, and other persons 
in charge of wholesale drug distribution, storage, and handling, 
including a description of their duties and a summary of their 
qualifications.
    (i) Compliance with Federal, State, and local law. Wholesale drug 
distributors shall operate in compliance with applicable Federal, State, 
and local laws and regulations.
    (1) Wholesale drug distributors shall permit the State licensing 
authority and authorized Federal, State, and local law enforcement 
officials to enter and inspect their premises and delivery vehicles, and 
to audit their records and

[[Page 133]]

written operating procedures, at reasonable times and in a reasonable 
manner, to the extent authorized by law.
    (2) Wholesale drug distributors that deal in controlled substances 
shall register with the appropriate State controlled substance authority 
and with the Drug Enforcement Administration (DEA), and shall comply 
with all applicable State, local, and DEA regulations.
    (j) Salvaging and reprocessing. Wholesale drug distributors shall be 
subject to the provisions of any applicable Federal, State, or local 
laws or regulations that relate to prescription drug product salvaging 
or reprocessing, including parts 207, 210, and 211 of this chapter.

(Approved by the Office of Management and Budget under control number 
0910-0251)

[55 FR 38023, Sept. 14, 1990, as amended at 64 FR 67763, Dec. 3, 1999]



PART 206_IMPRINTING OF SOLID ORAL DOSAGE FORM DRUG PRODUCTS FOR
HUMAN USE--Table of Contents



Sec.
206.1 Scope.
206.3 Definitions.
206.7 Exemptions.
206.10 Code imprint required.

    Authority: 21 U.S.C. 321, 331, 351, 352, 355, 371; 42 U.S.C. 262.

    Source: 58 FR 47958, Sept. 13, 1993, unless otherwise noted.



Sec.  206.1  Scope.

    This part applies to all solid oral dosage form human drug products, 
including prescription drug products, over-the-counter drug products, 
biological drug products, and homeopathic drug products, unless 
otherwise exempted under Sec.  206.7.



Sec.  206.3  Definitions.

    The following definitions apply to this part:
    The act means the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 
301 et seq.).
    Debossed means imprinted with a mark below the dosage form surface.
    Drug product means a finished dosage form, e.g., a tablet or capsule 
that contains a drug substance, generally, but not necessarily, in 
association with one or more other ingredients.
    Embossed means imprinted with a mark raised above the dosage form 
surface.
    Engraved means imprinted with a code that is cut into the dosage 
form surface after it has been completed.
    Imprinted means marked with an identification code by means of 
embossing, debossing, engraving, or printing with ink.
    Manufacturer means the manufacturer as described in Sec. Sec.  201.1 
and 600.3(t) of this chapter.
    Solid oral dosage form means capsules, tablets, or similar drug 
products intended for oral use.



Sec.  206.7  Exemptions.

    (a) The following classes of drug products are exempt from 
requirements of this part:
    (1) Drug products intended for use in a clinical investigation under 
section 505(i) of the act, but not including drugs distributed under a 
treatment IND under part 312 of this chapter or distributed as part of a 
nonconcurrently controlled study. Placebos intended for use in a 
clinical investigation are exempt from the requirements of this part if 
they are designed to copy the active drug products used in that 
investigation.
    (2) Drugs, other than reference listed drugs, intended for use in 
bioequivalence studies.
    (3) Drugs that are extemporaneously compounded by a licensed 
pharmacist, upon receipt of a valid prescription for an individual 
patient from a practitioner licensed by law to prescribe or administer 
drugs, to be used solely by the patient for whom they are prescribed.
    (4) Radiopharmaceutical drug products.
    (b) Exemption of drugs because of size or unique physical 
characteristics:
    (1) For a drug subject to premarket approval, FDA may provide an 
exemption from the requirements of Sec.  206.10 upon a showing that the 
product's size, shape, texture, or other physical characteristics make 
imprinting technologically infeasible or impossible.
    (i) Exemption requests for products with approved applications shall 
be

[[Page 134]]

made in writing to the appropriate review division in the Center for 
Drug Evaluation and Research (CDER), Food and Drug Administration, 5901-
B Ammendale Rd., Beltsville, MD 20705-1266 or the Food and Drug 
Administration, Center for Biologics Evaluation and Research, Document 
Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, Silver 
Spring, MD 20993-0002. If FDA denies the request, the holder of the 
approved application will have 1 year after the date of an agency denial 
to imprint the drug product.
    (ii) Exemption requests for products that have not yet received 
approval shall be made in writing to the appropriate review division in 
CDER or CBER.
    (2) Any product not subject to premarket approval is exempt from the 
requirement of Sec.  206.10 if, based on the product's size, shape, 
texture, or other physical characteristics, the manufacturer or 
distributor of the product is prepared to demonstrate that imprinting 
the dosage form is technologically infeasible or impossible.
    (c) For drugs that are administered solely in controlled health care 
settings and not provided to patients for self-administration, sponsors 
may submit requests for exemptions from the requirements of this rule. 
Controlled settings include physicians' offices and other health care 
facilities. Exemption requests should be submitted in writing to the 
appropriate review division in CDER or CBER.

[58 FR 47958, Sept. 13, 1993, as amended at 70 FR 14981, Mar. 24, 2005; 
74 FR 13112, Mar. 26, 2009; 80 FR 18091, Apr. 3, 2015]



Sec.  206.10  Code imprint required.

    (a) Unless exempted under Sec.  206.7, no drug product in solid oral 
dosage form may be introduced or delivered for introduction into 
interstate commerce unless it is clearly marked or imprinted with a code 
imprint that, in conjunction with the product's size, shape, and color, 
permits the unique identification of the drug product and the 
manufacturer or distributor of the product. Identification of the drug 
product requires identification of its active ingredients and its dosage 
strength. Inclusion of a letter or number in the imprint, while not 
required, is encouraged as a more effective means of identification than 
a symbol or logo by itself. Homeopathic drug products are required only 
to bear an imprint that identifies the manufacturer and their 
homeopathic nature.
    (b) A holder of an approved application who has, under Sec.  314.70 
(b) of this chapter, supplemented its application to provide for a new 
imprint is not required to bring its product into compliance with this 
section during the pendency of the agency's review. Once the review is 
complete, the drug product is subject to the requirements of the rule.
    (c) A solid oral dosage form drug product that does not meet the 
requirement for imprinting in paragraph (a) of this section and is not 
exempt from the requirement may be considered adulterated and misbranded 
and may be an unapproved new drug.
    (d) For purposes of this section, code imprint means any single 
letter or number or any combination of letters and numbers, including, 
e.g., words, company name, and National Drug Code, or a mark, symbol, 
logo, or monogram, or a combination of letters, numbers, and marks or 
symbols, assigned by a drug firm to a specific drug product.

[58 FR 47958, Sept. 13, 1993, as amended at 60 FR 19846, Apr. 21, 1995; 
69 FR 18763, Apr. 8, 2004]



  PART 207_REQUIREMENTS FOR FOREIGN AND DOMESTIC ESTABLISHMENT 
  REGISTRATION AND LISTING FOR HUMAN DRUGS, INCLUDING DRUGS THAT ARE
  REGULATED UNDER A BIOLOGICS LICENSE APPLICATION, AND ANIMAL DRUGS,
  AND THE NATIONAL DRUG CODE--Table of Contents



                            Subpart A_General

Sec.
207.1 What definitions and interpretations of terms apply to this part?
207.3 Bulk drug substance.
207.5 What is the purpose of this part?
207.9 Who does this part cover?
207.13 Who is exempt from the registration and listing requirements?

                         Subpart B_Registration

207.17 Who must register?

[[Page 135]]

207.21 When must initial registration information be provided?
207.25 What information is required for registration?
207.29 What are the requirements for reviewing and updating registration 
          information?

                      Subpart C_National Drug Code

207.33 What is the National Drug Code (NDC), how is it assigned, and 
          what are its requirements?
207.35 What changes require a new NDC?
207.37 What restrictions pertain to the use of the NDC?

                            Subpart D_Listing

207.41 Who must list drugs and what drugs must they list?
207.45 When, after initial registration of an establishment, must drug 
          listing information be submitted?
207.49 What listing information must a registrant submit for a drug that 
          it manufactures?
207.53 What listing information must a registrant submit for a drug that 
          it repacks or relabels?
207.54 What listing information must a registrant submit for a drug that 
          it salvages?
207.55 What additional drug listing information may FDA require?
207.57 What information must registrants submit when updating listing 
          information and when?

        Subpart E_Electronic Format for Registration and Listing

207.61 How is registration and listing information provided to FDA?
207.65 How can a waiver of the electronic submission requirement be 
          obtained?

                         Subpart F_Miscellaneous

207.69 What are the requirements for an official contact and a United 
          States agent?
207.77 What legal status is conferred by registration and listing?
207.81 What registration and listing information will FDA make available 
          for public disclosure?

    Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360b, 371, 374, 
381, 393; 42 U.S.C. 262, 264, 271.

    Source: 81 FR 60212, Aug. 31, 2016, unless otherwise noted.



                            Subpart A_General



Sec.  207.1  What definitions and interpretations of terms apply to 
this part?

    The definitions and interpretations of terms in sections 201 and 510 
of the Federal Food, Drug, and Cosmetic Act apply to the terms used in 
this part, if not otherwise defined in this section. The following 
definitions apply to this part:
    Active pharmaceutical ingredient means any substance that is 
intended for incorporation into a finished drug product and is intended 
to furnish pharmacological activity or other direct effect in the 
diagnosis, cure, mitigation, treatment, or prevention of disease, or to 
affect the structure or any function of the body. Active pharmaceutical 
ingredient does not include intermediates used in the synthesis of the 
substance.
    Bulk drug substance, as referenced in sections 503A(b)(1)(A) and 
503B(a)(2) of the Federal Food, Drug, and Cosmetic Act, means the same 
as ``active pharmaceutical ingredient'' as defined in this section.
    Commercial distribution means any distribution of a human drug, 
except for investigational use under part 312 of this chapter, and any 
distribution of an animal drug or an animal feed bearing or containing 
an animal drug, except for investigational use under part 511 of this 
chapter. The term does not include internal or interplant transfer 
between registered establishments under common ownership and control, 
including a parent, subsidiary, or affiliate company. For foreign 
establishments that manufacture, repack, relabel, or salvage, or for 
foreign private label distributors, the term ``commercial distribution'' 
has the same meaning except the term does not include distribution of 
any drug that is neither imported nor offered for import into the United 
States.
    Content of labeling means:
    (1) For human prescription drugs that are subject to section 505 of 
the Federal Food, Drug, and Cosmetic Act or section 351 of the Public 
Health Service Act: The content of the prescription drug labeling (as 
specified in

[[Page 136]]

Sec. Sec.  201.56, 201.57, and 201.80 of this chapter), including all 
text, tables, and figures.
    (2) For human prescription drugs that are not subject to section 505 
of the Federal Food, Drug, and Cosmetic Act or section 351 of the Public 
Health Service Act: The labeling equivalent to the content of the 
prescription drug labeling (as specified in Sec. Sec.  201.56, 201.57, 
and 201.80 of this chapter), including all text, tables, and figures.
    (3) For human over-the-counter (OTC) drugs: All text, tables, and 
figures including the drug facts labeling required by Sec.  201.66 of 
this chapter.
    (4) For animal drugs (including, but not limited to, drugs that are 
subject to section 512 of the Federal Food, Drug, and Cosmetic Act): The 
content of the labeling that accompanies the drug that is necessary to 
enable safe and proper administration of the drug (e.g., the labeling 
applicable to veterinary drugs specified in part 201 of this chapter), 
including all text, tables, and figures.
    Domestic for purposes of registration and listing under this part, 
when used to modify the term ``registrant,'' ``manufacturer,'' 
``repacker,'' ``relabeler,'' ``salvager,'' ``private label 
distributor,'' or ``establishment,'' refers to a registrant, 
manufacturer, repacker, relabeler, salvager, private label distributor, 
or establishment within any State or Territory of the United States, the 
District of Columbia, or the Commonwealth of Puerto Rico.
    Drug, for the purposes of registration and listing under this part, 
has the meaning given in section 201(g)(1) of the Federal Food, Drug, 
and Cosmetic Act.
    Establishment means a place of business under one management at one 
general physical location. The term includes, among others, independent 
laboratories that engage in control activities for a registered drug 
establishment (e.g., consulting laboratories), manufacturers of 
medicated feeds and of vitamin products that are drugs in accordance 
with section 201(g) of the Federal Food, Drug, and Cosmetic Act, human 
blood donor centers, and animal facilities used for the production or 
control testing of licensed biologicals, and establishments engaged in 
salvaging.
    Establishment registration number means the number assigned to the 
establishment, as identified by FDA, after the establishment 
registration required in this part.
    Finished drug product means a finished dosage form (e.g., tablet, 
capsule, or solution) that contains at least one active pharmaceutical 
ingredient, generally, but not necessarily, in association with other 
ingredients in finished package form suitable for distribution to 
pharmacies, hospitals, or other sellers or dispensers of the drug 
product to patients or consumers.
    Foreign for the purposes of registration and listing under this 
part:
    (1) When used to modify the term ``manufacturer,'' ``repacker,'' 
``relabeler,'' or ``salvager,'' refers to a manufacturer, repacker, 
relabeler, or salvager, who is located in a foreign country and who 
manufactures, repacks, relabels, or salvages a drug, or an animal feed 
bearing or containing a new animal drug, that is imported or offered for 
import into the United States.
    (2) When used to modify the term ``establishment'' refers to an 
establishment that is located in a foreign country and is engaged in the 
manufacture, repackaging, relabeling, or salvaging of any drug, or any 
animal feed bearing or containing a new animal drug, that is imported or 
offered for import into the United States.
    Importer means, for purposes of this part, a person in the United 
States that is an owner, consignee, or recipient, at the time of entry, 
of a foreign establishment's drug, or an animal feed bearing or 
containing a new animal drug, that is imported into the United States.
    Manufacture means each step in the manufacture, preparation, 
propagation, compounding, or processing of a drug or an animal feed 
bearing or containing a new animal drug. Manufacture includes the making 
by chemical, physical, biological, or other procedures or manipulations 
of a drug, or an animal feed bearing or containing a new animal drug, 
including control procedures applied to the final product or to any

[[Page 137]]

part of the process. Manufacture includes manipulation, sampling, 
testing, or control procedures applied to the final product or to any 
part of the process, including, for example, analytical testing of drugs 
for another registered establishment's drug. For purposes of this part, 
and in order to clarify the responsibilities of the entities engaged in 
different operations, the term manufacture is defined and used 
separately from the terms relabel, repackage, and salvage, although the 
term ``manufacture, preparation, propagation, compounding, or 
processing,'' as used in section 510 of the Federal Food, Drug, and 
Cosmetic Act, includes relabeling, repackaging, and salvaging 
activities.
    Manufacturer means a person who owns or operates an establishment 
that manufactures a drug or an animal feed bearing or containing a new 
animal drug. This term includes, but is not limited to, control 
laboratories, contract laboratories, contract manufacturers, contract 
packers, contract labelers, and other entities that manufacture a drug, 
or an animal feed bearing or containing a new animal drug, as defined in 
this paragraph. For purposes of this part, and in order to clarify the 
responsibilities of the entities engaged in different operations, the 
term manufacturer is defined and used separately from the terms 
relabeler, repacker, and salvager, although the term ``manufacture, 
preparation, propagation, compounding, or processing,'' as used in 
section 510 of the Federal Food, Drug, and Cosmetic Act, includes the 
activities of relabelers, repackers, and salvagers. Repackers, 
relabelers, and salvagers are subject to the provisions of this part 
that are applicable to repackers, relabelers, and salvagers, but are not 
subject to the provisions of this part that are applicable to 
manufacturers. When not modified by ``domestic'' or ``foreign,'' the 
term includes both domestic manufacturers and foreign manufacturers.
    Material change means any change in any drug listing information, as 
required under Sec. Sec.  207.49, 207.53, 207.54, 207.55, or 207.57 
except changes in format of labeling, labeling changes of an editorial 
nature, or inclusion of a bar code or initial inclusion of an NDC on the 
label.
    Outsourcing facility means a compounder that has elected to register 
with FDA under section 503B of the Federal Food, Drug, and Cosmetic Act 
and that meets all of the conditions of section 503B.
    Person who imports or offers for import means, for purposes of this 
part, the owner or exporter of a drug who consigns and ships a drug from 
a foreign country to the United States. This includes persons who send a 
drug to the United States by international mail or other private 
delivery service, but it does not include carriers who merely transport 
the drug.
    Private label distribution means commercial distribution of a drug 
under the label or trade name of a person who did not manufacture, 
repack, relabel, or salvage that drug.
    Private label distributor means, with respect to a particular drug, 
a person who did not manufacture, repack, relabel, or salvage the drug 
but under whose label or trade name the drug is commercially 
distributed.
    Registrant means any person that owns or operates an establishment 
that manufactures, repacks, relabels, or salvages a drug, and is not 
otherwise exempt from establishment registration requirements under 
section 510 of the Federal Food, Drug, and Cosmetic Act or this part.
    Relabel means to change the existing label or labels on a drug or 
drug package, or change or alter the existing labeling for a drug or 
drug package, without repacking the drug or drug package. This term does 
not include the addition or modification of information affixed solely 
for purposes of delivery to a customer, customer identification, and/or 
inventory management.
    Relabeler means a person who owns or operates an establishment that 
relabels a drug. When not modified by ``domestic'' or ``foreign,'' the 
term includes both domestic relabelers and foreign relabelers.
    Repack or repackage means the act of taking a finished drug product 
or unfinished drug from the container in which it was placed in 
commercial distribution and placing it into a different

[[Page 138]]

container without manipulating, changing, or affecting the composition 
or formulation of the drug.
    Repacker means a person who owns or operates an establishment that 
repacks a drug or drug package. When not modified by ``domestic'' or 
``foreign,'' the term includes both domestic repackers and foreign 
repackers.
    Representative sampling of advertisements means typical advertising 
material (including the promotional material described in Sec.  
202.1(l)(1) of this chapter, but excluding labeling as determined in 
Sec.  202.1(l)(2) of this chapter), that gives a balanced picture of the 
promotional claims used for the drug.
    Representative sampling of any other labeling means typical labeling 
material (including the labeling material described in Sec.  202.1(l)(2) 
of this chapter, but excluding labels and package inserts) that gives a 
balanced picture of the promotional claims used for the drug.
    Salvage means the act of segregating out those finished drug 
products that may have been subjected to improper storage conditions 
(such as extremes in temperature, humidity, smoke, fumes, pressure, age, 
or radiation) for the purpose of returning the products to the 
marketplace and includes applying manufacturing controls such as those 
required by current good manufacturing practice in parts 210 and 211 of 
this chapter.
    Salvager means a person who owns or operates an establishment that 
engages in salvaging. When not modified by ``domestic'' or ``foreign,'' 
the term includes both domestic and foreign salvagers.
    Unfinished drug means an active pharmaceutical ingredient either 
alone or together with one or more other ingredients but does not 
include finished drug products.

[81 FR 60212, Aug. 31, 2016, as amended at 86 FR 17061, Apr. 1, 2021]



Sec.  207.3  Bulk drug substance.

    Bulk drug substance, as referenced in sections 503A(b)(1)(A) and 
503B(a)(2) of the Federal Food, Drug, and Cosmetic Act, previously 
defined in Sec.  207.3(a)(4), means the same as ``active pharmaceutical 
ingredient'' as defined in Sec.  207.1.

[81 FR 60212, Aug. 31, 2016, as amended at 86 FR 17061, Apr. 1, 2021]



Sec.  207.5  What is the purpose of this part?

    Establishment registration information helps FDA identify who is 
manufacturing, repacking, relabeling, and salvaging drugs and where 
those operations are performed. Drug listing information gives FDA a 
current inventory of drugs manufactured, repacked, relabeled, or 
salvaged for commercial distribution. Both types of information 
facilitate implementation and enforcement of the Federal Food, Drug, and 
Cosmetic Act and are used for many important public health purposes.



Sec.  207.9  Who does this part cover?

    (a) Except as provided in paragraph (b) of this section, this part 
applies to:
    (1) Domestic manufacturers, domestic repackers, domestic relabelers 
and domestic salvagers, not exempt under section 510(g) of the Federal 
Food, Drug, and Cosmetic Act or Sec.  207.13, regardless of whether 
their drugs enter interstate commerce;
    (2) Foreign manufacturers, foreign repackers, foreign relabelers and 
foreign salvagers, not exempt under section 510(g) of the Federal Food, 
Drug, and Cosmetic Act or Sec.  207.13;
    (3) Private label distributors, because they must have labeler 
codes;
    (4) Establishments engaged in the manufacture, repacking, 
relabeling, or salvaging of human drugs regulated under a biologics 
license application (BLA). These establishments are subject to the 
requirements of this part unless they are required to register and list 
such drugs as human blood or blood products under part 607 of this 
chapter and do not engage in activities that would otherwise require 
them to register and list under this part.
    (5) Establishments engaged in the manufacture (as defined in Sec.  
1271.3(e) of this chapter) of human cells, tissues, and cellular and 
tissue-based products (HCT/Ps) (as defined in Sec.  1271.3(d) of this 
chapter) that, under Sec.  1271.20 of this chapter, are also drugs 
regulated under section 351 of the Public Health Service Act or section 
505 of the Federal Food,

[[Page 139]]

Drug, and Cosmetic Act. These establishments must register and list 
those HCT/Ps following the procedures described in this part.
    (b) This part does not apply to owners and operators of 
establishments that collect or process human whole blood and blood 
products unless the establishment also manufactures, repacks, or 
relabels other drugs. For purposes of this paragraph (b), human whole 
blood and blood products do not include plasma derivatives such as 
albumin, Immune Globulin, Factor VIII and Factor IX, and recombinant 
versions of plasma derivatives or animal derived plasma derivatives, or 
bulk product substances such as fractionation intermediates or pastes. 
Establishments that collect or process human whole blood and blood 
products as well as establishments involved in testing of human whole 
blood and blood products must register and list under part 607 of this 
chapter. Manufacturers of licensed devices and manufacturers of licensed 
biological products used in a licensed device must register and list 
under part 607 of this chapter.
    (c) This part does not apply to establishments that solely 
manufacture, prepare, propagate, compound, assemble, or process medical 
devices. Registration and listing regulations for such establishments 
are codified in part 807 of this chapter.



Sec.  207.13  Who is exempt from the registration and listing
requirements?

    Except as provided in Sec.  207.13(l), the following classes of 
persons are exempt from registration and drug listing in accordance with 
section 510(g) of the Federal Food, Drug, and Cosmetic Act or because 
FDA has determined, under section 510(g)(5) of the Federal Food, Drug, 
and Cosmetic Act, that their registration is not necessary for the 
protection of the public health. This exemption is limited to 
establishment registration and drug listing requirements and does not 
relieve a person from other statutory or regulatory obligations.
    (a)(1) Pharmacies that:
    (i) Operate in conformance with all applicable local laws regulating 
the practice of pharmacy and medicine, including all applicable local 
laws regulating the dispensing of prescription drugs;
    (ii) Regularly engage in dispensing prescription drugs upon a valid 
prescription by practitioners licensed by law to administer these drugs 
to patients under their professional care; and
    (iii) Do not manufacture, repack, relabel, or salvage drugs other 
than in the regular course of their business of dispensing or selling 
drugs at retail.
    (2) The exemption in this paragraph (a) is limited to pharmacies 
located in any State as defined in section 201(a)(1) of the Federal 
Food, Drug, and Cosmetic Act.
    (b)(1) Hospitals, clinics, other health care entities, and public 
health agencies that:
    (i) Operate establishments in conformance with all applicable local 
laws regulating the practice of pharmacy and medicine, including all 
applicable local laws regulating the dispensing of prescription drugs;
    (ii) Regularly engage in dispensing prescription drugs, other than 
human whole blood or blood products, upon a valid order or prescription 
by practitioners licensed by law to administer these drugs to patients 
under their professional care; and
    (iii) Do not manufacture, repack, relabel, or salvage drugs other 
than in the regular course of their practice of pharmacy, including 
dispensing.
    (2) The exemption in this paragraph (b) is limited to hospitals, 
clinics, other health care entities, and public health agencies located 
in any State as defined in section 201(a)(1) of the Federal Food, Drug, 
and Cosmetic Act.
    (c) Individuals or establishments under contract, agreement, or 
other arrangement with a registered establishment and engaged solely in 
recovering cells or tissues and sending the recovered cells or tissues 
to the registered establishment to become components of a biological 
product are exempt from registration and listing under this part unless 
FDA determines that drug establishment registration and listing is 
necessary for the protection of the public health.
    (d) Practitioners who are licensed by law to prescribe or administer 
drugs

[[Page 140]]

and who manufacture, repack, relabel, or salvage drugs solely for use in 
their professional practice.
    (e) Manufacturers, repackers, relabelers, or salvagers who 
manufacture, repack, relabel, or salvage drugs solely for use in 
research, teaching, or chemical analysis and not for sale.
    (f) Manufacturers, repackers, and relabelers of harmless inactive 
ingredients such as excipients, colorings, flavorings, emulsifiers, 
lubricants, preservatives, or solvents that become components of drugs.
    (g) Manufacturers, repackers, relabelers, or salvagers of Type B or 
Type C medicated feeds, except for persons who manufacture, repack, 
relabel, or salvage Type B or Type C medicated feeds starting from 
Category II, Type A medicated articles for which a medicated feed mill 
license approved under part 515 of this chapter is required. This 
exemption also does not apply to persons that would otherwise be 
required to register (such as manufacturers, repackers, relabelers, or 
salvagers of certain free-choice feeds, as defined in Sec.  510.455 of 
this chapter, or certain liquid feeds, as defined in Sec.  558.5 of this 
chapter, where the specifications and/or formulas are not published and 
a medicated feed mill license is required). All manufacturers, 
repackers, relabelers, or salvagers of Type B or Type C medicated feeds 
are exempt from listing.
    (h) Any manufacturer, repacker, relabeler, or salvager of a virus, 
serum, toxin, or analogous product intended for the treatment of 
domestic animals who holds an unsuspended and unrevoked license issued 
by the Secretary of Agriculture under the animal virus-serum-toxin law 
of March 4, 1913 (37 Stat. 832 (21 U.S.C. 151 et seq.)), provided that 
this exemption from registration applies only to the manufacturer, 
repacker, relabeler, or salvager of that animal virus, serum, toxin, or 
analogous product.
    (i) Carriers, in their receipt, carriage, holding, or delivery of 
drugs in the usual course of business as carriers.
    (j) Foreign establishments whose drugs are imported or offered for 
import into the United States must comply with the establishment 
registration and listing requirements of this part unless exempt under 
this section or unless:
    (1) Their drugs enter a foreign trade zone and are re-exported 
without having entered U.S. commerce, or
    (2) Their drugs are imported in conformance with section 801(d)(3) 
of the Federal Food, Drug, and Cosmetic Act.
    (k) Entities that are registered with FDA as outsourcing facilities 
and that compound drugs in conformance with section 503B of the Federal 
Food, Drug, and Cosmetic Act.
    (l) The exemptions provided in paragraphs (a) through (k) of this 
section do not apply to such persons if they:
    (1) Manufacture (as defined in Sec.  207.1), repack, relabel, or 
salvage compounded positron emission tomography drugs as defined in 
section 201(ii) of the Federal Food, Drug, and Cosmetic Act;
    (2) Manufacture (as defined in Sec.  600.3(u) of this chapter) a 
human biological product subject to licensing under section 351 of the 
Public Health Service Act; or
    (3) Engage in activities that would otherwise require them to 
register under this part.

[81 FR 60212, Aug. 31, 2016, as amended at 86 FR 17061, Apr. 1, 2021]



                         Subpart B_Registration



Sec.  207.17  Who must register?

    (a) Unless exempt under section 510(g) of the Federal Food, Drug, 
and Cosmetic Act or this part, all manufacturers, repackers, relabelers, 
and salvagers must register each domestic establishment that 
manufactures, repacks, relabels, or salvages a drug, or an animal feed 
bearing or containing a new animal drug, and each foreign establishment 
that manufactures, repacks, relabels, or salvages a drug, or an animal 
feed bearing or containing a new animal drug, that is imported or 
offered for import into the United States. When operations are conducted 
at more than one establishment and common ownership and control among 
all the establishments exists, the parent, subsidiary, or affiliate 
company may submit registration information for all establishments.
    (b) Private label distributors who do not also manufacture, repack, 
relabel, or salvage drugs are not required to

[[Page 141]]

register under this part. FDA will accept registration or listing 
information submitted by a private label distributor only if it is 
acting as an authorized agent for and submitting information that 
pertains to an establishment that manufactures, repacks, relabels, or 
salvages drugs.



Sec.  207.21  When must initial registration information be provided?

    (a) Registrants must register each domestic establishment no later 
than 5 calendar days after beginning to manufacture, repack, relabel, or 
salvage a drug or an animal feed bearing or containing a new animal drug 
at such establishment.
    (b) Registrants must register each foreign establishment before a 
drug or an animal feed bearing or containing a new animal drug 
manufactured, repacked, relabeled, or salvaged at the establishment is 
imported or offered for import into the United States.



Sec.  207.25  What information is required for registration?

    Registrants must provide the following information:
    (a) Name of the owner or operator of each establishment; if a 
partnership, the name of each partner; if a corporation, the name of 
each corporate officer and director, and the place of incorporation;
    (b) Each establishment's name, physical address, and telephone 
number(s);
    (c) All name(s) of the establishment, including names under which 
the establishment conducts business or names by which the establishment 
is known;
    (d) Registration number of each establishment, if previously 
assigned by FDA;
    (e) A Unique Facility Identifier in accordance with the system 
specified under section 510 of the Federal Food, Drug, and Cosmetic Act.
    (f) All types of operations performed at each establishment;
    (g) Name, mailing address, telephone number, and email address of 
the official contact for the establishment, as provided in Sec.  
207.69(a); and
    (h) Additionally, with respect to foreign establishments subject to 
registration, the name, mailing address, telephone number, and email 
address must be provided for:
    (1) The United States agent, as provided in Sec.  207.69(b);
    (2) Each importer in the United States of drugs manufactured, 
repacked, relabeled, or salvaged at the establishment that is known to 
the establishment; and
    (3) Each person who imports or offers for import such drug to the 
United States.



Sec.  207.29  What are the requirements for reviewing and updating
registration information?

    (a) Expedited updates. Registrants must update their registration 
information no later than 30 calendar days after:
    (1) Closing or selling an establishment;
    (2) Changing an establishment's name or physical address; or
    (3) Changing the name, mailing address, telephone number, or email 
address of the official contact or the United States agent. A 
registrant, official contact, or United States agent may notify FDA 
about a change of information for the designated official contact or 
United States agent, but only a registrant is permitted to designate a 
new official contact or United States agent.
    (b) Annual review and update of registration information. 
Registrants must review and update all registration information required 
under Sec.  207.25 for each establishment.
    (1) The first review and update must occur during the period 
beginning on October 1 and ending December 31 of the year of initial 
registration, if the initial registration occurs prior to October 1. 
Subsequent reviews and updates must occur annually, during the period 
beginning on October 1 and ending December 31 of each calendar year.
    (2) The updates must reflect all changes that have occurred since 
the last annual review and update.
    (3) If no changes have occurred since the last registration, 
registrants must certify that no changes have occurred.

[[Page 142]]



                      Subpart C_National Drug Code



Sec.  207.33  What is the National Drug Code (NDC), how is it assigned,
and what are its requirements?

    (a) What is the NDC for a drug and what products must have unique 
NDCs? The NDC for a drug is a numeric code. Each finished drug product 
or unfinished drug subject to the listing requirements of this part must 
have a unique NDC to identify its labeler, product, and package size and 
type.
    (b) What is the format of an NDC? (1) Except as described in 
paragraph (b)(4) of this section, the NDC must consist of 10 or 11 
digits, divided into three segments as follows:
    (i) The first segment of the NDC is the labeler code and consists of 
4, 5, or 6 digits. The labeler code is assigned by FDA.
    (ii) The second segment of the NDC is the product code and consists 
of 3 or 4 digits, as specified in paragraphs (b)(2) and (3) of this 
section.
    (iii) The third segment of the NDC is the package code and consists 
of 1 or 2 digits as specified in paragraphs (b)(2) and (3) of this 
section. The package code identifies the package size and type of the 
drug and differentiates between different quantitative and qualitative 
attributes of the product packaging.
    (2) The following combinations of labeler code, product code and 
package code character lengths are permissible:
    (i) If a labeler code is either 5 or 6 digits in length, it may be 
combined with:
    (A) A product code consisting of 4 digits and a package code 
consisting of 1 digit for a total NDC length of 10 or 11 digits (5-4-1 
or 6-4-1), or
    (B) A product code consisting of 3 digits and a package code 
consisting of 2 digits for a total NDC length of 10 or 11 digits (5-3-2 
or 6-3-2).
    (ii) If a labeler code is 4 digits in length, it may be combined 
only with a product code consisting of 4 digits and a package code 
consisting of 2 digits for a total NDC length of 10 digits (4-4-2).
    (3) A registrant or private label distributor with a given labeler 
code must use only one Product-Package Code configuration (e.g., a 3-
digit product code combined with a 2-digit package code or a 4-digit 
product code combined with a 1-digit package code). This single 
configuration must be used in all NDCs that include the given labeler 
code that are reserved in accordance with Sec.  207.33(d)(3) or listed 
in accordance with Sec.  207.49 or Sec.  207.53.
    (4) An alternatively formatted NDC that is approved for use by the 
relevant Center Director may be used for the following HCT/Ps if they 
are minimally manipulated: Hematopoietic stem/progenitor cells derived 
from peripheral and cord blood, and lymphocytes collected from 
peripheral blood.
    (c) Who must obtain an NDC labeler code and how is the code assigned 
and updated? (1) Each person who engages in manufacturing, repacking, 
relabeling, or private label distribution of a drug subject to listing 
under this part must apply for an NDC labeler code, by providing the 
following information:
    (i) The name, physical address, email address, and other contact 
information FDA may request, of the person for whom the NDC labeler code 
is requested;
    (ii) The type(s) of activities (e.g., manufacture or repacking) in 
which the person requesting the NDC labeler code engages with respect to 
human drugs; and
    (iii) The type(s) of drug(s) (human, animal, or both, and 
prescription, nonprescription, or both) to which the NDC labeler code 
will be applied.
    (2) Each person who is assigned an NDC labeler code must update the 
information submitted under paragraph (c)(1)of this section within 30 
calendar days after any change to that information.
    (d) How is an NDC proposed for assignment by FDA, when is an NDC 
assigned by FDA, and how can a proposed NDC be reserved? (1) An NDC is 
proposed for assignment by FDA when it is submitted for the first time 
with listing information in accordance with Sec.  207.49 or Sec.  
207.53, as applicable.
    (i) Each manufacturer, repacker, or relabeler must propose for 
assignment by FDA an NDC that includes its own labeler code for each 
package size and

[[Page 143]]

type of drug that it manufactures, repacks, or relabels for commercial 
distribution.
    (ii) In addition, if a drug is distributed under the trade name or 
label of a private label distributor, the manufacturer, repacker, or 
relabeler must also propose for assignment by FDA an NDC that includes 
the labeler code of the private label distributor under whose trade name 
or label the drug is distributed, for each package size and type so 
distributed.
    (2) If a proposed NDC conforms to the requirements of this section 
and is not reserved for a different drug or was not previously assigned 
to a different drug, FDA will assign the NDC to a drug when it receives 
listing information required for that drug under Sec.  207.49 or Sec.  
207.53.
    (3) A manufacturer, repacker, relabeler, or private label 
distributor may voluntarily reserve a proposed NDC for a drug, before 
the drug is listed, by submitting the following information:
    (i) A proposed NDC that conforms to the requirements of this 
section;
    (ii) The established name of the active ingredient(s) and the 
strength of each active ingredient in the drug; and
    (iii) In the case of a finished drug product, the dosage form, and 
route of administration.
    (4) If the required information is submitted and the proposed NDC is 
properly formatted and not already assigned or reserved, FDA will 
reserve the proposed NDC for a period of 2 years from the date of 
submission. If the drug for which the proposed NDC is reserved is not 
listed in accordance with Sec.  207.49 or Sec.  207.53 during such 2-
year period, the reservation of the proposed NDC will lapse. FDA may 
also cancel the reservation of a proposed NDC at any time on the request 
of the person whose labeler code is included in the proposed NDC.
    (e) How must the information be submitted to us? The information 
described in paragraphs (c) and (d) of this section must be submitted 
electronically unless FDA grants a waiver under Sec.  207.65.



Sec.  207.35  What changes require a new NDC?

    (a) Once an NDC has been assigned by FDA, the registrant must 
propose a new and unique NDC for a drug when there is a change, after 
the drug is initially marketed, to any of the information identified in 
paragraphs (b) and (c) of this section. A new NDC must be proposed to 
FDA for assignment through an updated listing in accordance with Sec.  
207.57.
    (b) The proposed new NDC must include a new product code when there 
is a change to any of the following information:
    (1) The drug's established name or proprietary name, if any;
    (2) Any active pharmaceutical ingredient or the strength of any 
active pharmaceutical ingredient;
    (3) The dosage form;
    (4) A change in the drug's status, between prescription and 
nonprescription, or for animal drugs, between prescription, 
nonprescription, or veterinary feed directive (VFD) status;
    (5) A change in the drug's intended use between human and animal; or
    (6) The drug's distinguishing characteristics such as size, shape, 
color, code imprint, flavor, and scoring (if any).
    (c) When there is a change only to the package size or type, 
including the immediate unit-of-use container, if any, the proposed new 
NDC must include only a new package code and retain the existing product 
code unless all available package codes have already been combined with 
the existing product code in NDCs assigned by FDA.



Sec.  207.37  What restrictions pertain to the use of the NDC?

    (a) A product may be deemed to be misbranded if an NDC is used:
    (1) To represent a different drug than the drug for which the NDC 
has been assigned, as described in Sec.  207.33;
    (2) To denote or imply FDA approval of a drug; or
    (3) On products that are not subject to parts 207, 607 of this 
chapter, or 1271 of this chapter, such as dietary supplements and 
medical devices.
    (b) If marketing is resumed for a discontinued drug, and no changes 
have been made to the drug that would require a new NDC under Sec.  
207.35, the

[[Page 144]]

drug must have the same NDC that was assigned to it as described in 
Sec.  207.33, before marketing was discontinued.



                            Subpart D_Listing



Sec.  207.41  Who must list drugs and what drugs must they list?

    (a) Each registrant must list each drug that it manufactures, 
repacks, relabels, or salvages for commercial distribution. Each 
domestic registrant must list each such drug regardless of whether the 
drug enters interstate commerce. When operations are conducted at more 
than one establishment, and common ownership and control exists among 
all the establishments, the parent, subsidiary, or affiliate company may 
submit listing information for any drug manufactured, repacked, 
relabeled, or salvaged at any such establishment. A drug manufactured, 
repacked, or relabeled for private label distribution must be listed in 
accordance with paragraph (c) of this section.
    (b) Registrants must provide listing information for each drug in 
accordance with the listing requirements described in Sec. Sec.  207.49, 
207.53, and 207.54 that correspond to the activity or activities they 
engage in for that drug.
    (c)(1) For both animal and human drugs, each registrant must list 
each drug it manufactures, repacks, or relabels for commercial 
distribution under the trade name or label of a private label 
distributor using an NDC that includes such private label distributor's 
labeler code.
    (2) Additionally, in the case of human drugs, each registrant must 
list each human drug it manufactures, repacks, or relabels using an NDC 
that includes the registrant's own labeler code, regardless of whether 
the drug is commercially distributed under the registrant's own label or 
trade name or under the label or trade name of a private label 
distributor.



Sec.  207.45  When, after initial registration of an establishment,
must drug listing information be submitted?

    For each drug being manufactured, repacked, relabeled, or salvaged 
for commercial distribution at an establishment at the time of initial 
registration, drug listing information must be submitted no later than 3 
calendar days after the initial registration of the establishment.



Sec.  207.49  What listing information must a registrant submit for
a drug it manufactures?

    (a) Each registrant must provide the following listing information 
for each drug it manufactures for commercial distribution.
    (1) The appropriate NDC(s), as described in Sec.  207.33, that 
include all package code variations. In the case of human drugs, the 
appropriate NDC(s) submitted under this paragraph include the 
registrant's labeler code. In the case of animal drugs, the appropriate 
NDC(s) submitted under this paragraph include the registrant's labeler 
code, except that when the drug is manufactured for commercial 
distribution under the trade name or label of a private label 
distributor, the appropriate NDC(s) for animal drugs include the private 
label distributor's labeler code;
    (2) Package type and volume information corresponding to the package 
code segment of the NDC;
    (3) The listed drug's established name and proprietary name, if any;
    (4) The name and quantity of each active pharmaceutical ingredient 
in the listed drug;
    (5) The name of each inactive ingredient in the listed drug, along 
with any assertions of confidentiality associated with individual 
inactive ingredients;
    (6) The dosage form;
    (7) The drug's approved U.S. application number, if any;
    (8) The drug type (e.g., as applicable, finished vs. unfinished, 
human vs. animal, prescription vs. nonprescription);
    (9) In the case of an unfinished drug, the number assigned to the 
Drug Master File or Veterinary Master File, if any, that describes the 
manufacture of the drug;
    (10) For each drug that is subject to the imprinting requirements of 
part 206 of this chapter including products that are exempted under 
Sec.  206.7(b), the drug's size, shape, color, scoring, and code imprint 
(if any);
    (11) The route or routes of administration of the drug;
    (12) For each drug bearing an NDC:

[[Page 145]]

    (i) The name and Unique Facility Identifier of the establishment 
where the registrant who lists the drug manufactures it and the type of 
operation performed on the drug at that establishment, and
    (ii) The name and Unique Facility Identifier of every other 
establishment where manufacturing is performed for the drug and the type 
of operation performed at each such establishment. This includes all 
establishments involved in the production of each unfinished drug 
received by the registrant for use in the production of the drug being 
listed. The names, Unique Facility Identifiers, and type of operations 
for establishments involved in production of each unfinished drug 
received by the registrant for use in the production of the drug being 
listed may be provided by including the properly assigned and listed NDC 
for such unfinished drug.
    (13) The schedule of the drug under section 202 of the Controlled 
Substances Act, if applicable;
    (14) Advertisements:
    (i) A representative sampling of advertisements for a human 
prescription drug that is not subject to section 505 of the Federal 
Food, Drug, and Cosmetic Act or section 351 of the Public Health Service 
Act;
    (ii) If FDA requests it, for good cause, a copy of all 
advertisements for a human prescription drug that is not subject to 
section 505 of the Federal Food, Drug, and Cosmetic Act or section 351 
of the Public Health Service Act, including those advertisements 
described in Sec.  202.1(l)(1) of this chapter. Such advertisements must 
be submitted within 30 calendar days after FDA's request.
    (15) For drugs bearing the NDC(s) reported under paragraph (a)(1) of 
this section, except those drugs manufactured exclusively for private 
label distribution and not distributed under the registrant's own name 
and label, provide the following labeling, as applicable:
    (i) Human prescription drugs. All current labeling except that only 
one representative container or carton label need be submitted where 
differences exist only in the quantity of contents statement or the bar 
code. This labeling submission must include the content of labeling, as 
defined in Sec.  207.1.
    (ii) Human nonprescription drugs. (A) For each human nonprescription 
drug subject to section 505 of the Federal Food, Drug, and Cosmetic Act 
or section 351 of the Public Health Service Act, all current labeling, 
except that only one representative container or carton label need be 
submitted where differences exist only in the quantity of contents 
statement or the bar code. This labeling submission must include the 
content of labeling, as defined in Sec.  207.1.
    (B) For each human nonprescription drug not subject to section 505 
of the Federal Food, Drug, and Cosmetic Act or section 351 of the Public 
Health Service Act, the current label (except that only one 
representative container or carton label need be submitted where 
differences exist only in the quantity of contents statement or the bar 
code), the package insert (if any), and a representative sampling of any 
other labeling. This labeling submission must include the content of 
labeling as defined in section Sec.  207.1.
    (iii) Animal drugs. (A) For each animal drug that is subject to 
section 512 of the Federal Food, Drug, and Cosmetic Act, which includes, 
but is not limited to, new animal drugs that have been approved, 
conditionally approved, or indexed under sections 512, 571, or 572 of 
the Federal Food, Drug, and Cosmetic Act, a copy of all current labeling 
(except that only one representative container or carton label need be 
submitted where differences exist only in the quantity of contents 
statement), including the content of labeling as defined in Sec.  207.1;
    (B) For all other animal drugs, a copy of the current label (except 
that only one representative container or carton label need be submitted 
where differences exist only in the quantity of contents statement), the 
package insert, the content of labeling as defined in Sec.  207.1, and a 
representative sampling of any other labeling;
    (iv) All other listed drugs. For all other listed drugs, including 
unfinished drugs, the label (if any), except that only one 
representative label need be submitted where differences exist only in 
the quantity of contents statement.

[[Page 146]]

    (16) Listing submissions described in Sec.  207.41(c)(2) for human 
drugs manufactured for private label distribution must include all 
information specified in Sec.  207.49(a)(2) through (14) and:
    (i) The appropriate NDC(s) (as described in Sec.  207.33) that 
include the private label distributor's labeler code and all package 
code variations;
    (ii) The name, mailing address, telephone number, and email address 
of the private label distributor; and
    (iii) For drugs bearing the NDC(s) reported under paragraph 
(a)(16)(i) of this section, labeling as described in paragraph (a)(15) 
of this section that accompanies the private label distributor's 
product.
    (b) Additionally, each registrant is requested, but not required, to 
provide the following information for each human drug it manufactures 
for commercial distribution:
    (1) The drug's over-the-counter monograph reference, if any; and
    (2) The date on which the drug was or will be introduced into 
commercial distribution.

[81 FR 60212, Aug. 31, 2016, as amended at 86 FR 17061, Apr. 1, 2021]



Sec.  207.53  What listing information must a registrant submit for
a drug that it repacks or relabels?

    Each registrant must provide the following listing information for 
each drug it repacks or relabels:
    (a) NDC. The appropriate NDC(s), as described in Sec.  207.33, that 
include the registrant's labeler code and all package code variations;
    (b) Source NDC. The NDC assigned to each finished drug received by 
the registrant for repacking or relabeling, with the exception of 
medical gases. Each such NDC must be associated with the corresponding 
NDC(s) for repacked or relabeled drugs, reported under paragraph (a) of 
this section.
    (c) Name and Unique Facility Identifier. For each drug identified by 
an NDC reported under paragraph (a) of this section, the name and Unique 
Facility Identifier of every establishment where repacking or relabeling 
is performed for the drug and the type of operation (repacking vs. 
relabeling) performed at each such establishment.
    (d) Labeling. For each drug identified by an NDC reported under 
paragraph (a) of this section, except those human drugs repacked or 
relabeled exclusively for private label distribution and not distributed 
under the registrant's own name and label, provide the following:
    (1) Human prescription drugs. All current labeling for the repacked 
or relabeled drug except that only one representative container or 
carton label need be submitted where differences exist only in the 
quantity of contents statement or the bar code. This labeling submission 
must include the content of labeling, as defined in section Sec.  207.1.
    (2) Human nonprescription drugs. (i) For each human nonprescription 
drug subject to section 505 of the Federal Food, Drug, and Cosmetic Act 
or section 351 of the Public Health Service Act, all current labeling, 
except that only one representative container or carton label need be 
submitted where differences exist only in the quantity of contents 
statement or the bar code. This labeling submission must include the 
content of labeling, as defined in Sec.  207.1.
    (ii) For each human nonprescription drug not subject to section 505 
of the Federal Food, Drug, and Cosmetic Act or section 351 of the Public 
Health Service Act, the current label (except that only one 
representative container or carton label need be submitted where 
differences exist only in the quantity of contents statement or the bar 
code), the package insert (if any), and a representative sampling of any 
other labeling. This labeling submission must include the content of 
labeling as defined in Sec.  207.1.
    (3) Animal drugs. (i) For each animal drug that is subject to 
section 512 of the Federal Food, Drug, and Cosmetic Act, which includes 
but is not limited to, new animal drugs that have been approved, 
conditionally approved, or indexed under sections 512, 571, or 572 of 
the Federal Food, Drug, and Cosmetic Act, a copy of all current labeling 
(except that only one representative container or carton label need be 
submitted where differences exist only in the quantity of contents 
statement), including the content of labeling as defined in Sec.  207.1;

[[Page 147]]

    (ii) For all other animal drugs, a copy of the current label (except 
that only one representative container or carton label need be submitted 
where differences exist only in the quantity of contents statement), the 
package insert, the content of labeling as defined in Sec.  207.1, and a 
representative sampling of any other labeling;
    (4) All other. For all other listed drugs, including unfinished 
drugs, the label (if any), except that only one representative label 
need be submitted where differences exist only in the quantity of 
contents statement.
    (e) Advertisements. (1) A representative sampling of advertisements 
for a human prescription drug that is not subject to section 505 of the 
Federal Food, Drug, and Cosmetic Act or section 351 of the Public Health 
Service Act;
    (2) If we request it for good cause, a copy of all advertisements 
for a particular drug described in paragraph (e)(1) of this section, 
including advertisements described in Sec.  202.1(l)(1) of this chapter. 
Such advertisements must be submitted within 30 calendar days after our 
request.
    (f) Private label distributor products. A listing submission for a 
human drug distributed by a private label distributor described in Sec.  
207.41(c)(2) must include information specified in Sec.  207.53(b) 
through (e) as applicable and:
    (1) The appropriate NDC(s) (as described in Sec.  207.33) that 
include the private label distributor's labeler code and all package 
code variations;
    (2) The name, mailing address, telephone number, and email address 
of the private label distributor; and
    (3) For drugs bearing the NDC(s) reported under paragraph (f)(1) of 
this section, labeling as described in paragraphs (d)(1) through (4) of 
this section, as applicable, that accompanies the private label 
distributor's product.

[81 FR 60212, Aug. 31, 2016, as amended at 86 FR 17061, Apr. 1, 2021]



Sec.  207.54  What listing information must a registrant submit for a
drug that it salvages?

    A registrant who also relabels or repacks a drug that it salvages 
must list the drug it relabels or repacks in accordance with Sec.  
207.53 rather than in accordance with this section. A registrant who 
performs only salvaging with respect to a drug must provide the 
following listing information for that drug.
    (a) The NDC assigned to the drug immediately before the drug is 
received by the registrant for salvaging;
    (b) The lot number and expiration date of the salvaged drug product; 
and
    (c) The name and Unique Facility Identifier for each establishment 
where the registrant salvages the drug.



Sec.  207.55  What additional drug listing information may FDA require?

    For a particular listed drug, upon our request, the registrant must 
briefly state the basis for its belief that the drug is not subject to 
section 505 or 512 of the Federal Food, Drug, and Cosmetic Act or 
section 351 of the Public Health Service Act.



Sec.  207.57  What information must registrants submit when updating
listing information and when?

    Registrants must review and update listing information at a minimum, 
as follows:
    (a) Registrants must provide listing information at the time of 
annual establishment registration for any drug manufactured, repacked, 
relabeled, or salvaged by them for commercial distribution that has not 
been listed previously.
    (b) Registrants must review and update their drug listing 
information each June and December. When doing so, registrants must:
    (1)(i) Provide listing information, in accordance with Sec. Sec.  
207.49, 207.53, and 207.54, for any drug manufactured, repacked, 
relabeled, or salvaged by them for commercial distribution that has not 
been previously listed;
    (ii) Submit the date that they discontinued the manufacture, 
repacking, relabeling or salvaging for commercial distribution of a 
listed drug and provide the expiration date of the last lot 
manufactured, repacked, relabeled, or salvaged;
    (iii) Submit the date that they resumed the manufacture, repacking, 
or relabeling for commercial distribution of a drug previously 
discontinued, and

[[Page 148]]

provide any required listing information not previously submitted; and
    (iv) Submit any material changes in any information previously 
submitted pursuant to Sec. Sec.  207.49, 207.53, 207.54, or other 
relevant sections of this part; or
    (2) For each listed drug, certify that no changes subject to 
reporting under paragraph (b)(1)(iv) of this section have occurred if no 
such changes have occurred since the last review and update. If a drug 
is discontinued and FDA has received the information required under 
paragraph (b)(1)(ii) of this section, no further certifications are 
necessary for the discontinued drug. After initial electronic listing, 
registrants may satisfy the listing update requirement with respect to 
unchanged listing information by making a single ``no changes'' 
certification during the annual registration update under Sec.  
207.29(b) applicable to all of the registrant's listed drugs for which 
no changes have been made since the previous annual registration update.
    (c) Registrants are encouraged to submit listing information for 
every drug subject to listing under this part prior to commercial 
distribution and are encouraged to update listing information at the 
time of any change affecting information previously submitted.



        Subpart E_Electronic Format for Registration and Listing



Sec.  207.61  How is registration and listing information provided
to FDA?

    (a) Electronic format. (1) Except as provided in Sec.  207.65, all 
information submitted under this part must be transmitted to FDA in 
electronic format by using our electronic drug registration and listing 
system, in a form that we can process, review, and archive. We may 
periodically issue guidance on how to provide registration and listing 
information in electronic format (specifying for example method of 
transmission, media, file formats, preparation, and organization of 
files).
    (2) Information provided in electronic format must comply with part 
11 of this chapter, except as follows:
    (i) Advertisements and labeling, including the content of labeling, 
required under this part are exempt from the requirements in Sec.  
11.10(a), (c) through (h), and (k) of this chapter and the corresponding 
requirements in Sec.  11.30 of this chapter.
    (ii) All other information submitted under this part is exempt from 
the requirements in Sec.  11.10(b), (c), and (e) of this chapter and the 
corresponding requirements in Sec.  11.30 of this chapter.
    (b) English language. Drug establishment registration and drug 
listing information must be provided in the English language. The 
content of labeling must be provided at a minimum in the English 
language. Where Sec.  201.15(c) of this chapter permits product labeling 
solely in a foreign language, the content of labeling must be submitted 
in that language along with an accurate English translation.



Sec.  207.65  How can a waiver of the electronic submission requirement
be obtained?

    (a) All information submitted under this part must be transmitted to 
FDA electronically in accordance with Sec.  207.61(a) unless FDA has 
granted a request for waiver of this requirement prior to the date on 
which submission of such information is due. Submission of a request for 
waiver does not excuse timely compliance with the registration and 
listing requirements. FDA will grant a waiver request if FDA determines 
that the use of electronic means for submission of registration and 
listing information is not reasonable for the registrant making the 
waiver request.
    (b) Waiver requests under this section must be submitted in writing 
and must include the specific reasons why electronic submission is not 
reasonable for the registrant and a U.S. telephone number and mailing 
address where FDA can contact the registrant. All waiver requests must 
be sent to: SPL Coordinator, U.S. Food and Drug Administration, 10903 
New Hampshire Ave., Bldg. 32, Silver Spring, MD 20993.
    (c) If FDA grants the waiver request, FDA may limit its duration and 
will specify terms of the waiver and provide information on how to 
submit establishment registration, drug listings, other information, and 
updates, as applicable.

[[Page 149]]



                         Subpart F_Miscellaneous



Sec.  207.69  What are the requirements for an official contact and
a United States agent?

    (a) Official contact. Registrants subject to the registration 
requirements of this part must designate an official contact for each 
establishment. The official contact is responsible for:
    (1) Ensuring the accuracy of registration and listing information; 
and
    (2) Reviewing, disseminating, routing, and responding to all 
communications from FDA including emergency communications.
    (b) United States agent. Registrants of foreign establishments 
subject to this part must designate a single United States agent. The 
United States agent must reside or maintain a place of business in the 
United States and may not be a mailbox, answering machine or service, or 
other place where a person acting as the United States agent is not 
physically present. The United States agent is responsible for:
    (1) Reviewing, disseminating, routing, and responding to all 
communications from FDA including emergency communications;
    (2) Responding to questions concerning those drugs that are imported 
or offered for import to the United States;
    (3) Assisting FDA in scheduling inspections; and
    (4) If FDA is unable to contact a foreign registrant directly or 
expeditiously, FDA may provide the information and/or documents to the 
United States agent. FDA's providing information and/or documents to the 
United States agent is equivalent to providing the same information and/
or documents to the foreign registrant.



Sec.  207.77  What legal status is conferred by registration and listing?

    (a) Registration of an establishment or listing of a drug does not 
denote approval of the establishment, the drug, or other drugs of the 
establishment, nor does it mean that a product may be legally marketed. 
Any representation that creates an impression of official approval or 
that a drug is approved or is legally marketable because of registration 
or listing is misleading and constitutes misbranding.
    (b) FDA's acceptance of registration and listing information, 
inclusion of a drug in our database of drugs, or assignment of an NDC 
does not denote approval of the establishment or the drug or any other 
drugs of the establishment, nor does it mean that the drug may be 
legally marketed. Any representation that creates the impression that a 
drug is approved or is legally marketable because it appears in our 
database of drugs, has been assigned or displays an NDC, or the 
establishment has been assigned an establishment registration number or 
Unique Facility Identifier is misleading and constitutes misbranding. 
Failure to comply with Sec.  207.37 may also constitute misbranding.
    (c) Neither registration nor listing constitutes a determination by 
FDA that a product is a drug as defined by section 201(g)(1) of the 
Federal Food, Drug, and Cosmetic Act. Registration or listing may, 
however, be evidence that a facility intends to or does manufacture, 
repack, relabel, distribute, or salvage drugs or that a product is 
intended to be a drug.



Sec.  207.81  What registration and listing information will FDA make
available for public disclosure?

    (a) Except as provided in paragraphs (b) and (c) of this section, 
the following information will be available for public disclosure, upon 
request or at FDA's discretion:
    (1) All establishment registration information, and
    (2) After a drug is marketed, information obtained under Sec.  
207.33, Sec.  207.49, Sec.  207.53, Sec.  207.54, or Sec.  207.57.
    (b) Unless such information is publicly available or FDA finds that 
confidentiality would be inconsistent with protection of the public 
health, FDA will not make publicly available:
    (1) Any information submitted under Sec.  207.55 as the basis upon 
which it has been determined that a particular drug is not subject to 
section 505 or 512 of the Federal Food, Drug, and Cosmetic Act or 
section 351 of the Public Health Service Act,
    (2) The names of any inactive ingredients submitted under Sec.  
207.49(a)(4) for

[[Page 150]]

which the registrant makes a valid assertion of confidentiality under 
Sec.  20.61 of this chapter or other provision of law, or
    (3) Drug listing information obtained under Sec.  207.33(d)(3), 
Sec.  207.49(a)(9) and (12), Sec.  207.53(b) and (c), or Sec.  207.54(a) 
or (c).
    (c) FDA may determine, in limited circumstances and on a case-by-
case basis, that it would be consistent with the protection of the 
public health and the Freedom of Information Act to exempt from public 
disclosure specific information identified in paragraph (a) of this 
section.



PART 208_MEDICATION GUIDES FOR PRESCRIPTION DRUG PRODUCTS-
-Table of Contents



                      Subpart A_General Provisions

Sec.
208.1 Scope and purpose.
208.3 Definitions.

          Subpart B_General Requirements for a Medication Guide

208.20 Content and format of a Medication Guide.
208.24 Distributing and dispensing a Medication Guide.
208.26 Exemptions and deferrals.

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 360, 
371, 374; 42 U.S.C. 262.

    Source: 63 FR 66396, Dec. 1, 1998, unless otherwise noted.



                      Subpart A_General Provisions



Sec.  208.1  Scope and purpose.

    (a) This part sets forth requirements for patient labeling for human 
prescription drug products, including biological products, that the Food 
and Drug Administration (FDA) determines pose a serious and significant 
public health concern requiring distribution of FDA-approved patient 
information. It applies primarily to human prescription drug products 
used on an outpatient basis without direct supervision by a health 
professional. This part shall apply to new prescriptions and refill 
prescriptions.
    (b) The purpose of patient labeling for human prescription drug 
products required under this part is to provide information when the FDA 
determines in writing that it is necessary to patients' safe and 
effective use of drug products.
    (c) Patient labeling will be required if the FDA determines that one 
or more of the following circumstances exists:
    (1) The drug product is one for which patient labeling could help 
prevent serious adverse effects.
    (2) The drug product is one that has serious risk(s) (relative to 
benefits) of which patients should be made aware because information 
concerning the risk(s) could affect patients' decision to use, or to 
continue to use, the product.
    (3) The drug product is important to health and patient adherence to 
directions for use is crucial to the drug's effectiveness.



Sec.  208.3  Definitions.

    For the purposes of this part, the following definitions shall 
apply:
    (a) Authorized dispenser means an individual licensed, registered, 
or otherwise permitted by the jurisdiction in which the individual 
practices to provide drug products on prescription in the course of 
professional practice.
    (b) Dispense to patients means the act of delivering a prescription 
drug product to a patient or an agent of the patient either:
    (1) By a licensed practitioner or an agent of a licensed 
practitioner, either directly or indirectly, for self-administration by 
the patient, or the patient's agent, or outside the licensed 
practitioner's direct supervision; or
    (2) By an authorized dispenser or an agent of an authorized 
dispenser under a lawful prescription of a licensed practitioner.
    (c) Distribute means the act of delivering, other than by 
dispensing, a drug product to any person.
    (d) Distributor means a person who distributes a drug product.
    (e) Drug product means a finished dosage form, e.g., tablet, 
capsule, or solution, that contains an active drug ingredient, 
generally, but not necessarily, in association with inactive 
ingredients. For purposes of this part, drug product also means 
biological product within the meaning of section 351(a) of the Public 
Health Service Act.

[[Page 151]]

    (f) Licensed practitioner means an individual licensed, registered, 
or otherwise permitted by the jurisdiction in which the individual 
practices to prescribe drug products in the course of professional 
practice.
    (g) Manufacturer means for a drug product that is not also a 
biological product, both the manufacturer as described in Sec.  201.1 
and the applicant as described in Sec.  314.3(b) of this chapter, and 
for a drug product that is also a biological product, the manufacturer 
as described in Sec.  600.3(t) of this chapter.
    (h) Medication Guide means FDA-approved patient labeling conforming 
to the specifications set forth in this part and other applicable 
regulations.
    (i) Packer means a person who packages a drug product.
    (j) Patient means any individual with respect to whom a drug product 
is intended to be, or has been, used.
    (k) Serious risk or serious adverse effect means an adverse drug 
experience, or the risk of such an experience, as that term is defined 
in Sec. Sec.  310.305, 312.32, 314.80, and 600.80 of this chapter.



          Subpart B_General Requirements for a Medication Guide



Sec.  208.20  Content and format of a Medication Guide.

    (a) A Medication Guide shall meet all of the following conditions:
    (1) The Medication Guide shall be written in English, in 
nontechnical, understandable language, and shall not be promotional in 
tone or content.
    (2) The Medication Guide shall be scientifically accurate and shall 
be based on, and shall not conflict with, the approved professional 
labeling for the drug product under Sec.  201.57 of this chapter, but 
the language of the Medication Guide need not be identical to the 
sections of approved labeling to which it corresponds.
    (3) The Medication Guide shall be specific and comprehensive.
    (4) The letter height or type size shall be no smaller than 10 
points (1 point = 0.0138 inches) for all sections of the Medication 
Guide, except the manufacturer's name and address and the revision date.
    (5) The Medication Guide shall be legible and clearly presented. 
Where appropriate, the Medication Guide shall also use boxes, bold or 
underlined print, or other highlighting techniques to emphasize specific 
portions of the text.
    (6) The words ``Medication Guide'' shall appear prominently at the 
top of the first page of a Medication Guide. The verbatim statement 
``This Medication Guide has been approved by the U.S. Food and Drug 
Administration'' shall appear at the bottom of a Medication Guide.
    (7) The brand and established or proper name of the drug product 
shall appear immediately below the words ``Medication Guide.'' The 
established or proper name shall be no less than one-half the height of 
the brand name.
    (b) A Medication Guide shall contain those of the following headings 
relevant to the drug product and to the need for the Medication Guide in 
the specified order. Each heading shall contain the specific information 
as follows:
    (1) The brand name (e.g., the trademark or proprietary name), if 
any, and established or proper name. Those products not having an 
established or proper name shall be designated by their active 
ingredients. The Medication Guide shall include the phonetic spelling of 
either the brand name or the established name, whichever is used 
throughout the Medication Guide.
    (2) The heading, ``What is the most important information I should 
know about (name of drug)?'' followed by a statement describing the 
particular serious and significant public health concern that has 
created the need for the Medication Guide. The statement should describe 
specifically what the patient should do or consider because of that 
concern, such as, weighing particular risks against the benefits of the 
drug, avoiding particular behaviors (e.g., activities, drugs), observing 
certain events (e.g., symptoms, signs) that could prevent or mitigate a 
serious adverse effect, or engaging in particular behaviors (e.g., 
adhering to the dosing regimen).
    (3) The heading, ``What is (name of drug)?'' followed by a section 
that identifies a drug product's indications for use. The Medication 
Guide may not

[[Page 152]]

identify an indication unless the indication is identified in the 
indications and usage section of the professional labeling for the 
product required under Sec.  201.57 of this chapter. In appropriate 
circumstances, this section may also explain the nature of the disease 
or condition the drug product is intended to treat, as well as the 
benefit(s) of treating the condition.
    (4) The heading, ``Who should not take (name of drug)?'' followed by 
information on circumstances under which the drug product should not be 
used for its labeled indication (its contraindications). The Medication 
Guide shall contain directions regarding what to do if any of the 
contraindications apply to a patient, such as contacting the licensed 
practitioner or discontinuing use of the drug product.
    (5) The heading, ``How should I take (name of drug)?'' followed by 
information on the proper use of the drug product, such as:
    (i) A statement stressing the importance of adhering to the dosing 
instructions, if this is particularly important;
    (ii) A statement describing any special instructions on how to 
administer the drug product, if they are important to the drug's safety 
or effectiveness;
    (iii) A statement of what patients should do in case of overdose of 
the drug product; and
    (iv) A statement of what patients should do if they miss taking a 
scheduled dose(s) of the drug product, where there are data to support 
the advice, and where the wrong behavior could cause harm or lack of 
effect.
    (6) The heading ``What should I avoid while taking (name of drug)?'' 
followed by a statement or statements of specific, important precautions 
patients should take to ensure proper use of the drug, including:
    (i) A statement that identifies activities (such as driving or 
sunbathing), and drugs, foods, or other substances (such as tobacco or 
alcohol) that patients should avoid when using the medication;
    (ii) A statement of the risks to mothers and fetuses from the use of 
the drug during pregnancy, if specific, important risks are known;
    (iii) A statement of the risks of the drug product to nursing 
infants, if specific, important risks are known;
    (iv) A statement about pediatric risks, if the drug product has 
specific hazards associated with its use in pediatric patients;
    (v) A statement about geriatric risks, if the drug product has 
specific hazards associated with its use in geriatric patients; and
    (vi) A statement of special precautions, if any, that apply to the 
safe and effective use of the drug product in other identifiable patient 
populations.
    (7) The heading, ``What are the possible or reasonably likely side 
effects of (name of drug)?'' followed by:
    (i) A statement of the adverse reactions reasonably likely to be 
caused by the drug product that are serious or occur frequently.
    (ii) A statement of the risk, if there is one, of patients' 
developing dependence on the drug product.
    (iii) For drug products approved under section 505 of the act, the 
following verbatim statement: ``Call your doctor for medical advice 
about side effects. You may report side effects to FDA at 1-800-FDA-
1088.''
    (8) General information about the safe and effective use of 
prescription drug products, including:
    (i) The verbatim statement that ``Medicines are sometimes prescribed 
for purposes other than those listed in a Medication Guide'' followed by 
a statement that patients should ask health professionals about any 
concerns, and a reference to the availability of professional labeling;
    (ii) A statement that the drug product should not be used for a 
condition other than that for which it is prescribed, or given to other 
persons;
    (iii) The name and place of business of the manufacturer, packer, or 
distributor of a drug product that is not also a biological product, or 
the name and place of business of the manufacturer or distributor of a 
drug product that is also a biological product, and in any case the name 
and place of business of the dispenser of the product may also be 
included; and

[[Page 153]]

    (iv) The date, identified as such, of the most recent revision of 
the Medication Guide placed immediately after the last section.
    (9) Additional headings and subheadings may be interspersed 
throughout the Medication Guide, if appropriate.

[63 FR 66396, Dec. 1, 1998, as amended at 73 FR 404, Jan. 3, 2008]



Sec.  208.24  Distributing and dispensing a Medication Guide.

    (a) The manufacturer of a drug product for which a Medication Guide 
is required under this part shall obtain FDA approval of the Medication 
Guide before the Medication Guide may be distributed.
    (b) Each manufacturer who ships a container of drug product for 
which a Medication Guide is required under this part is responsible for 
ensuring that Medication Guides are available for distribution to 
patients by either:
    (1) Providing Medication Guides in sufficient numbers to 
distributors, packers, or authorized dispensers to permit the authorized 
dispenser to provide a Medication Guide to each patient receiving a 
prescription for the drug product; or
    (2) Providing the means to produce Medication Guides in sufficient 
numbers to distributors, packers, or authorized dispensers to permit the 
authorized dispenser to provide a Medication Guide to each patient 
receiving a prescription for the drug product.
    (c) Each distributor or packer that receives Medication Guides, or 
the means to produce Medication Guides, from a manufacturer under 
paragraph (b) of this section shall provide those Medication Guides, or 
the means to produce Medication Guides, to each authorized dispenser to 
whom it ships a container of drug product.
    (d) The label of each container or package, where the container 
label is too small, of drug product for which a Medication Guide is 
required under this part shall instruct the authorized dispenser to 
provide a Medication Guide to each patient to whom the drug product is 
dispensed, and shall state how the Medication Guide is provided. These 
statements shall appear on the label in a prominent and conspicuous 
manner.
    (e) Each authorized dispenser of a prescription drug product for 
which a Medication Guide is required under this part shall, when the 
product is dispensed to a patient (or to a patient's agent), provide a 
Medication Guide directly to each patient (or to the patient's agent) 
unless an exemption applies under Sec.  208.26.
    (f) An authorized dispenser or wholesaler is not subject to section 
510 of the Federal Food, Drug, and Cosmetic Act, which requires the 
registration of producers of drugs and the listing of drugs in 
commercial distribution, solely because of an act performed by the 
authorized dispenser or wholesaler under this part.



Sec.  208.26  Exemptions and deferrals.

    (a) FDA on its own initiative, or in response to a written request 
from an applicant, may exempt or defer any Medication Guide content or 
format requirement, except those requirements in Sec.  208.20 (a)(2) and 
(a)(6), on the basis that the requirement is inapplicable, unnecessary, 
or contrary to patients' best interests. Requests from applicants should 
be submitted to the director of the FDA division responsible for 
reviewing the marketing application for the drug product, or for a 
biological product, to the application division in the office with 
product responsibility.
    (b) If the licensed practitioner who prescribes a drug product 
subject to this part determines that it is not in a particular patient's 
best interest to receive a Medication Guide because of significant 
concerns about the effect of a Medication Guide, the licensed 
practitioner may direct that the Medication Guide not be provided to the 
particular patient. However, the authorized dispenser of a prescription 
drug product subject to this part shall provide a Medication Guide to 
any patient who requests information when the drug product is dispensed 
regardless of any such direction by the licensed practitioner.

[[Page 154]]



PART 209_REQUIREMENT FOR AUTHORIZED DISPENSERS AND PHARMACIES TO 
DISTRIBUTE A SIDE EFFECTS STATEMENT--Table of Contents



                      Subpart A_General Provisions

Sec.
209.1 Scope and purpose.
209.2 Definitions.

                         Subpart B_Requirements

209.10 Content and format of the side effects statement.
209.11 Dispensing and distributing the side effects statement.

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 371; 42 
U.S.C. 241.

    Source: 73 FR 404, Jan. 3, 2008, unless otherwise noted.



                      Subpart A_General Provisions



Sec.  209.1  Scope and purpose.

    (a) This part sets forth requirements for human prescription drug 
products approved under section 505 of the Federal Food, Drug, and 
Cosmetic Act and dispensed by authorized dispensers and pharmacies to 
consumers. This part requires distribution of a side effects statement 
and applies to new and refill prescriptions. This part is not intended 
to apply to authorized dispensers dispensing or administering 
prescription drug products to inpatients in a hospital or health care 
facility under an order of a licensed practitioner, or as part of 
supervised home health care.
    (b) The purpose of providing the side effects statement is to enable 
consumers to report side effects of prescription drug products to FDA.



Sec.  209.2  Definitions.

    For the purposes of this part, the following definitions apply:
    Act means the Federal Food, Drug, and Cosmetic Act (sections 201-907 
(21 U.S.C. 301-397)).
    Authorized dispenser means an individual licensed, registered, or 
otherwise permitted by the jurisdiction in which the individual 
practices to provide drug products on prescription in the course of 
professional practice.
    Consumer medication information means written information 
voluntarily provided to consumers by dispensing pharmacists as part of 
patient medication counseling activities.
    Medication Guide means FDA-approved patient labeling conforming to 
the specifications set forth in part 208 of this chapter and other 
applicable regulations.
    Pharmacy includes, but is not limited to, a retail, mail order, 
Internet, hospital, university, or clinic pharmacy, or a public health 
agency, regularly and lawfully engaged in dispensing prescription drugs.
    Side effects statement means the following verbatim statement: 
``Call your doctor for medical advice about side effects. You may report 
side effects to FDA at 1-800-FDA-1088.''



                         Subpart B_Requirements



Sec.  209.10  Content and format of the side effects statement.

    (a) Content. The side effects statement provided with each 
prescription drug product approved under section 505 of the act must 
read: ``Call your doctor for medical advice about side effects. You may 
report side effects to FDA at 1-800-FDA-1088.''
    (b) Format. The side effects statement must be in a single, clear, 
easy-to-read type style. The letter height or type size used for the 
side effects statement in accordance with paragraphs (b)(1) and (b)(2) 
of Sec.  209.11 must be no smaller than 6 points (1 point = 0.0138 
inch). The letter height or type size for the side effects statement 
under paragraphs (b)(3), (b)(4), and (b)(5) of Sec.  209.11 must be no 
smaller than 10 points.



Sec.  209.11  Dispensing and distributing the side effects statement.

    (a) Each authorized dispenser or pharmacy must distribute the side 
effects statement with each prescription drug product approved under 
section 505 of the act and dispensed. The side effects statement must be 
distributed with new and refill prescriptions.
    (b) An authorized dispenser or pharmacy must choose one or more of 
the following options to distribute the side effects statement:
    (1) Distribute the side effects statement on a sticker attached to 
the unit package, vial, or container of the drug product;

[[Page 155]]

    (2) Distribute the side effects statement on a preprinted pharmacy 
prescription vial cap;
    (3) Distribute the side effects statement on a separate sheet of 
paper;
    (4) Distribute the side effects statement in consumer medication 
information; or
    (5) Distribute the appropriate FDA-approved Medication Guide that 
contains the side effects statement.



PART 210_CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, 
PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL--Table of Contents



Sec.
210.1 Status of current good manufacturing practice regulations.
210.2 Applicability of current good manufacturing practice regulations.
210.3 Definitions.

    Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42 U.S.C. 
216, 262, 263a, 264.

    Source: 43 FR 45076, Sept. 29, 1978, unless otherwise noted.



Sec.  210.1  Status of current good manufacturing practice regulations.

    (a) The regulations set forth in this part and in parts 211, 225, 
and 226 of this chapter contain the minimum current good manufacturing 
practice for methods to be used in, and the facilities or controls to be 
used for, the manufacture, processing, packing, or holding of a drug to 
assure that such drug meets the requirements of the act as to safety, 
and has the identity and strength and meets the quality and purity 
characteristics that it purports or is represented to possess.
    (b) The failure to comply with any regulation set forth in this part 
and in parts 211, 225, and 226 of this chapter in the manufacture, 
processing, packing, or holding of a drug shall render such drug to be 
adulterated under section 501(a)(2)(B) of the act and such drug, as well 
as the person who is responsible for the failure to comply, shall be 
subject to regulatory action.
    (c) Owners and operators of establishments engaged in the recovery, 
donor screening, testing (including donor testing), processing, storage, 
labeling, packaging, or distribution of human cells, tissues, and 
cellular and tissue-based products (HCT/Ps), as defined in Sec.  
1271.3(d) of this chapter, that are drugs (subject to review under an 
application submitted under section 505 of the act or under a biological 
product license application under section 351 of the Public Health 
Service Act), are subject to the donor-eligibility and applicable 
current good tissue practice procedures set forth in part 1271 subparts 
C and D of this chapter, in addition to the regulations in this part and 
in parts 211, 225, and 226 of this chapter. Failure to comply with any 
applicable regulation set forth in this part, in parts 211, 225, and 226 
of this chapter, in part 1271 subpart C of this chapter, or in part 1271 
subpart D of this chapter with respect to the manufacture, processing, 
packing or holding of a drug, renders an HCT/P adulterated under section 
501(a)(2)(B) of the act. Such HCT/P, as well as the person who is 
responsible for the failure to comply, is subject to regulatory action.

[43 FR 45076, Sept. 29, 1978, as amended at 69 FR 29828, May 25, 2004; 
74 FR 65431, Dec. 10, 2009]



Sec.  210.2  Applicability of current good manufacturing practice 
regulations.

    (a) The regulations in this part and in parts 211, 225, and 226 of 
this chapter as they may pertain to a drug; in parts 600 through 680 of 
this chapter as they may pertain to a biological product for human use; 
and in part 1271 of this chapter as they are applicable to a human cell, 
tissue, or cellular or tissue-based product (HCT/P) that is a drug 
(subject to review under an application submitted under section 505 of 
the act or under a biological product license application under section 
351 of the Public Health Service Act); shall be considered to 
supplement, not supersede, each other, unless the regulations explicitly 
provide otherwise. In the event of a conflict between applicable 
regulations in this part and in other parts of this chapter, the 
regulation specifically applicable to the drug product in question shall 
supersede the more general.
    (b) If a person engages in only some operations subject to the 
regulations in this part, in parts 211, 225, and 226 of this chapter, in 
parts 600 through 680 of

[[Page 156]]

this chapter, and in part 1271 of this chapter, and not in others, that 
person need only comply with those regulations applicable to the 
operations in which he or she is engaged.
    (c) An investigational drug for use in a phase 1 study, as described 
in Sec.  312.21(a) of this chapter, is subject to the statutory 
requirements set forth in 21 U.S.C. 351(a)(2)(B). The production of such 
drug is exempt from compliance with the regulations in part 211 of this 
chapter. However, this exemption does not apply to an investigational 
drug for use in a phase 1 study once the investigational drug has been 
made available for use by or for the sponsor in a phase 2 or phase 3 
study, as described in Sec.  312.21(b) and (c) of this chapter, or the 
drug has been lawfully marketed. If the investigational drug has been 
made available in a phase 2 or phase 3 study or the drug has been 
lawfully marketed, the drug for use in the phase 1 study must comply 
with part 211.

[69 FR 29828, May 25, 2004, as amended at 73 FR 40462, July 15, 2008; 74 
FR 65431, Dec. 10, 2009]



Sec.  210.3  Definitions.

    (a) The definitions and interpretations contained in section 201 of 
the act shall be applicable to such terms when used in this part and in 
parts 211, 225, and 226 of this chapter.
    (b) The following definitions of terms apply to this part and to 
parts 211, 225, and 226 of this chapter.
    (1) Act means the Federal Food, Drug, and Cosmetic Act, as amended 
(21 U.S.C. 301 et seq.).
    (2) Batch means a specific quantity of a drug or other material that 
is intended to have uniform character and quality, within specified 
limits, and is produced according to a single manufacturing order during 
the same cycle of manufacture.
    (3) Component means any ingredient intended for use in the 
manufacture of a drug product, including those that may not appear in 
such drug product.
    (4) Drug product means a finished dosage form, for example, tablet, 
capsule, solution, etc., that contains an active drug ingredient 
generally, but not necessarily, in association with inactive 
ingredients. The term also includes a finished dosage form that does not 
contain an active ingredient but is intended to be used as a placebo.
    (5) Fiber means any particulate contaminant with a length at least 
three times greater than its width.
    (6) Nonfiber releasing filter means any filter, which after 
appropriate pretreatment such as washing or flushing, will not release 
fibers into the component or drug product that is being filtered.
    (7) Active ingredient means any component that is intended to 
furnish pharmacological activity or other direct effect in the 
diagnosis, cure, mitigation, treatment, or prevention of disease, or to 
affect the structure or any function of the body of man or other 
animals. The term includes those components that may undergo chemical 
change in the manufacture of the drug product and be present in the drug 
product in a modified form intended to furnish the specified activity or 
effect.
    (8) Inactive ingredient means any component other than an active 
ingredient.
    (9) In-process material means any material fabricated, compounded, 
blended, or derived by chemical reaction that is produced for, and used 
in, the preparation of the drug product.
    (10) Lot means a batch, or a specific identified portion of a batch, 
having uniform character and quality within specified limits; or, in the 
case of a drug product produced by continuous process, it is a specific 
identified amount produced in a unit of time or quantity in a manner 
that assures its having uniform character and quality within specified 
limits.
    (11) Lot number, control number, or batch number means any 
distinctive combination of letters, numbers, or symbols, or any 
combination of them, from which the complete history of the manufacture, 
processing, packing, holding, and distribution of a batch or lot of drug 
product or other material can be determined.
    (12) Manufacture, processing, packing, or holding of a drug product 
includes packaging and labeling operations, testing, and quality control 
of drug products.
    (13) The term medicated feed means any Type B or Type C medicated 
feed as defined in Sec.  558.3 of this chapter. The

[[Page 157]]

feed contains one or more drugs as defined in section 201(g) of the act. 
The manufacture of medicated feeds is subject to the requirements of 
part 225 of this chapter.
    (14) The term medicated premix means a Type A medicated article as 
defined in Sec.  558.3 of this chapter. The article contains one or more 
drugs as defined in section 201(g) of the act. The manufacture of 
medicated premixes is subject to the requirements of part 226 of this 
chapter.
    (15) Quality control unit means any person or organizational element 
designated by the firm to be responsible for the duties relating to 
quality control.
    (16) Strength means:
    (i) The concentration of the drug substance (for example, weight/
weight, weight/volume, or unit dose/volume basis), and/or
    (ii) The potency, that is, the therapeutic activity of the drug 
product as indicated by appropriate laboratory tests or by adequately 
developed and controlled clinical data (expressed, for example, in terms 
of units by reference to a standard).
    (17) Theoretical yield means the quantity that would be produced at 
any appropriate phase of manufacture, processing, or packing of a 
particular drug product, based upon the quantity of components to be 
used, in the absence of any loss or error in actual production.
    (18) Actual yield means the quantity that is actually produced at 
any appropriate phase of manufacture, processing, or packing of a 
particular drug product.
    (19) Percentage of theoretical yield means the ratio of the actual 
yield (at any appropriate phase of manufacture, processing, or packing 
of a particular drug product) to the theoretical yield (at the same 
phase), stated as a percentage.
    (20) Acceptance criteria means the product specifications and 
acceptance/rejection criteria, such as acceptable quality level and 
unacceptable quality level, with an associated sampling plan, that are 
necessary for making a decision to accept or reject a lot or batch (or 
any other convenient subgroups of manufactured units).
    (21) Representative sample means a sample that consists of a number 
of units that are drawn based on rational criteria such as random 
sampling and intended to assure that the sample accurately portrays the 
material being sampled.
    (22) Gang-printed labeling means labeling derived from a sheet of 
material on which more than one item of labeling is printed.

[43 FR 45076, Sept. 29, 1978, as amended at 51 FR 7389, Mar. 3, 1986; 58 
FR 41353, Aug. 3, 1993; 73 FR 51931, Sept. 8, 2008; 74 FR 65431, Dec. 
10, 2009]



PART 211_CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS-
-Table of Contents



                      Subpart A_General Provisions

Sec.
211.1 Scope.
211.3 Definitions.

                  Subpart B_Organization and Personnel

211.22 Responsibilities of quality control unit.
211.25 Personnel qualifications.
211.28 Personnel responsibilities.
211.34 Consultants.

                   Subpart C_Buildings and Facilities

211.42 Design and construction features.
211.44 Lighting.
211.46 Ventilation, air filtration, air heating and cooling.
211.48 Plumbing.
211.50 Sewage and refuse.
211.52 Washing and toilet facilities.
211.56 Sanitation.
211.58 Maintenance.

                           Subpart D_Equipment

211.63 Equipment design, size, and location.
211.65 Equipment construction.
211.67 Equipment cleaning and maintenance.
211.68 Automatic, mechanical, and electronic equipment.
211.72 Filters.

Subpart E_Control of Components and Drug Product Containers and Closures

211.80 General requirements.
211.82 Receipt and storage of untested components, drug product 
          containers, and closures.

[[Page 158]]

211.84 Testing and approval or rejection of components, drug product 
          containers, and closures.
211.86 Use of approved components, drug product containers, and 
          closures.
211.87 Retesting of approved components, drug product containers, and 
          closures.
211.89 Rejected components, drug product containers, and closures.
211.94 Drug product containers and closures.

                Subpart F_Production and Process Controls

211.100 Written procedures; deviations.
211.101 Charge-in of components.
211.103 Calculation of yield.
211.105 Equipment identification.
211.110 Sampling and testing of in-process materials and drug products.
211.111 Time limitations on production.
211.113 Control of microbiological contamination.
211.115 Reprocessing.

                Subpart G_Packaging and Labeling Control

211.122 Materials examination and usage criteria.
211.125 Labeling issuance.
211.130 Packaging and labeling operations.
211.132 Tamper-evident packaging requirements for over-the-counter (OTC) 
          human drug products.
211.134 Drug product inspection.
211.137 Expiration dating.

                   Subpart H_Holding and Distribution

211.142 Warehousing procedures.
211.150 Distribution procedures.

                      Subpart I_Laboratory Controls

211.160 General requirements.
211.165 Testing and release for distribution.
211.166 Stability testing.
211.167 Special testing requirements.
211.170 Reserve samples.
211.173 Laboratory animals.
211.176 Penicillin contamination.

                      Subpart J_Records and Reports

211.180 General requirements.
211.182 Equipment cleaning and use log.
211.184 Component, drug product container, closure, and labeling 
          records.
211.186 Master production and control records.
211.188 Batch production and control records.
211.192 Production record review.
211.194 Laboratory records.
211.196 Distribution records.
211.198 Complaint files.

              Subpart K_Returned and Salvaged Drug Products

211.204 Returned drug products.
211.208 Drug product salvaging.

    Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42 U.S.C. 
216, 262, 263a, 264.

    Source: 43 FR 45077, Sept. 29, 1978, unless otherwise noted.



                      Subpart A_General Provisions



Sec.  211.1  Scope.

    (a) The regulations in this part contain the minimum current good 
manufacturing practice for preparation of drug products (excluding 
positron emission tomography drugs) for administration to humans or 
animals.
    (b) The current good manufacturing practice regulations in this 
chapter as they pertain to drug products; in parts 600 through 680 of 
this chapter, as they pertain to drugs that are also biological products 
for human use; and in part 1271 of this chapter, as they are applicable 
to drugs that are also human cells, tissues, and cellular and tissue-
based products (HCT/Ps) and that are drugs (subject to review under an 
application submitted under section 505 of the act or under a biological 
product license application under section 351 of the Public Health 
Service Act); supplement and do not supersede the regulations in this 
part unless the regulations explicitly provide otherwise. In the event 
of a conflict between applicable regulations in this part and in other 
parts of this chapter, or in parts 600 through 680 of this chapter, or 
in part 1271 of this chapter, the regulation specifically applicable to 
the drug product in question shall supersede the more general.
    (c) Pending consideration of a proposed exemption, published in the 
Federal Register of September 29, 1978, the requirements in this part 
shall not be enforced for OTC drug products if the products and all 
their ingredients are ordinarily marketed and consumed as human foods, 
and which products may also fall within the legal definition of drugs by 
virtue of their intended use. Therefore, until further notice, 
regulations under parts 110 and

[[Page 159]]

117 of this chapter, and where applicable, parts 113 through 129 of this 
chapter, shall be applied in determining whether these OTC drug products 
that are also foods are manufactured, processed, packed, or held under 
current good manufacturing practice.

[43 FR 45077, Sept. 29, 1978, as amended at 62 FR 66522, Dec. 19, 1997; 
69 FR 29828, May 25, 2004; 74 FR 65431, Dec. 10, 2009; 80 FR 56168, 
Sept. 17, 2015]



Sec.  211.3  Definitions.

    The definitions set forth in Sec.  210.3 of this chapter apply in 
this part.



                  Subpart B_Organization and Personnel



Sec.  211.22  Responsibilities of quality control unit.

    (a) There shall be a quality control unit that shall have the 
responsibility and authority to approve or reject all components, drug 
product containers, closures, in-process materials, packaging material, 
labeling, and drug products, and the authority to review production 
records to assure that no errors have occurred or, if errors have 
occurred, that they have been fully investigated. The quality control 
unit shall be responsible for approving or rejecting drug products 
manufactured, processed, packed, or held under contract by another 
company.
    (b) Adequate laboratory facilities for the testing and approval (or 
rejection) of components, drug product containers, closures, packaging 
materials, in-process materials, and drug products shall be available to 
the quality control unit.
    (c) The quality control unit shall have the responsibility for 
approving or rejecting all procedures or specifications impacting on the 
identity, strength, quality, and purity of the drug product.
    (d) The responsibilities and procedures applicable to the quality 
control unit shall be in writing; such written procedures shall be 
followed.



Sec.  211.25  Personnel qualifications.

    (a) Each person engaged in the manufacture, processing, packing, or 
holding of a drug product shall have education, training, and 
experience, or any combination thereof, to enable that person to perform 
the assigned functions. Training shall be in the particular operations 
that the employee performs and in current good manufacturing practice 
(including the current good manufacturing practice regulations in this 
chapter and written procedures required by these regulations) as they 
relate to the employee's functions. Training in current good 
manufacturing practice shall be conducted by qualified individuals on a 
continuing basis and with sufficient frequency to assure that employees 
remain familiar with CGMP requirements applicable to them.
    (b) Each person responsible for supervising the manufacture, 
processing, packing, or holding of a drug product shall have the 
education, training, and experience, or any combination thereof, to 
perform assigned functions in such a manner as to provide assurance that 
the drug product has the safety, identity, strength, quality, and purity 
that it purports or is represented to possess.
    (c) There shall be an adequate number of qualified personnel to 
perform and supervise the manufacture, processing, packing, or holding 
of each drug product.



Sec.  211.28  Personnel responsibilities.

    (a) Personnel engaged in the manufacture, processing, packing, or 
holding of a drug product shall wear clean clothing appropriate for the 
duties they perform. Protective apparel, such as head, face, hand, and 
arm coverings, shall be worn as necessary to protect drug products from 
contamination.
    (b) Personnel shall practice good sanitation and health habits.
    (c) Only personnel authorized by supervisory personnel shall enter 
those areas of the buildings and facilities designated as limited-access 
areas.
    (d) Any person shown at any time (either by medical examination or 
supervisory observation) to have an apparent illness or open lesions 
that may adversely affect the safety or quality of drug products shall 
be excluded from direct contact with components, drug product 
containers, closures, in-process materials, and drug products until the 
condition is corrected or determined by

[[Page 160]]

competent medical personnel not to jeopardize the safety or quality of 
drug products. All personnel shall be instructed to report to 
supervisory personnel any health conditions that may have an adverse 
effect on drug products.



Sec.  211.34  Consultants.

    Consultants advising on the manufacture, processing, packing, or 
holding of drug products shall have sufficient education, training, and 
experience, or any combination thereof, to advise on the subject for 
which they are retained. Records shall be maintained stating the name, 
address, and qualifications of any consultants and the type of service 
they provide.



                   Subpart C_Buildings and Facilities



Sec.  211.42  Design and construction features.

    (a) Any building or buildings used in the manufacture, processing, 
packing, or holding of a drug product shall be of suitable size, 
construction and location to facilitate cleaning, maintenance, and 
proper operations.
    (b) Any such building shall have adequate space for the orderly 
placement of equipment and materials to prevent mixups between different 
components, drug product containers, closures, labeling, in-process 
materials, or drug products, and to prevent contamination. The flow of 
components, drug product containers, closures, labeling, in-process 
materials, and drug products through the building or buildings shall be 
designed to prevent contamination.
    (c) Operations shall be performed within specifically defined areas 
of adequate size. There shall be separate or defined areas or such other 
control systems for the firm's operations as are necessary to prevent 
contamination or mixups during the course of the following procedures:
    (1) Receipt, identification, storage, and withholding from use of 
components, drug product containers, closures, and labeling, pending the 
appropriate sampling, testing, or examination by the quality control 
unit before release for manufacturing or packaging;
    (2) Holding rejected components, drug product containers, closures, 
and labeling before disposition;
    (3) Storage of released components, drug product containers, 
closures, and labeling;
    (4) Storage of in-process materials;
    (5) Manufacturing and processing operations;
    (6) Packaging and labeling operations;
    (7) Quarantine storage before release of drug products;
    (8) Storage of drug products after release;
    (9) Control and laboratory operations;
    (10) Aseptic processing, which includes as appropriate:
    (i) Floors, walls, and ceilings of smooth, hard surfaces that are 
easily cleanable;
    (ii) Temperature and humidity controls;
    (iii) An air supply filtered through high-efficiency particulate air 
filters under positive pressure, regardless of whether flow is laminar 
or nonlaminar;
    (iv) A system for monitoring environmental conditions;
    (v) A system for cleaning and disinfecting the room and equipment to 
produce aseptic conditions;
    (vi) A system for maintaining any equipment used to control the 
aseptic conditions.
    (d) Operations relating to the manufacture, processing, and packing 
of penicillin shall be performed in facilities separate from those used 
for other drug products for human use.

[43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan. 20, 1995]



Sec.  211.44  Lighting.

    Adequate lighting shall be provided in all areas.



Sec.  211.46  Ventilation, air filtration, air heating and cooling.

    (a) Adequate ventilation shall be provided.
    (b) Equipment for adequate control over air pressure, micro-
organisms, dust, humidity, and temperature shall be provided when 
appropriate for the manufacture, processing, packing, or holding of a 
drug product.

[[Page 161]]

    (c) Air filtration systems, including prefilters and particulate 
matter air filters, shall be used when appropriate on air supplies to 
production areas. If air is recirculated to production areas, measures 
shall be taken to control recirculation of dust from production. In 
areas where air contamination occurs during production, there shall be 
adequate exhaust systems or other systems adequate to control 
contaminants.
    (d) Air-handling systems for the manufacture, processing, and 
packing of penicillin shall be completely separate from those for other 
drug products for human use.



Sec.  211.48  Plumbing.

    (a) Potable water shall be supplied under continuous positive 
pressure in a plumbing system free of defects that could contribute 
contamination to any drug product. Potable water shall meet the 
standards prescribed in the Environmental Protection Agency's Primary 
Drinking Water Regulations set forth in 40 CFR part 141. Water not 
meeting such standards shall not be permitted in the potable water 
system.
    (b) Drains shall be of adequate size and, where connected directly 
to a sewer, shall be provided with an air break or other mechanical 
device to prevent back-siphonage.

[43 FR 45077, Sept. 29, 1978, as amended at 48 FR 11426, Mar. 18, 1983]



Sec.  211.50  Sewage and refuse.

    Sewage, trash, and other refuse in and from the building and 
immediate premises shall be disposed of in a safe and sanitary manner.



Sec.  211.52  Washing and toilet facilities.

    Adequate washing facilities shall be provided, including hot and 
cold water, soap or detergent, air driers or single-service towels, and 
clean toilet facilities easily accesible to working areas.



Sec.  211.56  Sanitation.

    (a) Any building used in the manufacture, processing, packing, or 
holding of a drug product shall be maintained in a clean and sanitary 
condition, Any such building shall be free of infestation by rodents, 
birds, insects, and other vermin (other than laboratory animals). Trash 
and organic waste matter shall be held and disposed of in a timely and 
sanitary manner.
    (b) There shall be written procedures assigning responsibility for 
sanitation and describing in sufficient detail the cleaning schedules, 
methods, equipment, and materials to be used in cleaning the buildings 
and facilities; such written procedures shall be followed.
    (c) There shall be written procedures for use of suitable 
rodenticides, insecticides, fungicides, fumigating agents, and cleaning 
and sanitizing agents. Such written procedures shall be designed to 
prevent the contamination of equipment, components, drug product 
containers, closures, packaging, labeling materials, or drug products 
and shall be followed. Rodenticides, insecticides, and fungicides shall 
not be used unless registered and used in accordance with the Federal 
Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. 135).
    (d) Sanitation procedures shall apply to work performed by 
contractors or temporary employees as well as work performed by full-
time employees during the ordinary course of operations.



Sec.  211.58  Maintenance.

    Any building used in the manufacture, processing, packing, or 
holding of a drug product shall be maintained in a good state of repair.



                           Subpart D_Equipment



Sec.  211.63  Equipment design, size, and location.

    Equipment used in the manufacture, processing, packing, or holding 
of a drug product shall be of appropriate design, adequate size, and 
suitably located to facilitate operations for its intended use and for 
its cleaning and maintenance.



Sec.  211.65  Equipment construction.

    (a) Equipment shall be constructed so that surfaces that contact 
components, in-process materials, or drug products shall not be 
reactive, additive, or absorptive so as to alter the safety, identity, 
strength, quality, or purity of the

[[Page 162]]

drug product beyond the official or other established requirements.
    (b) Any substances required for operation, such as lubricants or 
coolants, shall not come into contact with components, drug product 
containers, closures, in-process materials, or drug products so as to 
alter the safety, identity, strength, quality, or purity of the drug 
product beyond the official or other established requirements.



Sec.  211.67  Equipment cleaning and maintenance.

    (a) Equipment and utensils shall be cleaned, maintained, and, as 
appropriate for the nature of the drug, sanitized and/or sterilized at 
appropriate intervals to prevent malfunctions or contamination that 
would alter the safety, identity, strength, quality, or purity of the 
drug product beyond the official or other established requirements.
    (b) Written procedures shall be established and followed for 
cleaning and maintenance of equipment, including utensils, used in the 
manufacture, processing, packing, or holding of a drug product. These 
procedures shall include, but are not necessarily limited to, the 
following:
    (1) Assignment of responsibility for cleaning and maintaining 
equipment;
    (2) Maintenance and cleaning schedules, including, where 
appropriate, sanitizing schedules;
    (3) A description in sufficient detail of the methods, equipment, 
and materials used in cleaning and maintenance operations, and the 
methods of disassembling and reassembling equipment as necessary to 
assure proper cleaning and maintenance;
    (4) Removal or obliteration of previous batch identification;
    (5) Protection of clean equipment from contamination prior to use;
    (6) Inspection of equipment for cleanliness immediately before use.
    (c) Records shall be kept of maintenance, cleaning, sanitizing, and 
inspection as specified in Sec. Sec.  211.180 and 211.182.

[43 FR 45077, Sept. 29, 1978, as amended at 73 FR 51931, Sept. 8, 2008]



Sec.  211.68  Automatic, mechanical, and electronic equipment.

    (a) Automatic, mechanical, or electronic equipment or other types of 
equipment, including computers, or related systems that will perform a 
function satisfactorily, may be used in the manufacture, processing, 
packing, and holding of a drug product. If such equipment is so used, it 
shall be routinely calibrated, inspected, or checked according to a 
written program designed to assure proper performance. Written records 
of those calibration checks and inspections shall be maintained.
    (b) Appropriate controls shall be exercised over computer or related 
systems to assure that changes in master production and control records 
or other records are instituted only by authorized personnel. Input to 
and output from the computer or related system of formulas or other 
records or data shall be checked for accuracy. The degree and frequency 
of input/output verification shall be based on the complexity and 
reliability of the computer or related system. A backup file of data 
entered into the computer or related system shall be maintained except 
where certain data, such as calculations performed in connection with 
laboratory analysis, are eliminated by computerization or other 
automated processes. In such instances a written record of the program 
shall be maintained along with appropriate validation data. Hard copy or 
alternative systems, such as duplicates, tapes, or microfilm, designed 
to assure that backup data are exact and complete and that it is secure 
from alteration, inadvertent erasures, or loss shall be maintained.
    (c) Such automated equipment used for performance of operations 
addressed by Sec. Sec.  211.101(c) or (d), 211.103, 211.182, or 
211.188(b)(11) can satisfy the requirements included in those sections 
relating to the performance of an operation by one person and checking 
by another person if such equipment is used in conformity with this 
section,

[[Page 163]]

and one person checks that the equipment properly performed the 
operation.

[43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan. 20, 1995; 
73 FR 51932, Sept. 8, 2008]



Sec.  211.72  Filters.

    Filters for liquid filtration used in the manufacture, processing, 
or packing of injectable drug products intended for human use shall not 
release fibers into such products. Fiber-releasing filters may be used 
when it is not possible to manufacture such products without the use of 
these filters. If use of a fiber-releasing filter is necessary, an 
additional nonfiber-releasing filter having a maximum nominal pore size 
rating of 0.2 micron (0.45 micron if the manufacturing conditions so 
dictate) shall subsequently be used to reduce the content of particles 
in the injectable drug product. The use of an asbestos-containing filter 
is prohibited.

[73 FR 51932, Sept. 8, 2008]



Subpart E_Control of Components and Drug Product Containers and Closures



Sec.  211.80  General requirements.

    (a) There shall be written procedures describing in sufficient 
detail the receipt, identification, storage, handling, sampling, 
testing, and approval or rejection of components and drug product 
containers and closures; such written procedures shall be followed.
    (b) Components and drug product containers and closures shall at all 
times be handled and stored in a manner to prevent contamination.
    (c) Bagged or boxed components of drug product containers, or 
closures shall be stored off the floor and suitably spaced to permit 
cleaning and inspection.
    (d) Each container or grouping of containers for components or drug 
product containers, or closures shall be identified with a distinctive 
code for each lot in each shipment received. This code shall be used in 
recording the disposition of each lot. Each lot shall be appropriately 
identified as to its status (i.e., quarantined, approved, or rejected).



Sec.  211.82  Receipt and storage of untested components, drug product
containers, and closures.

    (a) Upon receipt and before acceptance, each container or grouping 
of containers of components, drug product containers, and closures shall 
be examined visually for appropriate labeling as to contents, container 
damage or broken seals, and contamination.
    (b) Components, drug product containers, and closures shall be 
stored under quarantine until they have been tested or examined, 
whichever is appropriate, and released. Storage within the area shall 
conform to the requirements of Sec.  211.80.

[43 FR 45077, Sept. 29, 1978, as amended at 73 FR 51932, Sept. 8, 2008]



Sec.  211.84  Testing and approval or rejection of components, drug
product containers, and closures.

    (a) Each lot of components, drug product containers, and closures 
shall be withheld from use until the lot has been sampled, tested, or 
examined, as appropriate, and released for use by the quality control 
unit.
    (b) Representative samples of each shipment of each lot shall be 
collected for testing or examination. The number of containers to be 
sampled, and the amount of material to be taken from each container, 
shall be based upon appropriate criteria such as statistical criteria 
for component variability, confidence levels, and degree of precision 
desired, the past quality history of the supplier, and the quantity 
needed for analysis and reserve where required by Sec.  211.170.
    (c) Samples shall be collected in accordance with the following 
procedures:
    (1) The containers of components selected shall be cleaned when 
necessary in a manner to prevent introduction of contaminants into the 
component.
    (2) The containers shall be opened, sampled, and resealed in a 
manner designed to prevent contamination of their contents and 
contamination of other components, drug product containers, or closures.
    (3) Sterile equipment and aseptic sampling techniques shall be used 
when necessary.

[[Page 164]]

    (4) If it is necessary to sample a component from the top, middle, 
and bottom of its container, such sample subdivisions shall not be 
composited for testing.
    (5) Sample containers shall be identified so that the following 
information can be determined: name of the material sampled, the lot 
number, the container from which the sample was taken, the date on which 
the sample was taken, and the name of the person who collected the 
sample.
    (6) Containers from which samples have been taken shall be marked to 
show that samples have been removed from them.
    (d) Samples shall be examined and tested as follows:
    (1) At least one test shall be conducted to verify the identity of 
each component of a drug product. Specific identity tests, if they 
exist, shall be used.
    (2) Each component shall be tested for conformity with all 
appropriate written specifications for purity, strength, and quality. In 
lieu of such testing by the manufacturer, a report of analysis may be 
accepted from the supplier of a component, provided that at least one 
specific identity test is conducted on such component by the 
manufacturer, and provided that the manufacturer establishes the 
reliability of the supplier's analyses through appropriate validation of 
the supplier's test results at appropriate intervals.
    (3) Containers and closures shall be tested for conformity with all 
appropriate written specifications. In lieu of such testing by the 
manufacturer, a certificate of testing may be accepted from the 
supplier, provided that at least a visual identification is conducted on 
such containers/closures by the manufacturer and provided that the 
manufacturer establishes the reliability of the supplier's test results 
through appropriate validation of the supplier's test results at 
appropriate intervals.
    (4) When appropriate, components shall be microscopically examined.
    (5) Each lot of a component, drug product container, or closure that 
is liable to contamination with filth, insect infestation, or other 
extraneous adulterant shall be examined against established 
specifications for such contamination.
    (6) Each lot of a component, drug product container, or closure with 
potential for microbiological contamination that is objectionable in 
view of its intended use shall be subjected to microbiological tests 
before use.
    (e) Any lot of components, drug product containers, or closures that 
meets the appropriate written specifications of identity, strength, 
quality, and purity and related tests under paragraph (d) of this 
section may be approved and released for use. Any lot of such material 
that does not meet such specifications shall be rejected.

[43 FR 45077, Sept. 29, 1978, as amended at 63 FR 14356, Mar. 25, 1998; 
73 FR 51932, Sept. 8, 2008]



Sec.  211.86  Use of approved components, drug product containers,
and closures.

    Components, drug product containers, and closures approved for use 
shall be rotated so that the oldest approved stock is used first. 
Deviation from this requirement is permitted if such deviation is 
temporary and appropriate.



Sec.  211.87  Retesting of approved components, drug product containers,
and closures.

    Components, drug product containers, and closures shall be retested 
or reexamined, as appropriate, for identity, strength, quality, and 
purity and approved or rejected by the quality control unit in 
accordance with Sec.  211.84 as necessary, e.g., after storage for long 
periods or after exposure to air, heat or other conditions that might 
adversely affect the component, drug product container, or closure.



Sec.  211.89  Rejected components, drug product containers, and closures.

    Rejected components, drug product containers, and closures shall be 
identified and controlled under a quarantine system designed to prevent 
their use in manufacturing or processing operations for which they are 
unsuitable.

[[Page 165]]



Sec.  211.94  Drug product containers and closures.

    (a) Drug product containers and closures shall not be reactive, 
additive, or absorptive so as to alter the safety, identity, strength, 
quality, or purity of the drug beyond the official or established 
requirements.
    (b) Container closure systems shall provide adequate protection 
against foreseeable external factors in storage and use that can cause 
deterioration or contamination of the drug product.
    (c) Drug product containers and closures shall be clean and, where 
indicated by the nature of the drug, sterilized and processed to remove 
pyrogenic properties to assure that they are suitable for their intended 
use. Such depyrogenation processes shall be validated.
    (d) Standards or specifications, methods of testing, and, where 
indicated, methods of cleaning, sterilizing, and processing to remove 
pyrogenic properties shall be written and followed for drug product 
containers and closures.
    (e) Medical gas containers and closures must meet the following 
requirements--(1) Gas-specific use outlet connections. Portable 
cryogenic medical gas containers that are not manufactured with 
permanent gas use outlet connections (e.g., those that have been silver-
brazed) must have gas-specific use outlet connections that are attached 
to the valve body so that they cannot be readily removed or replaced 
(without making the valve inoperable and preventing the containers' use) 
except by the manufacturer. For the purposes of this paragraph, the term 
``manufacturer'' includes any individual or firm that fills high-
pressure medical gas cylinders or cryogenic medical gas containers. For 
the purposes of this section, a ``portable cryogenic medical gas 
container'' is one that is capable of being transported and is intended 
to be attached to a medical gas supply system within a hospital, health 
care entity, nursing home, other facility, or home health care setting, 
or is a base unit used to fill small cryogenic gas containers for use by 
individual patients. The term does not include cryogenic containers that 
are not designed to be connected to a medical gas supply system, e.g., 
tank trucks, trailers, rail cars, or small cryogenic gas containers for 
use by individual patients (including portable liquid oxygen units as 
defined at Sec.  868.5655 of this chapter).
    (2) Label and coloring requirements. The labeling specified at Sec.  
201.328(a) of this chapter must be affixed to the container in a manner 
that does not interfere with other labeling and such that it is not 
susceptible to becoming worn or inadvertently detached during normal 
use. Each such label as well as materials used for coloring medical gas 
containers must be reasonably resistant to fading, durable when exposed 
to atmospheric conditions, and not readily soluble in water.

[43 FR 45077, Sept. 29, 1978, as amended at 73 FR 51932, Sept. 8, 2008; 
81 FR 81697, Nov. 18, 2016]



                Subpart F_Production and Process Controls



Sec.  211.100  Written procedures; deviations.

    (a) There shall be written procedures for production and process 
control designed to assure that the drug products have the identity, 
strength, quality, and purity they purport or are represented to 
possess. Such procedures shall include all requirements in this subpart. 
These written procedures, including any changes, shall be drafted, 
reviewed, and approved by the appropriate organizational units and 
reviewed and approved by the quality control unit.
    (b) Written production and process control procedures shall be 
followed in the execution of the various production and process control 
functions and shall be documented at the time of performance. Any 
deviation from the written procedures shall be recorded and justified.



Sec.  211.101  Charge-in of components.

    Written production and control procedures shall include the 
following, which are designed to assure that the drug products produced 
have the identity, strength, quality, and purity they purport or are 
represented to possess:
    (a) The batch shall be formulated with the intent to provide not 
less than 100 percent of the labeled or established amount of active 
ingredient.

[[Page 166]]

    (b) Components for drug product manufacturing shall be weighed, 
measured, or subdivided as appropriate. If a component is removed from 
the original container to another, the new container shall be identified 
with the following information:
    (1) Component name or item code;
    (2) Receiving or control number;
    (3) Weight or measure in new container;
    (4) Batch for which component was dispensed, including its product 
name, strength, and lot number.
    (c) Weighing, measuring, or subdividing operations for components 
shall be adequately supervised. Each container of component dispensed to 
manufacturing shall be examined by a second person to assure that:
    (1) The component was released by the quality control unit;
    (2) The weight or measure is correct as stated in the batch 
production records;
    (3) The containers are properly identified. If the weighing, 
measuring, or subdividing operations are performed by automated 
equipment under Sec.  211.68, only one person is needed to assure 
paragraphs (c)(1), (c)(2), and (c)(3) of this section.
    (d) Each component shall either be added to the batch by one person 
and verified by a second person or, if the components are added by 
automated equipment under Sec.  211.68, only verified by one person.

[43 FR 45077, Sept. 29, 1978, as amended at 73 FR 51932, Sept. 8, 2008]



Sec.  211.103  Calculation of yield.

    Actual yields and percentages of theoretical yield shall be 
determined at the conclusion of each appropriate phase of manufacturing, 
processing, packaging, or holding of the drug product. Such calculations 
shall either be performed by one person and independently verified by a 
second person, or, if the yield is calculated by automated equipment 
under Sec.  211.68, be independently verified by one person.

[73 FR 51932, Sept. 8, 2008]



Sec.  211.105  Equipment identification.

    (a) All compounding and storage containers, processing lines, and 
major equipment used during the production of a batch of a drug product 
shall be properly identified at all times to indicate their contents 
and, when necessary, the phase of processing of the batch.
    (b) Major equipment shall be identified by a distinctive 
identification number or code that shall be recorded in the batch 
production record to show the specific equipment used in the manufacture 
of each batch of a drug product. In cases where only one of a particular 
type of equipment exists in a manufacturing facility, the name of the 
equipment may be used in lieu of a distinctive identification number or 
code.



Sec.  211.110  Sampling and testing of in-process materials and drug
products.

    (a) To assure batch uniformity and integrity of drug products, 
written procedures shall be established and followed that describe the 
in-process controls, and tests, or examinations to be conducted on 
appropriate samples of in-process materials of each batch. Such control 
procedures shall be established to monitor the output and to validate 
the performance of those manufacturing processes that may be responsible 
for causing variability in the characteristics of in-process material 
and the drug product. Such control procedures shall include, but are not 
limited to, the following, where appropriate:
    (1) Tablet or capsule weight variation;
    (2) Disintegration time;
    (3) Adequacy of mixing to assure uniformity and homogeneity;
    (4) Dissolution time and rate;
    (5) Clarity, completeness, or pH of solutions.
    (6) Bioburden testing.
    (b) Valid in-process specifications for such characteristics shall 
be consistent with drug product final specifications and shall be 
derived from previous acceptable process average and process variability 
estimates where possible and determined by the application of suitable 
statistical procedures where appropriate. Examination and testing of 
samples shall assure that the drug

[[Page 167]]

product and in-process material conform to specifications.
    (c) In-process materials shall be tested for identity, strength, 
quality, and purity as appropriate, and approved or rejected by the 
quality control unit, during the production process, e.g., at 
commencement or completion of significant phases or after storage for 
long periods.
    (d) Rejected in-process materials shall be identified and controlled 
under a quarantine system designed to prevent their use in manufacturing 
or processing operations for which they are unsuitable.

[43 FR 45077, Sept. 29, 1978, as amended at 73 FR 51932, Sept. 8, 2008]



Sec.  211.111  Time limitations on production.

    When appropriate, time limits for the completion of each phase of 
production shall be established to assure the quality of the drug 
product. Deviation from established time limits may be acceptable if 
such deviation does not compromise the quality of the drug product. Such 
deviation shall be justified and documented.



Sec.  211.113  Control of microbiological contamination.

    (a) Appropriate written procedures, designed to prevent 
objectionable microorganisms in drug products not required to be 
sterile, shall be established and followed.
    (b) Appropriate written procedures, designed to prevent 
microbiological contamination of drug products purporting to be sterile, 
shall be established and followed. Such procedures shall include 
validation of all aseptic and sterilization processes.

[43 FR 45077, Sept. 29, 1978, as amended at 73 FR 51932, Sept. 8, 2008]



Sec.  211.115  Reprocessing.

    (a) Written procedures shall be established and followed prescribing 
a system for reprocessing batches that do not conform to standards or 
specifications and the steps to be taken to insure that the reprocessed 
batches will conform with all established standards, specifications, and 
characteristics.
    (b) Reprocessing shall not be performed without the review and 
approval of the quality control unit.



                Subpart G_Packaging and Labeling Control



Sec.  211.122  Materials examination and usage criteria.

    (a) There shall be written procedures describing in sufficient 
detail the receipt, identification, storage, handling, sampling, 
examination, and/or testing of labeling and packaging materials; such 
written procedures shall be followed. Labeling and packaging materials 
shall be representatively sampled, and examined or tested upon receipt 
and before use in packaging or labeling of a drug product.
    (b) Any labeling or packaging materials meeting appropriate written 
specifications may be approved and released for use. Any labeling or 
packaging materials that do not meet such specifications shall be 
rejected to prevent their use in operations for which they are 
unsuitable.
    (c) Records shall be maintained for each shipment received of each 
different labeling and packaging material indicating receipt, 
examination or testing, and whether accepted or rejected.
    (d) Labels and other labeling materials for each different drug 
product, strength, dosage form, or quantity of contents shall be stored 
separately with suitable identification. Access to the storage area 
shall be limited to authorized personnel.
    (e) Obsolete and outdated labels, labeling, and other packaging 
materials shall be destroyed.
    (f) Use of gang-printed labeling for different drug products, or 
different strengths or net contents of the same drug product, is 
prohibited unless the labeling from gang-printed sheets is adequately 
differentiated by size, shape, or color.
    (g) If cut labeling is used for immediate container labels, 
individual unit cartons, or multiunit cartons containing immediate 
containers that are not packaged in individual unit cartons, packaging 
and labeling operations shall include one of the following special 
control procedures:

[[Page 168]]

    (1) Dedication of labeling and packaging lines to each different 
strength of each different drug product;
    (2) Use of appropriate electronic or electromechanical equipment to 
conduct a 100-percent examination for correct labeling during or after 
completion of finishing operations; or
    (3) Use of visual inspection to conduct a 100-percent examination 
for correct labeling during or after completion of finishing operations 
for hand-applied labeling. Such examination shall be performed by one 
person and independently verified by a second person.
    (4) Use of any automated technique, including differentiation by 
labeling size and shape, that physically prevents incorrect labeling 
from being processed by labeling and packaging equipment.
    (h) Printing devices on, or associated with, manufacturing lines 
used to imprint labeling upon the drug product unit label or case shall 
be monitored to assure that all imprinting conforms to the print 
specified in the batch production record.

[43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41353, Aug. 3, 1993; 
77 FR 16163, Mar. 20, 2012]



Sec.  211.125  Labeling issuance.

    (a) Strict control shall be exercised over labeling issued for use 
in drug product labeling operations.
    (b) Labeling materials issued for a batch shall be carefully 
examined for identity and conformity to the labeling specified in the 
master or batch production records.
    (c) Procedures shall be used to reconcile the quantities of labeling 
issued, used, and returned, and shall require evaluation of 
discrepancies found between the quantity of drug product finished and 
the quantity of labeling issued when such discrepancies are outside 
narrow preset limits based on historical operating data. Such 
discrepancies shall be investigated in accordance with Sec.  211.192. 
Labeling reconciliation is waived for cut or roll labeling if a 100-
percent examination for correct labeling is performed in accordance with 
Sec.  211.122(g)(2). Labeling reconciliation is also waived for 360[deg] 
wraparound labels on portable cryogenic medical gas containers.
    (d) All excess labeling bearing lot or control numbers shall be 
destroyed.
    (e) Returned labeling shall be maintained and stored in a manner to 
prevent mixups and provide proper identification.
    (f) Procedures shall be written describing in sufficient detail the 
control procedures employed for the issuance of labeling; such written 
procedures shall be followed.

[43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41354, Aug. 3, 1993; 
81 FR 81697, Nov. 18, 2016]



Sec.  211.130  Packaging and labeling operations.

    There shall be written procedures designed to assure that correct 
labels, labeling, and packaging materials are used for drug products; 
such written procedures shall be followed. These procedures shall 
incorporate the following features:
    (a) Prevention of mixups and cross-contamination by physical or 
spatial separation from operations on other drug products.
    (b) Identification and handling of filled drug product containers 
that are set aside and held in unlabeled condition for future labeling 
operations to preclude mislabeling of individual containers, lots, or 
portions of lots. Identification need not be applied to each individual 
container but shall be sufficient to determine name, strength, quantity 
of contents, and lot or control number of each container.
    (c) Identification of the drug product with a lot or control number 
that permits determination of the history of the manufacture and control 
of the batch.
    (d) Examination of packaging and labeling materials for suitability 
and correctness before packaging operations, and documentation of such 
examination in the batch production record.
    (e) Inspection of the packaging and labeling facilities immediately 
before use to assure that all drug products have been removed from 
previous operations. Inspection shall also be made to

[[Page 169]]

assure that packaging and labeling materials not suitable for subsequent 
operations have been removed. Results of inspection shall be documented 
in the batch production records.

[43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41354, Aug. 3, 1993]



Sec.  211.132  Tamper-evident packaging requirements for 
over-the-counter (OTC) human drug products.

    (a) General. The Food and Drug Administration has the authority 
under the Federal Food, Drug, and Cosmetic Act (the act) to establish a 
uniform national requirement for tamper-evident packaging of OTC drug 
products that will improve the security of OTC drug packaging and help 
assure the safety and effectiveness of OTC drug products. An OTC drug 
product (except a dermatological, dentifrice, insulin, or lozenge 
product) for retail sale that is not packaged in a tamper-resistant 
package or that is not properly labeled under this section is 
adulterated under section 501 of the act or misbranded under section 502 
of the act, or both.
    (b) Requirements for tamper-evident package. (1) Each manufacturer 
and packer who packages an OTC drug product (except a dermatological, 
dentifrice, insulin, or lozenge product) for retail sale shall package 
the product in a tamper-evident package, if this product is accessible 
to the public while held for sale. A tamper-evident package is one 
having one or more indicators or barriers to entry which, if breached or 
missing, can reasonably be expected to provide visible evidence to 
consumers that tampering has occurred. To reduce the likelihood of 
successful tampering and to increase the likelihood that consumers will 
discover if a product has been tampered with, the package is required to 
be distinctive by design or by the use of one or more indicators or 
barriers to entry that employ an identifying characteristic (e.g., a 
pattern, name, registered trademark, logo, or picture). For purposes of 
this section, the term ``distinctive by design'' means the packaging 
cannot be duplicated with commonly available materials or through 
commonly available processes. A tamper-evident package may involve an 
immediate-container and closure system or secondary-container or carton 
system or any combination of systems intended to provide a visual 
indication of package integrity. The tamper-evident feature shall be 
designed to and shall remain intact when handled in a reasonable manner 
during manufacture, distribution, and retail display.
    (2) In addition to the tamper-evident packaging feature described in 
paragraph (b)(1) of this section, any two-piece, hard gelatin capsule 
covered by this section must be sealed using an acceptable tamper-
evident technology.
    (c) Labeling. (1) In order to alert consumers to the specific 
tamper-evident feature(s) used, each retail package of an OTC drug 
product covered by this section (except ammonia inhalant in crushable 
glass ampules, containers of compressed medical oxygen, or aerosol 
products that depend upon the power of a liquefied or compressed gas to 
expel the contents from the container) is required to bear a statement 
that:
    (i) Identifies all tamper-evident feature(s) and any capsule sealing 
technologies used to comply with paragraph (b) of this section;
    (ii) Is prominently placed on the package; and
    (iii) Is so placed that it will be unaffected if the tamper-evident 
feature of the package is breached or missing.
    (2) If the tamper-evident feature chosen to meet the requirements in 
paragraph (b) of this section uses an identifying characteristic, that 
characteristic is required to be referred to in the labeling statement. 
For example, the labeling statement on a bottle with a shrink band could 
say ``For your protection, this bottle has an imprinted seal around the 
neck.''
    (d) Request for exemptions from packaging and labeling requirements. 
A manufacturer or packer may request an exemption from the packaging and 
labeling requirements of this section. A request for an exemption is 
required to be submitted in the form of a citizen petition under Sec.  
10.30 of this chapter and should be clearly identified on the envelope 
as a ``Request for Exemption from the Tamper-Evident Packaging Rule.'' 
The petition is required to contain the following:

[[Page 170]]

    (1) The name of the drug product or, if the petition seeks an 
exemption for a drug class, the name of the drug class, and a list of 
products within that class.
    (2) The reasons that the drug product's compliance with the tamper-
evident packaging or labeling requirements of this section is 
unnecessary or cannot be achieved.
    (3) A description of alternative steps that are available, or that 
the petitioner has already taken, to reduce the likelihood that the 
product or drug class will be the subject of malicious adulteration.
    (4) Other information justifying an exemption.
    (e) OTC drug products subject to approved new drug applications. 
Holders of approved new drug applications for OTC drug products are 
required under Sec.  314.70 of this chapter to provide the agency with 
notification of changes in packaging and labeling to comply with the 
requirements of this section. Changes in packaging and labeling required 
by this regulation may be made before FDA approval, as provided under 
Sec.  314.70(c) of this chapter. Manufacturing changes by which capsules 
are to be sealed require prior FDA approval under Sec.  314.70(b) of 
this chapter.
    (f) Poison Prevention Packaging Act of 1970. This section does not 
affect any requirements for ``special packaging'' as defined under Sec.  
310.3(l) of this chapter and required under the Poison Prevention 
Packaging Act of 1970.

(Approved by the Office of Management and Budget under OMB control 
number 0910-0149)

[54 FR 5228, Feb. 2, 1989, as amended at 63 FR 59470, Nov. 4, 1998]



Sec.  211.134  Drug product inspection.

    (a) Packaged and labeled products shall be examined during finishing 
operations to provide assurance that containers and packages in the lot 
have the correct label.
    (b) A representative sample of units shall be collected at the 
completion of finishing operations and shall be visually examined for 
correct labeling.
    (c) Results of these examinations shall be recorded in the batch 
production or control records.



Sec.  211.137  Expiration dating.

    (a) To assure that a drug product meets applicable standards of 
identity, strength, quality, and purity at the time of use, it shall 
bear an expiration date determined by appropriate stability testing 
described in Sec.  211.166.
    (b) Expiration dates shall be related to any storage conditions 
stated on the labeling, as determined by stability studies described in 
Sec.  211.166.
    (c) If the drug product is to be reconstituted at the time of 
dispensing, its labeling shall bear expiration information for both the 
reconstituted and unreconstituted drug products.
    (d) Expiration dates shall appear on labeling in accordance with the 
requirements of Sec.  201.17 of this chapter.
    (e) Homeopathic drug products shall be exempt from the requirements 
of this section.
    (f) Allergenic extracts that are labeled ``No U.S. Standard of 
Potency'' are exempt from the requirements of this section.
    (g) New drug products for investigational use are exempt from the 
requirements of this section, provided that they meet appropriate 
standards or specifications as demonstrated by stability studies during 
their use in clinical investigations. Where new drug products for 
investigational use are to be reconstituted at the time of dispensing, 
their labeling shall bear expiration information for the reconstituted 
drug product.
    (h) Pending consideration of a proposed exemption, published in the 
Federal Register of September 29, 1978, the requirements in this section 
shall not be enforced for human OTC drug products if their labeling does 
not bear dosage limitations and they are stable for at least 3 years as 
supported by appropriate stability data.

[43 FR 45077, Sept. 29, 1978, as amended at 46 FR 56412, Nov. 17, 1981; 
60 FR 4091, Jan. 20, 1995]



                   Subpart H_Holding and Distribution



Sec.  211.142  Warehousing procedures.

    Written procedures describing the warehousing of drug products shall 
be

[[Page 171]]

established and followed. They shall include:
    (a) Quarantine of drug products before release by the quality 
control unit.
    (b) Storage of drug products under appropriate conditions of 
temperature, humidity, and light so that the identity, strength, 
quality, and purity of the drug products are not affected.



Sec.  211.150  Distribution procedures.

    Written procedures shall be established, and followed, describing 
the distribution of drug products. They shall include:
    (a) A procedure whereby the oldest approved stock of a drug product 
is distributed first. Deviation from this requirement is permitted if 
such deviation is temporary and appropriate.
    (b) A system by which the distribution of each lot of drug product 
can be readily determined to facilitate its recall if necessary.



                      Subpart I_Laboratory Controls



Sec.  211.160  General requirements.

    (a) The establishment of any specifications, standards, sampling 
plans, test procedures, or other laboratory control mechanisms required 
by this subpart, including any change in such specifications, standards, 
sampling plans, test procedures, or other laboratory control mechanisms, 
shall be drafted by the appropriate organizational unit and reviewed and 
approved by the quality control unit. The requirements in this subpart 
shall be followed and shall be documented at the time of performance. 
Any deviation from the written specifications, standards, sampling 
plans, test procedures, or other laboratory control mechanisms shall be 
recorded and justified.
    (b) Laboratory controls shall include the establishment of 
scientifically sound and appropriate specifications, standards, sampling 
plans, and test procedures designed to assure that components, drug 
product containers, closures, in-process materials, labeling, and drug 
products conform to appropriate standards of identity, strength, 
quality, and purity. Laboratory controls shall include:
    (1) Determination of conformity to applicable written specifications 
for the acceptance of each lot within each shipment of components, drug 
product containers, closures, and labeling used in the manufacture, 
processing, packing, or holding of drug products. The specifications 
shall include a description of the sampling and testing procedures used. 
Samples shall be representative and adequately identified. Such 
procedures shall also require appropriate retesting of any component, 
drug product container, or closure that is subject to deterioration.
    (2) Determination of conformance to written specifications and a 
description of sampling and testing procedures for in-process materials. 
Such samples shall be representative and properly identified.
    (3) Determination of conformance to written descriptions of sampling 
procedures and appropriate specifications for drug products. Such 
samples shall be representative and properly identified.
    (4) The calibration of instruments, apparatus, gauges, and recording 
devices at suitable intervals in accordance with an established written 
program containing specific directions, schedules, limits for accuracy 
and precision, and provisions for remedial action in the event accuracy 
and/or precision limits are not met. Instruments, apparatus, gauges, and 
recording devices not meeting established specifications shall not be 
used.

[43 FR 45077, Sept. 29, 1978, as amended at 73 FR 51932, Sept. 8, 2008]



Sec.  211.165  Testing and release for distribution.

    (a) For each batch of drug product, there shall be appropriate 
laboratory determination of satisfactory conformance to final 
specifications for the drug product, including the identity and strength 
of each active ingredient, prior to release. Where sterility and/or 
pyrogen testing are conducted on specific batches of shortlived 
radiopharmaceuticals, such batches may be released prior to completion 
of sterility and/or pyrogen testing, provided such testing is completed 
as soon as possible.

[[Page 172]]

    (b) There shall be appropriate laboratory testing, as necessary, of 
each batch of drug product required to be free of objectionable 
microorganisms.
    (c) Any sampling and testing plans shall be described in written 
procedures that shall include the method of sampling and the number of 
units per batch to be tested; such written procedure shall be followed.
    (d) Acceptance criteria for the sampling and testing conducted by 
the quality control unit shall be adequate to assure that batches of 
drug products meet each appropriate specification and appropriate 
statistical quality control criteria as a condition for their approval 
and release. The statistical quality control criteria shall include 
appropriate acceptance levels and/or appropriate rejection levels.
    (e) The accuracy, sensitivity, specificity, and reproducibility of 
test methods employed by the firm shall be established and documented. 
Such validation and documentation may be accomplished in accordance with 
Sec.  211.194(a)(2).
    (f) Drug products failing to meet established standards or 
specifications and any other relevant quality control criteria shall be 
rejected. Reprocessing may be performed. Prior to acceptance and use, 
reprocessed material must meet appropriate standards, specifications, 
and any other relevant criteria.



Sec.  211.166  Stability testing.

    (a) There shall be a written testing program designed to assess the 
stability characteristics of drug products. The results of such 
stability testing shall be used in determining appropriate storage 
conditions and expiration dates. The written program shall be followed 
and shall include:
    (1) Sample size and test intervals based on statistical criteria for 
each attribute examined to assure valid estimates of stability;
    (2) Storage conditions for samples retained for testing;
    (3) Reliable, meaningful, and specific test methods;
    (4) Testing of the drug product in the same container-closure system 
as that in which the drug product is marketed;
    (5) Testing of drug products for reconstitution at the time of 
dispensing (as directed in the labeling) as well as after they are 
reconstituted.
    (b) An adequate number of batches of each drug product shall be 
tested to determine an appropriate expiration date and a record of such 
data shall be maintained. Accelerated studies, combined with basic 
stability information on the components, drug products, and container-
closure system, may be used to support tentative expiration dates 
provided full shelf life studies are not available and are being 
conducted. Where data from accelerated studies are used to project a 
tentative expiration date that is beyond a date supported by actual 
shelf life studies, there must be stability studies conducted, including 
drug product testing at appropriate intervals, until the tentative 
expiration date is verified or the appropriate expiration date 
determined.
    (c) For homeopathic drug products, the requirements of this section 
are as follows:
    (1) There shall be a written assessment of stability based at least 
on testing or examination of the drug product for compatibility of the 
ingredients, and based on marketing experience with the drug product to 
indicate that there is no degradation of the product for the normal or 
expected period of use.
    (2) Evaluation of stability shall be based on the same container-
closure system in which the drug product is being marketed.
    (d) Allergenic extracts that are labeled ``No U.S. Standard of 
Potency'' are exempt from the requirements of this section.

[43 FR 45077, Sept. 29, 1978, as amended at 46 FR 56412, Nov. 17, 1981]



Sec.  211.167  Special testing requirements.

    (a) For each batch of drug product purporting to be sterile and/or 
pyrogen-free, there shall be appropriate laboratory testing to determine 
conformance to such requirements. The test procedures shall be in 
writing and shall be followed.
    (b) For each batch of ophthalmic ointment, there shall be 
appropriate testing to determine conformance to specifications regarding 
the presence of foreign particles and harsh or abrasive

[[Page 173]]

substances. The test procedures shall be in writing and shall be 
followed.
    (c) For each batch of controlled-release dosage form, there shall be 
appropriate laboratory testing to determine conformance to the 
specifications for the rate of release of each active ingredient. The 
test procedures shall be in writing and shall be followed.



Sec.  211.170  Reserve samples.

    (a) An appropriately identified reserve sample that is 
representative of each lot in each shipment of each active ingredient 
shall be retained. The reserve sample consists of at least twice the 
quantity necessary for all tests required to determine whether the 
active ingredient meets its established specifications, except for 
sterility and pyrogen testing. The retention time is as follows:
    (1) For an active ingredient in a drug product other than those 
described in paragraphs (a) (2) and (3) of this section, the reserve 
sample shall be retained for 1 year after the expiration date of the 
last lot of the drug product containing the active ingredient.
    (2) For an active ingredient in a radioactive drug product, except 
for nonradioactive reagent kits, the reserve sample shall be retained 
for:
    (i) Three months after the expiration date of the last lot of the 
drug product containing the active ingredient if the expiration dating 
period of the drug product is 30 days or less; or
    (ii) Six months after the expiration date of the last lot of the 
drug product containing the active ingredient if the expiration dating 
period of the drug product is more than 30 days.
    (3) For an active ingredient in an OTC drug product that is exempt 
from bearing an expiration date under Sec.  211.137, the reserve sample 
shall be retained for 3 years after distribution of the last lot of the 
drug product containing the active ingredient.
    (b) An appropriately identified reserve sample that is 
representative of each lot or batch of drug product shall be retained 
and stored under conditions consistent with product labeling. The 
reserve sample shall be stored in the same immediate container-closure 
system in which the drug product is marketed or in one that has 
essentially the same characteristics. The reserve sample consists of at 
least twice the quantity necessary to perform all the required tests, 
except those for sterility and pyrogens. Except for those for drug 
products described in paragraph (b)(2) of this section, reserve samples 
from representative sample lots or batches selected by acceptable 
statistical procedures shall be examined visually at least once a year 
for evidence of deterioration unless visual examination would affect the 
integrity of the reserve sample. Any evidence of reserve sample 
deterioration shall be investigated in accordance with Sec.  211.192. 
The results of the examination shall be recorded and maintained with 
other stability data on the drug product. Reserve samples of compressed 
medical gases need not be retained. The retention time is as follows:
    (1) For a drug product other than those described in paragraphs (b) 
(2) and (3) of this section, the reserve sample shall be retained for 1 
year after the expiration date of the drug product.
    (2) For a radioactive drug product, except for nonradioactive 
reagent kits, the reserve sample shall be retained for:
    (i) Three months after the expiration date of the drug product if 
the expiration dating period of the drug product is 30 days or less; or
    (ii) Six months after the expiration date of the drug product if the 
expiration dating period of the drug product is more than 30 days.
    (3) For an OTC drug product that is exempt for bearing an expiration 
date under Sec.  211.137, the reserve sample must be retained for 3 
years after the lot or batch of drug product is distributed.

[48 FR 13025, Mar. 29, 1983, as amended at 60 FR 4091, Jan. 20, 1995]



Sec.  211.173  Laboratory animals.

    Animals used in testing components, in-process materials, or drug 
products for compliance with established specifications shall be 
maintained and controlled in a manner that assures their suitability for 
their intended use. They shall be identified, and adequate records shall 
be maintained showing the history of their use.

[[Page 174]]



Sec.  211.176  Penicillin contamination.

    If a reasonable possibility exists that a non-penicillin drug 
product has been exposed to cross-contamination with penicillin, the 
non-penicillin drug product shall be tested for the presence of 
penicillin. Such drug product shall not be marketed if detectable levels 
are found when tested according to procedures specified in `Procedures 
for Detecting and Measuring Penicillin Contamination in Drugs,' which is 
incorporated by reference. Copies are available from the Division of 
Research and Testing (HFD-470), Center for Drug Evaluation and Research, 
Food and Drug Administration, 5001 Campus Dr., College Park, MD 20740, 
or available for inspection at the National Archives and Records 
Administration (NARA). For information on the availability of this 
material at NARA, call 202-741-6030, or go to: http://www.archives.gov/
federal_register/code_of_federal_regulations/ibr_locations.html.

[43 FR 45077, Sept. 29, 1978, as amended at 47 FR 9396, Mar. 5, 1982; 50 
FR 8996, Mar. 6, 1985; 55 FR 11577, Mar. 29, 1990; 66 FR 56035, Nov. 6, 
2001; 69 FR 18803, Apr. 9, 2004; 81 FR 49897, July 29, 2016]



                      Subpart J_Records and Reports



Sec.  211.180  General requirements.

    (a) Any production, control, or distribution record that is required 
to be maintained in compliance with this part and is specifically 
associated with a batch of a drug product shall be retained for at least 
1 year after the expiration date of the batch or, in the case of certain 
OTC drug products lacking expiration dating because they meet the 
criteria for exemption under Sec.  211.137, 3 years after distribution 
of the batch.
    (b) Records shall be maintained for all components, drug product 
containers, closures, and labeling for at least 1 year after the 
expiration date or, in the case of certain OTC drug products lacking 
expiration dating because they meet the criteria for exemption under 
Sec.  211.137, 3 years after distribution of the last lot of drug 
product incorporating the component or using the container, closure, or 
labeling.
    (c) All records required under this part, or copies of such records, 
shall be readily available for authorized inspection during the 
retention period at the establishment where the activities described in 
such records occurred. These records or copies thereof shall be subject 
to photocopying or other means of reproduction as part of such 
inspection. Records that can be immediately retrieved from another 
location by computer or other electronic means shall be considered as 
meeting the requirements of this paragraph.
    (d) Records required under this part may be retained either as 
original records or as true copies such as photocopies, microfilm, 
microfiche, or other accurate reproductions of the original records. 
Where reduction techniques, such as microfilming, are used, suitable 
reader and photocopying equipment shall be readily available.
    (e) Written records required by this part shall be maintained so 
that data therein can be used for evaluating, at least annually, the 
quality standards of each drug product to determine the need for changes 
in drug product specifications or manufacturing or control procedures. 
Written procedures shall be established and followed for such 
evaluations and shall include provisions for:
    (1) A review of a representative number of batches, whether approved 
or rejected, and, where applicable, records associated with the batch.
    (2) A review of complaints, recalls, returned or salvaged drug 
products, and investigations conducted under Sec.  211.192 for each drug 
product.
    (f) Procedures shall be established to assure that the responsible 
officials of the firm, if they are not personally involved in or 
immediately aware of such actions, are notified in writing of any 
investigations conducted under Sec. Sec.  211.198, 211.204, or 211.208 
of these regulations, any recalls, reports of inspectional observations 
issued by the Food and Drug Administration, or any regulatory actions 
relating to good manufacturing practices brought by the Food and Drug 
Administration.

[43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan. 20, 1995]

[[Page 175]]



Sec.  211.182  Equipment cleaning and use log.

    A written record of major equipment cleaning, maintenance (except 
routine maintenance such as lubrication and adjustments), and use shall 
be included in individual equipment logs that show the date, time, 
product, and lot number of each batch processed. If equipment is 
dedicated to manufacture of one product, then individual equipment logs 
are not required, provided that lots or batches of such product follow 
in numerical order and are manufactured in numerical sequence. In cases 
where dedicated equipment is employed, the records of cleaning, 
maintenance, and use shall be part of the batch record. The persons 
performing and double-checking the cleaning and maintenance (or, if the 
cleaning and maintenance is performed using automated equipment under 
Sec.  211.68, just the person verifying the cleaning and maintenance 
done by the automated equipment) shall date and sign or initial the log 
indicating that the work was performed. Entries in the log shall be in 
chronological order.

[73 FR 51933, Sept. 8, 2008]



Sec.  211.184  Component, drug product container, closure, and 
labeling records.

    These records shall include the following:
    (a) The identity and quantity of each shipment of each lot of 
components, drug product containers, closures, and labeling; the name of 
the supplier; the supplier's lot number(s) if known; the receiving code 
as specified in Sec.  211.80; and the date of receipt. The name and 
location of the prime manufacturer, if different from the supplier, 
shall be listed if known.
    (b) The results of any test or examination performed (including 
those performed as required by Sec.  211.82(a), Sec.  211.84(d), or 
Sec.  211.122(a)) and the conclusions derived therefrom.
    (c) An individual inventory record of each component, drug product 
container, and closure and, for each component, a reconciliation of the 
use of each lot of such component. The inventory record shall contain 
sufficient information to allow determination of any batch or lot of 
drug product associated with the use of each component, drug product 
container, and closure.
    (d) Documentation of the examination and review of labels and 
labeling for conformity with established specifications in accord with 
Sec. Sec.  211.122(c) and 211.130(c).
    (e) The disposition of rejected components, drug product containers, 
closure, and labeling.



Sec.  211.186  Master production and control records.

    (a) To assure uniformity from batch to batch, master production and 
control records for each drug product, including each batch size 
thereof, shall be prepared, dated, and signed (full signature, 
handwritten) by one person and independently checked, dated, and signed 
by a second person. The preparation of master production and control 
records shall be described in a written procedure and such written 
procedure shall be followed.
    (b) Master production and control records shall include:
    (1) The name and strength of the product and a description of the 
dosage form;
    (2) The name and weight or measure of each active ingredient per 
dosage unit or per unit of weight or measure of the drug product, and a 
statement of the total weight or measure of any dosage unit;
    (3) A complete list of components designated by names or codes 
sufficiently specific to indicate any special quality characteristic;
    (4) An accurate statement of the weight or measure of each 
component, using the same weight system (metric, avoirdupois, or 
apothecary) for each component. Reasonable variations may be permitted, 
however, in the amount of components necessary for the preparation in 
the dosage form, provided they are justified in the master production 
and control records;
    (5) A statement concerning any calculated excess of component;
    (6) A statement of theoretical weight or measure at appropriate 
phases of processing;
    (7) A statement of theoretical yield, including the maximum and 
minimum percentages of theoretical yield beyond

[[Page 176]]

which investigation according to Sec.  211.192 is required;
    (8) A description of the drug product containers, closures, and 
packaging materials, including a specimen or copy of each label and all 
other labeling signed and dated by the person or persons responsible for 
approval of such labeling;
    (9) Complete manufacturing and control instructions, sampling and 
testing procedures, specifications, special notations, and precautions 
to be followed.



Sec.  211.188  Batch production and control records.

    Batch production and control records shall be prepared for each 
batch of drug product produced and shall include complete information 
relating to the production and control of each batch. These records 
shall include:
    (a) An accurate reproduction of the appropriate master production or 
control record, checked for accuracy, dated, and signed;
    (b) Documentation that each significant step in the manufacture, 
processing, packing, or holding of the batch was accomplished, 
including:
    (1) Dates;
    (2) Identity of individual major equipment and lines used;
    (3) Specific identification of each batch of component or in-process 
material used;
    (4) Weights and measures of components used in the course of 
processing;
    (5) In-process and laboratory control results;
    (6) Inspection of the packaging and labeling area before and after 
use;
    (7) A statement of the actual yield and a statement of the 
percentage of theoretical yield at appropriate phases of processing;
    (8) Complete labeling control records, including specimens or copies 
of all labeling used;
    (9) Description of drug product containers and closures;
    (10) Any sampling performed;
    (11) Identification of the persons performing and directly 
supervising or checking each significant step in the operation, or if a 
significant step in the operation is performed by automated equipment 
under Sec.  211.68, the identification of the person checking the 
significant step performed by the automated equipment.
    (12) Any investigation made according to Sec.  211.192.
    (13) Results of examinations made in accordance with Sec.  211.134.

[43 FR 45077, Sept. 29, 1978, as amended at 73 FR 51933, Sept. 8, 2008]



Sec.  211.192  Production record review.

    All drug product production and control records, including those for 
packaging and labeling, shall be reviewed and approved by the quality 
control unit to determine compliance with all established, approved 
written procedures before a batch is released or distributed. Any 
unexplained discrepancy (including a percentage of theoretical yield 
exceeding the maximum or minimum percentages established in master 
production and control records) or the failure of a batch or any of its 
components to meet any of its specifications shall be thoroughly 
investigated, whether or not the batch has already been distributed. The 
investigation shall extend to other batches of the same drug product and 
other drug products that may have been associated with the specific 
failure or discrepancy. A written record of the investigation shall be 
made and shall include the conclusions and followup.



Sec.  211.194  Laboratory records.

    (a) Laboratory records shall include complete data derived from all 
tests necessary to assure compliance with established specifications and 
standards, including examinations and assays, as follows:
    (1) A description of the sample received for testing with 
identification of source (that is, location from where sample was 
obtained), quantity, lot number or other distinctive code, date sample 
was taken, and date sample was received for testing.
    (2) A statement of each method used in the testing of the sample. 
The statement shall indicate the location of data that establish that 
the methods used in the testing of the sample meet proper standards of 
accuracy and reliability as applied to the product tested. (If the 
method employed is in the current revision of the United States 
Pharmacopeia, National Formulary,

[[Page 177]]

AOAC INTERNATIONAL, Book of Methods, \1\ or in other recognized standard 
references, or is detailed in an approved new drug application and the 
referenced method is not modified, a statement indicating the method and 
reference will suffice). The suitability of all testing methods used 
shall be verified under actual conditions of use.
---------------------------------------------------------------------------

    \1\ Copies may be obtained from: AOAC INTERNATIONAL, 481 North 
Frederick Ave., suite 500, Gaithersburg, MD 20877.
---------------------------------------------------------------------------

    (3) A statement of the weight or measure of sample used for each 
test, where appropriate.
    (4) A complete record of all data secured in the course of each 
test, including all graphs, charts, and spectra from laboratory 
instrumentation, properly identified to show the specific component, 
drug product container, closure, in-process material, or drug product, 
and lot tested.
    (5) A record of all calculations performed in connection with the 
test, including units of measure, conversion factors, and equivalency 
factors.
    (6) A statement of the results of tests and how the results compare 
with established standards of identity, strength, quality, and purity 
for the component, drug product container, closure, in-process material, 
or drug product tested.
    (7) The initials or signature of the person who performs each test 
and the date(s) the tests were performed.
    (8) The initials or signature of a second person showing that the 
original records have been reviewed for accuracy, completeness, and 
compliance with established standards.
    (b) Complete records shall be maintained of any modification of an 
established method employed in testing. Such records shall include the 
reason for the modification and data to verify that the modification 
produced results that are at least as accurate and reliable for the 
material being tested as the established method.
    (c) Complete records shall be maintained of any testing and 
standardization of laboratory reference standards, reagents, and 
standard solutions.
    (d) Complete records shall be maintained of the periodic calibration 
of laboratory instruments, apparatus, gauges, and recording devices 
required by Sec.  211.160(b)(4).
    (e) Complete records shall be maintained of all stability testing 
performed in accordance with Sec.  211.166.

[43 FR 45077, Sept. 29, 1978, as amended at 55 FR 11577, Mar. 29, 1990; 
65 FR 18889, Apr. 10, 2000; 70 FR 40880, July 15, 2005; 70 FR 67651, 
Nov. 8, 2005]



Sec.  211.196  Distribution records.

    Distribution records shall contain the name and strength of the 
product and description of the dosage form, name and address of the 
consignee, date and quantity shipped, and lot or control number of the 
drug product. For compressed medical gas products, distribution records 
are not required to contain lot or control numbers.

(Approved by the Office of Management and Budget under control number 
0910-0139)

[49 FR 9865, Mar. 16, 1984]



Sec.  211.198  Complaint files.

    (a) Written procedures describing the handling of all written and 
oral complaints regarding a drug product shall be established and 
followed. Such procedures shall include provisions for review by the 
quality control unit, of any complaint involving the possible failure of 
a drug product to meet any of its specifications and, for such drug 
products, a determination as to the need for an investigation in 
accordance with Sec.  211.192. Such procedures shall include provisions 
for review to determine whether the complaint represents a serious and 
unexpected adverse drug experience which is required to be reported to 
the Food and Drug Administration in accordance with Sec. Sec.  310.305 
and 514.80 of this chapter.
    (b) A written record of each complaint shall be maintained in a file 
designated for drug product complaints. The file regarding such drug 
product complaints shall be maintained at the establishment where the 
drug product involved was manufactured, processed, or packed, or such 
file may be maintained at another facility if the written records in 
such files are readily available for inspection at that other facility. 
Written records involving a drug product shall be maintained until at 
least 1 year after the expiration date of

[[Page 178]]

the drug product, or 1 year after the date that the complaint was 
received, whichever is longer. In the case of certain OTC drug products 
lacking expiration dating because they meet the criteria for exemption 
under Sec.  211.137, such written records shall be maintained for 3 
years after distribution of the drug product.
    (1) The written record shall include the following information, 
where known: the name and strength of the drug product, lot number, name 
of complainant, nature of complaint, and reply to complainant.
    (2) Where an investigation under Sec.  211.192 is conducted, the 
written record shall include the findings of the investigation and 
followup. The record or copy of the record of the investigation shall be 
maintained at the establishment where the investigation occurred in 
accordance with Sec.  211.180(c).
    (3) Where an investigation under Sec.  211.192 is not conducted, the 
written record shall include the reason that an investigation was found 
not to be necessary and the name of the responsible person making such a 
determination.

[43 FR 45077, Sept. 29, 1978, as amended at 51 FR 24479, July 3, 1986; 
68 FR 15364, Mar. 31, 2003]



              Subpart K_Returned and Salvaged Drug Products



Sec.  211.204  Returned drug products.

    Returned drug products shall be identified as such and held. If the 
conditions under which returned drug products have been held, stored, or 
shipped before or during their return, or if the condition of the drug 
product, its container, carton, or labeling, as a result of storage or 
shipping, casts doubt on the safety, identity, strength, quality or 
purity of the drug product, the returned drug product shall be destroyed 
unless examination, testing, or other investigations prove the drug 
product meets appropriate standards of safety, identity, strength, 
quality, or purity. A drug product may be reprocessed provided the 
subsequent drug product meets appropriate standards, specifications, and 
characteristics. Records of returned drug products shall be maintained 
and shall include the name and label potency of the drug product dosage 
form, lot number (or control number or batch number), reason for the 
return, quantity returned, date of disposition, and ultimate disposition 
of the returned drug product. If the reason for a drug product being 
returned implicates associated batches, an appropriate investigation 
shall be conducted in accordance with the requirements of Sec.  211.192. 
Procedures for the holding, testing, and reprocessing of returned drug 
products shall be in writing and shall be followed.



Sec.  211.208  Drug product salvaging.

    Drug products that have been subjected to improper storage 
conditions including extremes in temperature, humidity, smoke, fumes, 
pressure, age, or radiation due to natural disasters, fires, accidents, 
or equipment failures shall not be salvaged and returned to the 
marketplace. Whenever there is a question whether drug products have 
been subjected to such conditions, salvaging operations may be conducted 
only if there is (a) evidence from laboratory tests and assays 
(including animal feeding studies where applicable) that the drug 
products meet all applicable standards of identity, strength, quality, 
and purity and (b) evidence from inspection of the premises that the 
drug products and their associated packaging were not subjected to 
improper storage conditions as a result of the disaster or accident. 
Organoleptic examinations shall be acceptable only as supplemental 
evidence that the drug products meet appropriate standards of identity, 
strength, quality, and purity. Records including name, lot number, and 
disposition shall be maintained for drug products subject to this 
section.



PART 212_CURRENT GOOD MANUFACTURING PRACTICE FOR POSITRON EMISSION 
TOMOGRAPHY DRUGS--Table of Contents



                      Subpart A_General Provisions

Sec.
212.1 What are the meanings of the technical terms used in these 
          regulations?
212.2 What is current good manufacturing practice for PET drugs?
212.5 To what drugs do the regulations in this part apply?

[[Page 179]]

                    Subpart B_Personnel and Resources

212.10 What personnel and resources must I have?

                       Subpart C_Quality Assurance

212.20 What activities must I perform to ensure drug quality?

                   Subpart D_Facilities and Equipment

212.30 What requirements must my facilities and equipment meet?

        Subpart E_Control of Components, Containers, and Closures

212.40 How must I control the components I use to produce PET drugs and 
          the containers and closures I package them in?

                Subpart F_Production and Process Controls

212.50 What production and process controls must I have?

                      Subpart G_Laboratory Controls

212.60 What requirements apply to the laboratories where I test 
          components, in-process materials, and finished PET drug 
          products?
212.61 What must I do to ensure the stability of my PET drug products 
          through expiry?

    Subpart H_Finished Drug Product Controls and Acceptance Criteria

212.70 What controls and acceptance criteria must I have for my finished 
          PET drug products?
212.71 What actions must I take if a batch of PET drug product does not 
          conform to specifications?

                    Subpart I_Packaging and Labeling

212.80 What are the requirements associated with labeling and packaging 
          PET drug products?

                         Subpart J_Distribution

212.90 What actions must I take to control the distribution of PET drug 
          products?

                      Subpart K_Complaint Handling

212.100 What do I do if I receive a complaint about a PET drug product 
          produced at my facility?

                            Subpart L_Records

212.110 How must I maintain records of my production of PET drugs?

    Authority: 21 U.S.C. 321, 351, 352, 355, 371, 374; Sec. 121, Pub. L. 
105-115, 111 Stat. 2296.

    Source: 74 FR 65431, Dec. 10, 2009, unless otherwise noted.



                      Subpart A_General Provisions



Sec.  212.1  What are the meanings of the technical terms used in
these regulations?

    The following definitions apply to words and phrases as they are 
used in this part. Other definitions of these words may apply when they 
are used in other parts of this chapter.
    Acceptance criteria means numerical limits, ranges, or other 
criteria for tests that are used for or in making a decision to accept 
or reject a unit, lot, or batch of a PET drug product.
    Act means the Federal Food, Drug, and Cosmetic Act, as amended (21 
U.S.C. 321 et seq.).
    Active pharmaceutical ingredient means a substance that is intended 
for incorporation into a finished PET drug product and is intended to 
furnish pharmacological activity or other direct effect in the diagnosis 
or monitoring of a disease or a manifestation of a disease in humans, 
but does not include intermediates used in the synthesis of such 
substance.
    Batch means a specific quantity of PET drug intended to have uniform 
character and quality, within specified limits, that is produced 
according to a single production order during the same cycle of 
production.
    Batch production and control record means a unique record that 
references an accepted master production and control record and 
documents specific details on production, labeling, and quality control 
for a single batch of a PET drug.
    Component means any ingredient intended for use in the production of 
a PET drug, including any ingredients that may not appear in the final 
PET drug product.
    Conditional final release means a final release made prior to 
completion of a required finished-product test because of a malfunction 
involving analytical equipment.
    Final release means the authoritative decision by a responsible 
person in a PET production facility to permit the

[[Page 180]]

use of a batch of a PET drug in humans.
    Inactive ingredient means any intended component of the PET drug 
other than the active pharmaceutical ingredient.
    In-process material means any material fabricated, compounded, 
blended, or derived by chemical reaction that is produced for, and is 
used in, the preparation of a PET drug.
    Lot means a batch, or a specifically identified portion of a batch, 
having uniform character and quality within specified limits. In the 
case of a PET drug produced by continuous process, a lot is a 
specifically identified amount produced in a unit of time or quantity in 
a manner that ensures its having uniform character and quality within 
specified limits.
    Lot number, control number, or batch number means any distinctive 
combination of letters, numbers, or symbols from which the complete 
history of the production, processing, packing, holding, and 
distribution of a batch or lot of a PET drug can be determined.
    Master production and control record means a compilation of 
instructions containing the procedures and specifications for the 
production of a PET drug.
    Material release means the authoritative decision by a responsible 
person in a PET production facility to permit the use of a component, 
container and closure, in-process material, packaging material, or 
labeling in the production of a PET drug.
    PET means positron emission tomography.
    PET drug means a radioactive drug that exhibits spontaneous 
disintegration of unstable nuclei by the emission of positrons and is 
used for providing dual photon positron emission tomographic diagnostic 
images. The definition includes any nonradioactive reagent, reagent kit, 
ingredient, nuclide generator, accelerator, target material, electronic 
synthesizer, or other apparatus or computer program to be used in the 
preparation of a PET drug. ``PET drug'' includes a ``PET drug product'' 
as defined in this section.
    PET drug product means a finished dosage form of a PET drug, whether 
or not in association with one or more other ingredients.
    PET drug production facility means a facility that is engaged in the 
production of a PET drug.
    Production means the manufacturing, compounding, processing, 
packaging, labeling, reprocessing, repacking, relabeling, and testing of 
a PET drug.
    Quality assurance means a system for ensuring the quality of active 
ingredients, PET drugs, intermediates, components that yield an active 
pharmaceutical ingredient, analytical supplies, and other components, 
including container-closure systems and in-process materials, through 
procedures, tests, analytical methods, and acceptance criteria.
    Receiving facility means any hospital, institution, nuclear 
pharmacy, imaging facility, or other entity or part of an entity that 
accepts a PET drug product that has been given final release, but does 
not include a common or contract carrier that transports a PET drug 
product from a PET production facility to a receiving facility.
    Specifications means the tests, analytical procedures, and 
appropriate acceptance criteria to which a PET drug, PET drug product, 
component, container-closure system, in-process material, or other 
material used in PET drug production must conform to be considered 
acceptable for its intended use. Conformance to specifications means 
that a PET drug, PET drug product, component, container-closure system, 
in-process material, or other material used in PET drug production, when 
tested according to the described analytical procedures, meets the 
listed acceptance criteria.
    Strength means the concentration of the active pharmaceutical 
ingredient (radioactivity amount per volume or weight at the time of 
calibration).
    Sub-batch means a quantity of PET drug having uniform character and 
quality, within specified limits, that is produced during one succession 
of multiple irradiations, using a given synthesis and/or purification 
operation.
    Verification means confirmation that an established method, process, 
or system meets predetermined acceptance criteria.

[[Page 181]]



Sec.  212.2  What is current good manufacturing practice for PET drugs?

    Current good manufacturing practice for PET drugs is the minimum 
requirements for the methods to be used in, and the facilities and 
controls used for, the production, quality assurance, holding, or 
distribution of PET drugs intended for human use. Current good 
manufacturing practice is intended to ensure that each PET drug meets 
the requirements of the act as to safety and has the identity and 
strength, and meets the quality and purity characteristics, that it is 
supposed to have.



Sec.  212.5  To what drugs do the regulations in this part apply?

    (a) Application solely to PET drugs. The regulations in this part 
apply only to the production, quality assurance, holding, and 
distribution of PET drugs. Any human drug that does not meet the 
definition of a PET drug must be manufactured in accordance with the 
current good manufacturing practice requirements in parts 210 and 211 of 
this chapter.
    (b) Investigational and research PET drugs. For investigational PET 
drugs for human use produced under an investigational new drug 
application in accordance with part 312 of this chapter, and PET drugs 
produced with the approval of a Radioactive Drug Research Committee in 
accordance with part 361 of this chapter, the requirement under the act 
to follow current good manufacturing practice is met by complying with 
the regulations in this part or by producing PET drugs in accordance 
with Chapter 823, ``Radiopharmaceuticals for Positron Emission 
Tomography--Compounding,'' May 1, 2009, pp. 365-369, 32d ed. of the 
United States Pharmacopeia (USP) National Formulary (NF) (USP 32/NF 27) 
(2009). The Director of the Federal Register approves this incorporation 
by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. You 
may obtain a copy from the United States Pharmacopeial Convention, Inc., 
12601 Twinbrook Pkwy., Rockville, MD 20852, Geeta M. Tirumalai, 301-816-
8352, e-mail: [email protected], Internet address: http://www.usp.org/USPNF/
notices. You may inspect a copy at the Food and Drug Administration 
Biosciences Library, 10903 New Hampshire Ave., Silver Spring, MD, 20993-
0002, 301-796-3504, or at the National Archives and Records 
Administration (NARA). For information on the availability of this 
material at NARA, call 202-741-6030, or go to http://www.archives.gov/
federal_register/code_of_federal_regulations/ibr_locations.html.



                    Subpart B_Personnel and Resources



Sec.  212.10  What personnel and resources must I have?

    You must have a sufficient number of personnel with the necessary 
education, background, training, and experience to perform their 
assigned functions. You must have adequate resources, including 
facilities and equipment, to enable your personnel to perform their 
functions.



                       Subpart C_Quality Assurance



Sec.  212.20  What activities must I perform to ensure drug quality?

    (a) Production operations. You must oversee production operations to 
ensure that each PET drug meets the requirements of the act as to safety 
and has the identity and strength, and meets the quality and purity 
characteristics, that it is supposed to have.
    (b) Materials. You must examine and approve or reject components, 
containers, closures, in-process materials, packaging materials, 
labeling, and finished dosage forms to ensure compliance with procedures 
and specifications affecting the identity, strength, quality, or purity 
of a PET drug.
    (c) Specifications and processes. You must approve or reject, before 
implementation, any initial specifications, methods, processes, or 
procedures, and any proposed changes to existing specifications, 
methods, processes, or procedures, to ensure that they maintain the 
identity, strength, quality, and purity of a PET drug. You must 
demonstrate that any change does not adversely affect the identity, 
strength, quality, or purity of any PET drug.
    (d) Production records. You must review production records to 
determine whether errors have occurred. If errors have occurred, or a 
production batch or

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any component of the batch fails to meet any of its specifications, you 
must determine the need for an investigation, conduct investigations 
when necessary, and take appropriate corrective actions.
    (e) Quality assurance. You must establish and follow written quality 
assurance procedures.



                   Subpart D_Facilities and Equipment



Sec.  212.30  What requirements must my facilities and equipment meet?

    (a) Facilities. You must provide adequate facilities to ensure the 
orderly handling of materials and equipment, the prevention of mix-ups, 
and the prevention of contamination of equipment or product by 
substances, personnel, or environmental conditions that could reasonably 
be expected to have an adverse effect on product quality.
    (b) Equipment procedures. You must implement procedures to ensure 
that all equipment that could reasonably be expected to adversely affect 
the identity, strength, quality, or purity of a PET drug, or give 
erroneous or invalid test results when improperly used or maintained, is 
clean, suitable for its intended purposes, properly installed, 
maintained, and capable of repeatedly producing valid results. You must 
document your activities in accordance with these procedures.
    (c) Equipment construction and maintenance. Equipment must be 
constructed and maintained so that surfaces that contact components, in-
process materials, or PET drugs are not reactive, additive, or 
absorptive so as to alter the quality of PET drugs.



        Subpart E_Control of Components, Containers, and Closures



Sec.  212.40  How must I control the components I use to produce PET
drugs and the containers and closures I package them in?

    (a) Written procedures. You must establish, maintain, and follow 
written procedures describing the receipt, login, identification, 
storage, handling, testing, and acceptance and/or rejection of 
components and drug product containers and closures. The procedures must 
be adequate to ensure that the components, containers, and closures are 
suitable for their intended use.
    (b) Written specifications. You must establish appropriate written 
specifications for the identity, quality, and purity of components and 
for the identity and quality of drug product containers and closures.
    (c) Examination and testing. Upon receipt, each lot of components 
and containers and closures must be uniquely identified and tested or 
examined to determine whether the lot complies with your specifications. 
You must not use in PET drug production any lot that does not meet its 
specifications, including any expiration date if applicable, or that has 
not yet received its material release. Any incoming lot must be 
appropriately designated as quarantined, accepted, or rejected. You must 
use a reliable supplier as a source of each lot of each component, 
container, and closure.
    (1)(i) If you conduct finished-product testing of a PET drug product 
that includes testing to ensure that the correct components have been 
used, you must determine that each lot of incoming components used in 
that PET drug product complies with written specifications by examining 
a certificate of analysis provided by the supplier. You are not required 
to perform a specific identity test on any of those components.
    (ii) If you do not conduct finished-product testing of a PET drug 
product that ensures that the correct components have been used, you 
must conduct identity testing on each lot of a component that yields an 
active ingredient and each lot of an inactive ingredient used in that 
PET drug product. This testing must be conducted using tests that are 
specific to each component that yields an active ingredient and each 
inactive ingredient. For any other component, such as a solvent or 
reagent, that is not the subject of finished-product testing, you must 
determine that each lot complies with written specifications by 
examining a certificate of analysis provided by the supplier; if you use 
such a component to prepare an inactive ingredient on site,

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you must perform an identity test on the components used to make the 
inactive ingredient before the components are released for use. However, 
if you use as an inactive ingredient a product that is approved under 
section 505 of the act (21 U.S.C. 355) and is marketed as a finished 
drug product intended for intravenous administration, you need not 
perform a specific identity test on that ingredient.
    (2) You must examine a representative sample of each lot of 
containers and closures for conformity to its written specifications. 
You must perform at least a visual identification of each lot of 
containers and closures.
    (d) Handling and storage. You must handle and store components, 
containers, and closures in a manner that prevents contamination, mix-
ups, and deterioration and ensures that they are and remain suitable for 
their intended use.
    (e) Records. You must keep a record for each shipment of each lot of 
components, containers, and closures that you receive. The record must 
include the identity and quantity of each shipment, the supplier's name 
and lot number, the date of receipt, the results of any testing 
performed, the disposition of rejected material, and the expiration date 
(where applicable).



                Subpart F_Production and Process Controls



Sec.  212.50  What production and process controls must I have?

    You must have adequate production and process controls to ensure the 
consistent production of a PET drug that meets the applicable standards 
of identity, strength, quality, and purity.
    (a) Written control procedures. You must have written production and 
process control procedures to ensure and document that all key process 
parameters are controlled and that any deviations from the procedures 
are justified.
    (b) Master production and control records. You must have master 
production and control records that document all steps in the PET drug 
production process. The master production and control records must 
include the following information:
    (1) The name and strength of the PET drug;
    (2) If applicable, the name and radioactivity or other measurement 
of each active pharmaceutical ingredient and each inactive ingredient 
per batch or per unit of radioactivity or other measurement of the drug 
product, and a statement of the total radioactivity or other measurement 
of any dosage unit;
    (3) A complete list of components designated by names and codes 
sufficiently specific to indicate any special quality characteristic;
    (4) Identification of all major pieces of equipment used in 
production;
    (5) An accurate statement of the weight or measurement of each 
component, using the same weight system (metric, avoirdupois, or 
apothecary) for each component. Reasonable variations are permitted in 
the amount of component necessary if they are specified in the master 
production and control records;
    (6) A statement of action limits on radiochemical yield, i.e., the 
minimum percentage of yield beyond which investigation and corrective 
action are required;
    (7) Complete production and control instructions, sampling and 
testing procedures, specifications, special notations, and precautions 
to be followed; and
    (8) A description of the PET drug product containers, closures, and 
packaging materials, including a specimen or copy of each label and all 
other labeling.
    (c) Batch production and control records. Each time a batch of a PET 
drug is produced, a unique batch production and control record must be 
created. The batch production record must include the following 
information:
    (1) Name and strength of the PET drug;
    (2) Identification number or other unique identifier of the specific 
batch that was produced;
    (3) The name and radioactivity or other measure of each active 
pharmaceutical ingredient and each inactive ingredient per batch or per 
unit of radioactivity or other measurement of the drug product;

[[Page 184]]

    (4) Each major production step (obtained from the approved 
appropriate master production and control record);
    (5) Weights (or other measure of quantity) and identification codes 
of components;
    (6) Dates of production steps and times of critical production 
steps;
    (7) Identification of major pieces of equipment used in production 
of the batch;
    (8) Testing results;
    (9) Labeling;
    (10) Initials or signatures of persons performing or checking each 
significant step in the operation; and
    (11) Results of any investigations conducted.
    (d) Area and equipment checks. The production area and all equipment 
in the production area must be checked to ensure cleanliness and 
suitability immediately before use. A record of these checks must be 
kept.
    (e) In-process materials controls. Process controls must include 
control of in-process materials to ensure that the materials are 
controlled until required tests or other verification activities have 
been completed or necessary approvals are received and documented.
    (f) Process verification. (1) For a PET drug for which each entire 
batch undergoes full finished-product testing to ensure that the product 
meets all specifications, process verification, as described in 
paragraph (f)(2) of this section, is not required.
    (2) When the results of the production of an entire batch of a PET 
drug are not fully verified through finished-product testing or when 
only the initial sub-batch in a series is tested, the PET drug producer 
must demonstrate that the process for producing the PET drug is 
reproducible and is capable of producing a drug product that meets the 
predetermined acceptance criteria. Process verification activities and 
results must be documented. Documentation must include the date and 
signature of the individual(s) performing the verification, the 
monitoring and control methods and data, and the major equipment 
qualified.



                      Subpart G_Laboratory Controls



Sec.  212.60  What requirements apply to the laboratories where I test 
components, in-process materials, and finished PET drug products?

    (a) Testing procedures. Each laboratory used to conduct testing of 
components, in-process materials, and finished PET drug products must 
have and follow written procedures for the conduct of each test and for 
the documentation of the results.
    (b) Specifications and standards. Each laboratory must have sampling 
and testing procedures designed to ensure that components, in-process 
materials, and PET drug products conform to appropriate standards, 
including established standards of identity, strength, quality, and 
purity.
    (c) Analytical methods. Laboratory analytical methods must be 
suitable for their intended use and must be sufficiently sensitive, 
specific, accurate, and reproducible.
    (d) Materials. The identity, purity, and quality of reagents, 
solutions, and supplies used in testing procedures must be adequately 
controlled. All solutions that you prepare must be properly labeled to 
show their identity and expiration date.
    (e) Equipment. All equipment used to perform the testing must be 
suitable for its intended purposes and capable of producing valid 
results.
    (f) Equipment maintenance. Each laboratory must have and follow 
written procedures to ensure that equipment is routinely calibrated, 
inspected, checked, and maintained, and that these activities are 
documented.
    (g) Test records. Each laboratory performing tests related to the 
production of a PET drug must keep complete records of all tests 
performed to ensure compliance with established specifications and 
standards, including examinations and assays, as follows:
    (1) A suitable identification of the sample received for testing.
    (2) A description of each method used in the testing of the sample, 
a record of all calculations performed in connection with each test, and 
a statement of the weight or measurement of the sample used for each 
test.

[[Page 185]]

    (3) A complete record of all data obtained in the course of each 
test, including the date and time the test was conducted, and all 
graphs, charts, and spectra from laboratory instrumentation, properly 
identified to show the specific component, in-process material, or drug 
product for each lot tested.
    (4) A statement of the results of tests and how the results compare 
with established acceptance criteria.
    (5) The initials or signature of the person performing the test and 
the date on which the test was performed.



Sec.  212.61  What must I do to ensure the stability of my PET drug
products through expiry?

    (a) Stability testing program. You must establish, follow, and 
maintain a written testing program to assess the stability 
characteristics of your PET drug products. The test methods must be 
reliable, meaningful, and specific. The samples tested for stability 
must be representative of the lot or batch from which they were obtained 
and must be stored under suitable conditions.
    (b) Storage conditions and expiration dates. The results of such 
stability testing must be documented and used in determining appropriate 
storage conditions and expiration dates and times for each PET drug 
product you produce.



         Subpart H_Finished Drug Product Controls and Acceptance



Sec.  212.70  What controls and acceptance criteria must I have for my
finished PET drug products?

    (a) Specifications. You must establish specifications for each PET 
drug product, including criteria for determining identity, strength, 
quality, purity, and, if appropriate, sterility and pyrogens.
    (b) Test procedures. Before you implement a new test procedure in a 
specification, you must establish and document the accuracy, 
sensitivity, specificity, and reproducibility of the procedure. If you 
use an established compendial test procedure in a specification, you 
must first verify and document that the test works under the conditions 
of actual use.
    (c) Conformance to specifications. Before final release, you must 
conduct an appropriate laboratory determination to ensure that each 
batch of a PET drug product conforms to specifications, except for 
sterility. For a PET drug product produced in sub-batches, before final 
release, you must conduct an appropriate laboratory determination to 
ensure that each sub-batch conforms to specifications, except for 
sterility.
    (d) Final release procedures. Except as conditional final release is 
permitted in accordance with paragraph (f) of this section, you must 
establish and follow procedures to ensure that each batch of a PET drug 
product is not given final release until the following are done:
    (1) An appropriate laboratory determination under paragraph (c) of 
this section is completed;
    (2) Associated laboratory data and documentation are reviewed and 
they demonstrate that the PET drug product meets specifications, except 
for sterility; and
    (3) A designated qualified individual authorizes final release by 
dated signature.
    (e) Sterility testing. Sterility testing need not be completed 
before final release but must be started within 30 hours after 
completion of production. The 30-hour requirement may be exceeded due to 
a weekend or holiday. If the sample for sterility testing is held longer 
than 30 hours, you must demonstrate that the longer period does not 
adversely affect the sample and the test results obtained will be 
equivalent to test results that would have been obtained if the test had 
been started within the 30-hour time period. Tested samples must be from 
individual batches and not pooled. If the product fails to meet a 
criterion for sterility, you must immediately notify all facilities that 
received the product of the test results and provide any appropriate 
recommendations. The notification must be documented. Upon completion of 
an investigation into the failure to meet a criterion for sterility, you 
must notify all facilities that received the product of the findings 
from the investigation.
    (f) Conditional final release. (1) If you cannot complete one of the 
required

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finished-product tests for a batch of a PET drug product because of a 
malfunction involving analytical equipment, you may approve the 
conditional final release of the product if you meet the following 
conditions:
    (i) You have data documenting that preceding consecutive batches, 
produced using the same methods used for the conditionally released 
batch, demonstrate that the conditionally released batch will likely 
meet the established specifications;
    (ii) You determine that all other acceptance criteria are met;
    (iii) You retain a reserve sample of the conditionally released 
batch of drug product;
    (iv) You promptly correct the malfunction of analytical equipment, 
complete the omitted test using the reserve sample after the malfunction 
is corrected, and document that reasonable efforts have been made to 
prevent recurrence of the malfunction;
    (v) If you obtain an out-of-specification result when testing the 
reserve sample, you immediately notify the receiving facility; and
    (vi) You document all actions regarding the conditional final 
release of the drug product, including the justification for the 
release, all followup actions, results of completed testing, all 
notifications, and corrective actions to prevent recurrence of the 
malfunction involving analytical equipment.
    (2) Even if the criteria in paragraph (f)(1) of this section are 
met, you may not approve the conditional final release of the product if 
the malfunction involving analytical equipment prevents the performance 
of a radiochemical identity/purity test or prevents the determination of 
the product's specific activity.
    (3) You may not release another batch of the PET drug product until 
you have corrected the problem concerning the malfunction of analytical 
equipment and completed the omitted finished-product test.



Sec.  212.71  What actions must I take if a batch of PET drug product
does not conform to specifications?

    (a) Rejection of nonconforming product. You must reject a batch of a 
PET drug product that does not conform to specifications. You must have 
and follow procedures to identify and segregate the product to avoid 
mix-ups. You must have and follow procedures to investigate the cause(s) 
of the nonconforming product. The investigation must include, but is not 
limited to, examination of processes, operations, records, complaints, 
and any other relevant sources of information concerning the 
nonconforming product.
    (b) Investigation. You must document the investigation of a PET drug 
product that does not meet specifications, including the results of the 
investigation and what happened to the rejected PET drug product.
    (c) Correction of problems. You must take action to correct any 
identified problems to prevent recurrence of a nonconforming product or 
other quality problem.
    (d) Reprocessing. If appropriate, you may reprocess a batch of a PET 
drug product that does not conform to specifications. If material that 
does not meet acceptance criteria is reprocessed, you must follow 
procedures stated in the product's approved application and the finished 
product must conform to specifications, except for sterility, before 
final release.



                    Subpart I_Packaging and Labeling



Sec.  212.80  What are the requirements associated with labeling and 
packaging PET drug products?

    (a) A PET drug product must be suitably labeled and packaged to 
protect the product from alteration, contamination, and damage during 
the established conditions of shipping, distribution, handling, and use.
    (b) Labels must be legible and applied so as to remain legible and 
affixed during the established conditions of processing, storage, 
handling, distribution, and use.
    (c) All information stated on each label must also be contained in 
each batch production record.
    (d) Labeling and packaging operations must be controlled to prevent 
labeling and product mix-ups.

[[Page 187]]



                         Subpart J_Distribution



Sec.  212.90  What actions must I take to control the distribution of
PET drug products?

    (a) Written distribution procedures. You must establish, maintain, 
and follow written procedures for the control of distribution of PET 
drug products shipped from the PET drug production facility to ensure 
that the method of shipping chosen will not adversely affect the 
identity, purity, or quality of the PET drug product.
    (b) Distribution records. You must maintain distribution records for 
each PET drug product that include or refer to the following:
    (1) The name, address, and telephone number of the receiving 
facility that received each batch of a PET drug product;
    (2) The name and quantity of the PET drug product shipped;
    (3) The lot number, control number, or batch number for the PET drug 
product shipped; and
    (4) The date and time you shipped the PET drug product.



                      Subpart K_Complaint Handling



Sec.  212.100  What do I do if I receive a complaint about a PET drug 
product produced at my facility?

    (a) Written complaint procedures. You must develop and follow 
written procedures for the receipt and handling of all complaints 
concerning the quality or purity of, or possible adverse reactions to, a 
PET drug product.
    (b) Complaint review. The procedures must include review by a 
designated person of any complaint involving the possible failure of a 
PET drug product to meet any of its specifications and an investigation 
to determine the cause of the failure.
    (c) Complaint records. A written record of each complaint must be 
maintained in a file designated for PET drug product complaints. The 
record must include the name and strength of the PET drug product, the 
batch number, the name of the complainant, the date the complaint was 
received, the nature of the complaint, and the response to the 
complaint. It must also include the findings of any investigation and 
followup.
    (d) Returned products. A PET drug product that is returned because 
of a complaint or for any other reason may not be reprocessed and must 
be destroyed in accordance with applicable Federal and State law.



                            Subpart L_Records



Sec.  212.110  How must I maintain records of my production of PET drugs?

    (a) Record availability. Records must be maintained at the PET drug 
production facility or another location that is reasonably accessible to 
responsible officials of the production facility and to employees of FDA 
designated to perform inspections.
    (b) Record quality. All records, including those not stored at the 
inspected establishment, must be legible, stored to prevent 
deterioration or loss, and readily available for review and copying by 
FDA employees.
    (c) Record retention period. You must maintain all records and 
documentation referenced in this part for a period of at least 1 year 
from the date of final release, including conditional final release, of 
a PET drug product.



PART 216_HUMAN DRUG COMPOUNDING--Table of Contents



Subpart A--General Provisions [Reserved]

                   Subpart B_Compounded Drug Products

Sec.
216.23 Bulk drug substances that can be used to compound drug products 
          in accordance with section 503A of the Federal Food, Drug, and 
          Cosmetic Act.
216.24 Drug products withdrawn or removed from the market for reasons of 
          safety or effectiveness.

    Authority: 21 U.S.C. 351, 352, 353a, 353b, 355, and 371.

    Source: 64 FR 10944, Mar. 8, 1999, unless otherwise noted.

Subpart A--General Provisions [Reserved]

[[Page 188]]



                   Subpart B_Compounded Drug Products



Sec.  216.23  Bulk drug substances that can be used to compound drug
products in accordance with section 503A of the Federal Food, Drug, 
and Cosmetic Act.

    (a) The following bulk drug substances can be used in compounding 
under section 503A(b)(1)(A)(i)(III) of the Federal Food, Drug, and 
Cosmetic Act.
    (1) Brilliant Blue G, also known as Coomassie Brilliant Blue G-250.
    (2) Cantharidin (for topical use only).
    (3) Diphenylcyclopropenone (for topical use only).
    (4) N-acetyl-D-glucosamine (for topical use only).
    (5) Squaric acid dibutyl ester (for topical use only).
    (6) Thymol iodide (for topical use only).
    (b) After balancing the criteria set forth in paragraph (c) of this 
section, FDA has determined that the following bulk drug substances will 
not be included on the list of substances that can be used in 
compounding set forth in paragraph (a) of this section:
    (1) Oxitriptan.
    (2) Piracetam.
    (3) Silver Protein Mild.
    (4) Tranilast.
    (c) FDA will use the following criteria in evaluating substances 
considered for inclusion on the list set forth in paragraph (a) of this 
section:
    (1) The physical and chemical characterization of the substance;
    (2) Any safety issues raised by the use of the substance in 
compounded drug products;
    (3) The available evidence of the effectiveness or lack of 
effectiveness of a drug product compounded with the substance, if any 
such evidence exists; and
    (4) Historical use of the substance in compounded drug products, 
including information about the medical condition(s) the substance has 
been used to treat and any references in peer-reviewed medical 
literature.
    (d) Based on evidence currently available, there are inadequate data 
to demonstrate the safety or efficacy of any drug product compounded 
using any of the drug substances listed in paragraph (a) of this 
section, or to establish general recognition of the safety or 
effectiveness of any such drug product. Any person who represents that a 
compounded drug made with a bulk drug substance that appears on this 
list is FDA approved, or otherwise endorsed by FDA generally or for a 
particular indication, will cause the drug to be misbranded under 
section 502(a) and/or 502(bb) of the Federal Food, Drug, and Cosmetic 
Act.

[84 FR 4710, Feb. 19, 2019]



Sec.  216.24  Drug products withdrawn or removed from the market for
reasons of safety or effectiveness.

    The following drug products were withdrawn or removed from the 
market because such drug products or components of such drug products 
have been found to be unsafe or not effective. The following drug 
products may not be compounded under the exemptions provided by section 
503A(a) or section 503B(a) of the Federal Food, Drug, and Cosmetic Act:

Adenosine phosphate: All drug products containing adenosine phosphate.
Adrenal cortex: All drug products containing adrenal cortex.
Alatrofloxacin mesylate: All drug products containing alatrofloxacin 
mesylate.
Aminopyrine: All drug products containing aminopyrine.
Astemizole: All drug products containing astemizole.
Azaribine: All drug products containing azaribine.
Benoxaprofen: All drug products containing benoxaprofen.
Bithionol: All drug products containing bithionol.
Bromfenac sodium: All drug products containing bromfenac sodium (except 
ophthalmic solutions).
Bromocriptine mesylate: All drug products containing bromocriptine 
mesylate for prevention of physiological lactation.
Butamben: All parenteral drug products containing butamben.
Camphorated oil: All drug products containing camphorated oil.
Carbetapentane citrate: All oral gel drug products containing 
carbetapentane citrate.
Casein, iodinated: All drug products containing iodinated casein.
Cerivastatin sodium: All drug products containing cerivastatin sodium.
Chloramphenicol: All oral drug products containing chloramphenicol.
Chlorhexidine gluconate: All tinctures of chlorhexidine gluconate 
formulated for use as a patient preoperative skin preparation.

[[Page 189]]

Chlormadinone acetate: All drug products containing chlormadinone 
acetate.
Chloroform: All drug products containing chloroform.
Cisapride: All drug products containing cisapride.
Cobalt: All drug products containing cobalt salts (except radioactive 
forms of cobalt and its salts and cobalamin and its derivatives).
Dexfenfluramine hydrochloride: All drug products containing 
dexfenfluramine hydrochloride.
Diamthazole dihydrochloride: All drug products containing diamthazole 
dihydrochloride.
Dibromsalan: All drug products containing dibromsalan.
Diethylstilbestrol: All oral and parenteral drug products containing 25 
milligrams or more of diethylstilbestrol per unit dose.
Dihydrostreptomycin sulfate: All drug products containing 
dihydrostreptomycin sulfate.
Dipyrone: All drug products containing dipyrone.
Encainide hydrochloride: All drug products containing encainide 
hydrochloride.
Esmolol hydrochloride: All parenteral dosage form drug products 
containing esmolol hydrochloride that supply 250 milligrams/milliliter 
of concentrated esmolol per 10-milliliter ampule.
Etretinate: All drug products containing etretinate.
Fenfluramine hydrochloride: All drug products containing fenfluramine 
hydrochloride.
Flosequinan: All drug products containing flosequinan.
Gatifloxacin: All drug products containing gatifloxacin (except 
ophthalmic solutions).
Gelatin: All intravenous drug products containing gelatin.
Glycerol, iodinated: All drug products containing iodinated glycerol.
Gonadotropin, chorionic: All drug products containing chorionic 
gonadotropins of animal origin.
Grepafloxacin: All drug products containing grepafloxacin.
Mepazine: All drug products containing mepazine hydrochloride or 
mepazine acetate.
Metabromsalan: All drug products containing metabromsalan.
Methamphetamine hydrochloride: All parenteral drug products containing 
methamphetamine hydrochloride.
Methapyrilene: All drug products containing methapyrilene.
Methopholine: All drug products containing methopholine.
Methoxyflurane: All drug products containing methoxyflurane.
Mibefradil dihydrochloride: All drug products containing mibefradil 
dihydrochloride.
Nitrofurazone: All drug products containing nitrofurazone (except 
topical drug products formulated for dermatologic application).
Nomifensine maleate: All drug products containing nomifensine maleate.
Novobiocin sodium: All drug products containing novobiocin sodium.
Ondansetron hydrochloride: All intravenous drug products containing 
greater than a 16 milligram single dose of ondansetron hydrochloride.
Oxyphenisatin: All drug products containing oxyphenisatin.
Oxyphenisatin acetate: All drug products containing oxyphenisatin 
acetate.
Pemoline: All drug products containing pemoline.
Pergolide mesylate: All drug products containing pergolide mesylate.
Phenacetin: All drug products containing phenacetin.
Phenformin hydrochloride: All drug products containing phenformin 
hydrochloride.
Phenylpropanolamine: All drug products containing phenylpropanolamine.
Pipamazine: All drug products containing pipamazine.
Polyethylene glycol 3350, sodium chloride, sodium bicarbonate, potassium 
chloride, and bisacodyl: All drug products containing polyethylene 
glycol 3350, sodium chloride, sodium bicarbonate, and potassium chloride 
for oral solution, and 10 milligrams or more of bisacodyl delayed-
release tablets.
Potassium arsenite: All drug products containing potassium arsenite.
Potassium chloride: All solid oral dosage form drug products containing 
potassium chloride that supply 100 milligrams or more of potassium per 
dosage unit (except for controlled-release dosage forms and those 
products formulated for preparation of solution prior to ingestion).
Povidone: All intravenous drug products containing povidone.
Propoxyphene: All drug products containing propoxyphene.
Rapacuronium bromide: All drug products containing rapacuronium bromide.
Reserpine: All oral dosage form drug products containing more than 1 
milligram of reserpine.
Rofecoxib: All drug products containing rofecoxib.
Sibutramine hydrochloride: All drug products containing sibutramine 
hydrochloride.
Sparteine sulfate: All drug products containing sparteine sulfate.
Sulfadimethoxine: All drug products containing sulfadimethoxine.
Sulfathiazole: All drug products containing sulfathiazole (except for 
those formulated for vaginal use).
Suprofen: All drug products containing suprofen (except ophthalmic 
solutions).
Sweet spirits of nitre: All drug products containing sweet spirits of 
nitre.

[[Page 190]]

Tegaserod maleate: All drug products containing tegaserod maleate.
Temafloxacin hydrochloride: All drug products containing temafloxacin 
hydrochloride.
Terfenadine: All drug products containing terfenadine.
3,3[min],4[min],5-tetrachlorosalicylanilide: All drug products 
containing 3,3[min],4[min],5-tetrachlorosalicylanilide.
Tetracycline: All liquid oral drug products formulated for pediatric use 
containing tetracycline in a concentration greater than 25 milligrams/
milliliter.
Ticrynafen: All drug products containing ticrynafen.
Tribromsalan: All drug products containing tribromsalan.
Trichloroethane: All aerosol drug products intended for inhalation 
containing trichloroethane.
Troglitazone: All drug products containing troglitazone.
Trovafloxacin mesylate: All drug products containing trovafloxacin 
mesylate.
Urethane: All drug products containing urethane.
Valdecoxib: All drug products containing valdecoxib.
Vinyl chloride: All aerosol drug products containing vinyl chloride.
Zirconium: All aerosol drug products containing zirconium.
Zomepirac sodium: All drug products containing zomepirac sodium.

[81 FR 69676, Oct. 7, 2016, as amended at 83 FR 63573, Dec. 11, 2018]



PART 225_CURRENT GOOD MANUFACTURING PRACTICE FOR MEDICATED FEEDS-
-Table of Contents



                      Subpart A_General Provisions

Sec.
225.1 Current good manufacturing practice.
225.10 Personnel.

   Subpart B_Construction and Maintenance of Facilities and Equipment

225.20 Buildings.
225.30 Equipment.
225.35 Use of work areas, equipment, and storage areas for other 
          manufacturing and storage purpose.

                    Subpart C_Product Quality Control

225.42 Components.
225.58 Laboratory controls.
225.65 Equipment cleanout procedures.

                    Subpart D_Packaging and Labeling

225.80 Labeling.

                      Subpart E_Records and Reports

225.102 Master record file and production records.
225.110 Distribution records.
225.115 Complaint files.

                   Subpart F_Facilities and Equipment

225.120 Buildings and grounds.
225.130 Equipment.
225.135 Work and storage areas.

                   Subpart G_Product Quality Assurance

225.142 Components.
225.158 Laboratory assays.
225.165 Equipment cleanout procedures.

                           Subpart H_Labeling

225.180 Labeling.

                            Subpart I_Records

225.202 Formula, production, and distribution records.

    Authority: 21 U.S.C. 351, 352, 360b, 371, 374.

    Source: 41 FR 52618, Nov. 30, 1976, unless otherwise noted.



                      Subpart A_General Provisions



Sec.  225.1  Current good manufacturing practice.

    (a) Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act 
provides that a drug (including a drug contained in a medicated feed) 
shall be deemed to be adulterated if the methods used in, or the 
facilities or controls used for, its manufacture, processing, packing, 
or holding do not conform to or are not operated or administered in 
conformity with current good manufacturing practice to assure that such 
drug meets the requirement of the act as to safety and has the identity 
and strength, and meets the quality and purity characteristics, which it 
purports or is represented to possess.
    (b)(1) The provisions of this part set forth the criteria for 
determining whether the manufacture of a medicated feed is in compliance 
with current good manufacturing practice. These regulations shall apply 
to all types of facilities and equipment used in the production of 
medicated feeds, and they shall also govern those instances in which 
failure to adhere to the regulations has caused nonmedicated feeds that 
are manufactured,

[[Page 191]]

processed, packed, or held to be adulterated. In such cases, the 
medicated feed shall be deemed to be adulterated within the meaning of 
section 501(a)(2)(B) of the act, and the nonmedicated feed shall be 
deemed to be adulterated within the meaning of section 402(a)(2)(C)(ii) 
of the act.
    (2) The regulations in Sec. Sec.  225.10 through 225.115 apply to 
facilities manufacturing one or more medicated feeds for which an 
approved medicated feed mill license is required. The regulations in 
Sec. Sec.  225.120 through 225.202 apply to facilities manufacturing 
solely medicated feeds for which an approved license is not required.
    (c) In addition to the recordkeeping requirements in this part, Type 
B and Type C medicated feeds made from Type A articles or Type B feeds 
under approved NADAs or indexed listings and a medicated feed mill 
license are subject to the requirements of Sec.  510.301 of this 
chapter.

[41 FR 52618, Nov. 30, 1976, as amended at 51 FR 7389, Mar. 3, 1986; 64 
FR 63203, Nov. 19, 1999; 72 FR 69120, Dec. 6, 2007; 79 FR 3739, Jan. 23, 
2014]



Sec.  225.10  Personnel.

    (a) Qualified personnel and adequate personnel training and 
supervision are essential for the proper formulation, manufacture, and 
control of medicated feeds. Training and experience leads to proper use 
of equipment, maintenance of accurate records, and detection and 
prevention of possible deviations from current good manufacturing 
practices.
    (b)(1) All employees involved in the manufacture of medicated feeds 
shall have an understanding of the manufacturing or control operation(s) 
which they perform, including the location and proper use of equipment.
    (2) The manufacturer shall provide an on-going program of evaluation 
and supervision of employees in the manufacture of medicated feeds.

[41 FR 52618, Nov. 30, 1976, as amended at 42 FR 12426, Mar. 4, 1977]



   Subpart B_Construction and Maintenance of Facilities and Equipment



Sec.  225.20  Buildings.

    (a) The location, design, construction, and physical size of the 
buildings and other production facilities are factors important to the 
manufacture of medicated feed. The features of facilities necessary for 
the proper manufacture of medicated feed include provision for ease of 
access to structures and equipment in need of routine maintenance; ease 
of cleaning of equipment and work areas; facilities to promote personnel 
hygiene; structural conditions for control and prevention of vermin and 
pest infestation; adequate space for the orderly receipt and storage of 
drugs and feed ingredients and the controlled flow of these materials 
through the processing and manufacturing operations; and the equipment 
for the accurate packaging and delivery of a medicated feed of specified 
labeling and composition.
    (b) The construction and maintenance of buildings in which medicated 
feeds are manufactured, processed, packaged, labeled, or held shall 
conform to the following:
    (1) The building grounds shall be adequately drained and routinely 
maintained so that they are reasonably free from litter, waste, refuse, 
uncut weeds or grass, standing water, and improperly stored equipment.
    (2) The building(s) shall be maintained in a reasonably clean and 
orderly manner.
    (3) The building(s) shall be of suitable construction to minimize 
access by rodents, birds, insects, and other pests.
    (4) The buildings shall provide adequate space and lighting for the 
proper performance of the following medicated feed manufacturing 
operations:
    (i) The receipt, control, and storage of components.
    (ii) Component processing.
    (iii) Medicated feed manufacturing.
    (iv) Packaging and labeling.
    (v) Storage of containers, packaging materials, labeling and 
finished products.
    (vi) Routine maintenance of equipment.

[[Page 192]]



Sec.  225.30  Equipment.

    (a) Equipment which is designed to perform its intended function and 
is properly installed and used is essential to the manufacture of 
medicated feeds. Such equipment permits production of feeds of uniform 
quality, facilitates cleaning, and minimizes spillage of drug components 
and finished product.
    (b)(1) All equipment shall possess the capability to produce a 
medicated feed of intended potency, safety, and purity.
    (2) All equipment shall be maintained in a reasonably clean and 
orderly manner.
    (3) All equipment, including scales and liquid metering devices, 
shall be of suitable size, design, construction, precision, and accuracy 
for its intended purpose.
    (4) All scales and metering devices shall be tested for accuracy 
upon installation and at least once a year thereafter, or more 
frequently as may be necessary to insure their accuracy.
    (5) All equipment shall be so constructed and maintained as to 
prevent lubricants and coolants from becoming unsafe additives in feed 
components or medicated feed.
    (6) All equipment shall be designed, constructed, installed and 
maintained so as to facilitate inspection and use of cleanout 
procedure(s).



Sec.  225.35  Use of work areas, equipment, and storage areas for other
manufacturing and storage purpose.

    (a) Many manufacturers of medicated feeds are also involved in the 
manufacture, storage, or handling of products which are not intended for 
animal feed use, such as fertilizers, herbicides, insecticides, 
fungicides, rodenticides, and other pesticides. Manufacturing, storage, 
or handling of nonfeed and feed products in the same facilities may 
cause adulteration of feed products with toxic or otherwise unapproved 
feed additives.
    (b) Work areas and equipment used for the manufacture or storage of 
medicated feeds or components thereof shall not be used for, and shall 
be physically separated from, work areas and equipment used for the 
manufacture of fertilizers, herbicides, insecticides, fungicides, 
rodenticides, and other pesticides unless such articles are approved 
drugs, indexed drugs, or approved food additives intended for use in the 
manufacture of medicated feed.

[41 FR 52618, Nov. 30, 1976, as amended at 72 FR 69120, Dec. 6, 2007]



                    Subpart C_Product Quality Control



Sec.  225.42  Components.

    (a) A medicated feed, in addition to providing nutrients, is a 
vehicle for the administration of a drug, or drugs, to animals. To 
ensure proper safety and effectiveness, such medicated feeds must 
contain the labeled amounts of drugs. It is necessary that adequate 
procedures be established for the receipt, storage, and inventory 
control for all such drugs to aid in assuring their identity, strength, 
quality, and purity when incorporated into products.
    (b) The receipt, storage, and inventory of drugs, including 
undiluted drug components, medicated premixes, and semiprocessed (i.e., 
intermediate premixes, inplant premixes and concentrates) intermediate 
mixes containing drugs, which are used in the manufacture and processing 
of medicated feeds shall conform to the following:
    (1) Incoming shipments of drugs shall be visually examined for 
identity and damage. Drugs which have been subjected to conditions which 
may have adversely affected their identity, strength, quality, or purity 
shall not be accepted for use.
    (2) Packaged drugs in the storage areas shall be stored in their 
original closed containers.
    (3) Bulk drugs shall be identified and stored in a manner such that 
their identity, strength, quality, and purity will be maintained.
    (4) Drugs in the mixing areas shall be properly identified, stored, 
handled, and controlled to maintain their integrity and identity. 
Sufficient space shall be provided for the location of each drug.

[[Page 193]]

    (5) A receipt record shall be prepared and maintained for each lot 
of drug received. The receipt record shall accurately indicate the 
identity and quantity of the drug, the name of the supplier, the 
supplier's lot number or an identifying number assigned by the feed 
manufacturer upon receipt which relates to the particular shipment, the 
date of receipt, the condition of the drug when received, and the return 
of any damaged drugs.
    (6) A daily inventory record for each drug used shall be maintained 
and shall list by manufacturer's lot number or the feed manufacturer's 
shipment identification number at least the following information:
    (i) The quantity of drug on hand at the beginning and end of the 
work day (the beginning amount being the same as the previous day's 
closing inventory if this amount has been established to be correct); 
the quantity shall be determined by weighing, counting, or measuring, as 
appropriate.
    (ii) The amount of each drug used, sold, or otherwise disposed of.
    (iii) The batches or production runs of medicated feed in which each 
drug was used.
    (iv) When the drug is used in the preparation of a semiprocessed 
intermediate mix intended for use in the manufacture of medicated feed, 
any additional information which may be required for the purpose of 
paragraph (b)(7) of this section.
    (v) Action taken to reconcile any discrepancies in the daily 
inventory record.
    (7) Drug inventory shall be maintained of each lot or shipment of 
drug by means of a daily comparison of the actual amount of drug used 
with the theoretical drug usage in terms of the semiprocessed, 
intermediate and finished medicated feeds manufactured. Any significant 
discrepancy shall be investigated and corrective action taken. The 
medicated feed(s) remaining on the premises which are affected by this 
discrepancy shall be detained until the discrepancy is reconciled.
    (8) All records required by this section shall be maintained on the 
premises for at least one year after complete use of a drug component of 
a specific lot number or feed manufacturer's shipment identification 
number.



Sec.  225.58  Laboratory controls.

    (a) The periodic assay of medicated feeds for drug components 
provides a measure of performance of the manufacturing process in 
manufacturing a uniform product of intended potency.
    (b) The following assay requirements shall apply to medicated feeds:
    (1) For feeds requiring a medicated feed mill license (Form FDA 
3448) for their manufacture and marketing, at least three representative 
samples of medicated feed containing each drug or drug combination used 
in the establishment shall be collected and assayed by approved official 
methods, at periodic intervals during the calendar year, unless 
otherwise specified in this chapter. At least one of these assays shall 
be performed on the first batch using the drug. If a medicated feed 
contains a combination of drugs, only one of the drugs need be subject 
to analysis each time, provided the one tested is different from the 
one(s) previously tested.
    (2) [Reserved]
    (c) The originals or copies of all results of assays, including 
those from State feed control officials and any other governmental 
agency, shall be maintained on the premises for a period of not less 
than 1 year after distribution of the medicated feed. The results of 
assays performed by State feed control officials may be considered 
toward fulfillment of the periodic assay requirements of this section.
    (d) Where the results of assays indicate that the medicated feed is 
not in accord with label specifications or is not within permissible 
assay limits as specified in this chapter, investigation and corrective 
action shall be implemented and an original or copy of the record of 
such action maintained on the premises.
    (e) Corrective action shall include provisions for discontinuing 
distribution where the medicated feed fails to meet the labeled drug 
potency. Distribution of subsequent production of the particular feed 
shall not begin

[[Page 194]]

until it has been determined that proper control procedures have been 
established.

[41 FR 52618, Nov. 30, 1976, as amended at 51 FR 7390, Mar. 3, 1986; 55 
FR 11577, Mar. 29, 1990; 64 FR 63203, Nov. 19, 1999]



Sec.  225.65  Equipment cleanout procedures.

    (a) Adequate cleanout procedures for all equipment used in the 
manufacture and distribution of medicated feeds are essential to 
maintain proper drug potency and avoid unsafe contamination of feeds 
with drugs. Such procedures may consist of cleaning by physical means, 
e.g., vacuuming, sweeping, washing, etc. Alternatively, flushing or 
sequencing or other equally effective techniques may be used whereby the 
equipment is cleaned either through use of a feed containing the same 
drug(s) or through use of drug free feedstuffs.
    (b) All equipment, including that used for storage, processing, 
mixing, conveying, and distribution that comes in contact with the 
active drug component, feeds in process, or finished medicated feed 
shall be subject to all reasonable and effective procedures to prevent 
unsafe contamination of manufactured feed. The steps used to prevent 
unsafe contamination of feeds shall include one or more of the 
following, or other equally effective procedures:
    (1) Such procedures shall, where appropriate, consist of physical 
means (vacuuming, sweeping, or washing), flushing, and/or sequential 
production of feeds.
    (2) If flushing is utilized, the flush material shall be properly 
identified, stored, and used in a manner to prevent unsafe contamination 
of other feeds.
    (3) If sequential production of medicated feeds is utilized, it 
shall be on a predetermined basis designed to prevent unsafe 
contamination of feeds with residual drugs.



                    Subpart D_Packaging and Labeling



Sec.  225.80  Labeling.

    (a) Appropriate labeling identifies the medicated feed, and provides 
the user with directions for use which, if adhered to, will assure that 
the article is safe and effective for its intended purposes.
    (b)(1) Labels and labeling, including placards, shall be received, 
handled, and stored in a manner that prevents labeling mixups and 
assures that correct labeling is employed for the medicated feed.
    (2) Labels and labeling, including placards, upon receipt from the 
printer shall be proofread against the Master Record File to verify 
their suitability and accuracy. The proofread label shall be dated, 
initialed by a responsible individual, and kept for 1 year after all the 
labels from that batch have been used.
    (3) In those instances where medicated feeds are distributed in 
bulk, complete labeling shall accompany the shipment and be supplied to 
the consignee at the time of delivery. Such labeling may consist of a 
placard or other labels attached to the invoice or delivery ticket, or 
manufacturer's invoice that identifies the medicated feed and includes 
adequate information for the safe and effective use of the medicated 
feed.
    (4) Label stock shall be reviewed periodically and discontinued 
labels shall be discarded.



                      Subpart E_Records and Reports



Sec.  225.102  Master record file and production records.

    (a) The Master Record File provides the complete procedure for 
manufacturing a specific product, setting forth the formulation, 
theoretical yield, manufacturing procedures, assay requirements, and 
labeling of batches or production runs. The production record(s) 
includes the complete history of a batch or production run. This record 
includes the amounts of drugs used, the amount of medicated feed 
manufactured, and provides a check for the daily inventory record of 
drug components.
    (b) The Master Record File and production records shall comply with 
the following provisions:
    (1) A Master Record File shall be prepared, checked, dated, and 
signed or initialed by a qualified person and shall be retained for not 
less than 1

[[Page 195]]

year after production of the last batch or production run of medicated 
feed to which it pertains. The Master Record File or card shall include 
at least the following:
    (i) The name of the medicated feed.
    (ii) The name and weight percentage or measure of each drug or drug 
combination and each nondrug ingredient to be used in manufacturing a 
stated weight of the medicated feed.
    (iii) A copy or description of the label or labeling that will 
accompany the medicated feed.
    (iv) Manufacturing instructions or reference thereto that have been 
determined to yield a properly mixed medicated feed of the specified 
formula for each medicated feed produced on a batch or continuous 
operation basis, including mixing steps, mixing times and, in the case 
of medicated feeds produced by continuous production run, any additional 
manufacturing directions including, when indicated, the settings of 
equipment.
    (v) Appropriate control directions or reference thereto, including 
the manner and frequency of collecting the required number of samples 
for specified laboratory assay.
    (2) The original production record or copy thereof shall be prepared 
by qualified personnel for each batch or run of medicated feed produced 
and shall be retained on the premises for not less than 1 year. The 
production record shall include at least the following:
    (i) Product identification, date of production, and a written 
endorsement in the form of a signature or initials by a responsible 
individual.
    (ii) The quantity and name of drug components used.
    (iii) The theoretical quantity of medicated feed to be produced.
    (iv) The actual quantity of medicated feed produced. In those 
instances where the finished feed is stored in bulk and actual yield 
cannot be accurately determined, the firm shall estimate the quantity 
produced and provide the basis for such estimate in the Master Record 
File.
    (3) In the case of a custom formula feed made to the specifications 
of a customer, the Master Record File and production records required by 
this section shall consist either of such records or of copies of the 
customer's purchase orders and the manufacturer's invoices bearing the 
information required by this section. When a custom order is received by 
telephone, the manufacturer shall prepare the required production 
records.
    (4) Batch production records shall be checked by a responsible 
individual at the end of the working day in which the product was 
manufactured to determine whether all required production steps have 
been performed. If significant discrepancies are noted, an investigation 
shall be instituted immediately, and the production record shall 
describe the corrective action taken.
    (5) Each batch or production run of medicated feed shall be 
identified with its own individual batch or production run number, code, 
date, or other suitable identification applied to the label, package, 
invoice or shipping document. This identification shall permit the 
tracing of the complete and accurate manufacturing history of the 
product by the manufacturer.



Sec.  225.110  Distribution records.

    (a) Distribution records permit the manufacturer to relate 
complaints to specific batches and/or production runs of medicated feed. 
This information may be helpful in instituting a recall.
    (b) Distribution records for each shipment of a medicated feed shall 
comply with the following provisions:
    (1) Each distribution record shall include the date of shipment, the 
name and address of purchaser, the quantity shipped, and the name of the 
medicated feed. A lot or control number, or date of manufacture or other 
suitable identification shall appear on the distribution record or the 
label issued with each shipment.
    (2) The originals or copies of the distribution records shall be 
retained on the premises for not less than one year after the date of 
shipment of the medicated feed.



Sec.  225.115  Complaint files.

    (a) Complaints and reports of experiences of product defects 
relative to the drug's efficacy or safety may provide an indicator as to 
whether or not medicated feeds have been manufactured in

[[Page 196]]

conformity with current good manufacturing practices. These complaints 
and experiences may reveal the existence of manufacturing problems not 
otherwise detected through the normal quality control procedures. Timely 
and appropriate follow-up action can serve to correct a problem and 
minimize future problems.
    (b) The medicated feed manufacturer shall maintain on the premises a 
file which contains the following information:
    (1) The original or copy of a record of each oral and written 
complaint received relating to the safety and effectiveness of the 
product produced. The record shall include the date of the complaint, 
the complainant's name and address, name and lot or control number or 
date of manufacture of the medicated feed involved, and the specific 
details of the complaint. This record shall also include all 
correspondence from the complainant and/or memoranda of conversations 
with the complainant, and a description of all investigations made by 
the manufacturer and of the method of disposition of the complaint.
    (2) For medicated feeds whose manufacture require a medicated feed 
mill license (Form FDA 3448), records and reports of clinical and other 
experience with the drug shall be maintained and reported, under Sec.  
510.301 of this chapter.

[41 FR 52618, Nov. 30, 1976, as amended at 51 FR 7390, Mar. 3, 1986; 57 
FR 6475, Feb. 25, 1992; 64 FR 63203, Nov. 19, 1999]



                   Subpart F_Facilities and Equipment

    Source: 51 FR 7390, Mar. 3, 1986, unless otherwise noted.



Sec.  225.120  Buildings and grounds.

    Buildings used for production of medicated feed shall provide 
adequate space for equipment, processing, and orderly receipt and 
storage of medicated feed. Areas shall include access for routine 
maintenance and cleaning of equipment. Buildings and grounds shall be 
constructed and maintained in a manner to minimize vermin and pest 
infestation.



Sec.  225.130  Equipment.

    Equipment shall be capable of producing a medicated feed of intended 
potency and purity, and shall be maintained in a reasonably clean and 
orderly manner. Scales and liquid metering devices shall be accurate and 
of suitable size, design, construction, precision, and accuracy for 
their intended purposes. All equipment shall be designed, constructed, 
installed, and maintained so as to facilitate inspection and use of 
cleanout procedure(s).



Sec.  225.135  Work and storage areas.

    Work areas and equipment used for the production or storage of 
medicated feeds or components thereof shall not be used for, and shall 
be physically separated from, work areas and equipment used for the 
manufacture and storage of fertilizers, herbicides, insecticides, 
fungicides, rodenticides, and other pesticides unless such articles are 
approved or index listed for use in the manufacture of animal feed.

[72 FR 69120, Dec. 6, 2007]



                   Subpart G_Product Quality Assurance

    Source: 51 FR 7390, Mar. 3, 1986, unless otherwise noted.



Sec.  225.142  Components.

    Adequate procedures shall be established and maintained for the 
identification, storage, and inventory control (receipt and use) of all 
Type A medicated articles and Type B medicated feeds intended for use in 
the manufacture of medicated feeds to aid in assuring the identity, 
strength, quality, and purity of these drug sources. Packaged Type A 
medicated articles and Type B medicated feeds shall be stored in 
designated areas in their original closed containers. Bulk Type A 
medicated articles and bulk Type B medicated feeds shall be identified 
and stored in a manner such that their identity, strength, quality, and 
purity will be maintained. All Type A medicated articles and Type B 
medicated feeds shall be used in accordance with their labeled mixing 
directions.

[[Page 197]]



Sec.  225.158  Laboratory assays.

    Where the results of laboratory assays of drug components, including 
assays by State feed control officials, indicate that the medicated feed 
is not in accord with the permissible limits specified in this chapter, 
investigation and corrective action shall be implemented immediately by 
the firm and such records shall be maintained on the premises for a 
period of 1 year.



Sec.  225.165  Equipment cleanout procedures.

    Adequate procedures shall be established and used for all equipment 
used in the production and distribution of medicated feeds to avoid 
unsafe contamination of medicated and nonmedicated feeds.



                           Subpart H_Labeling



Sec.  225.180  Labeling.

    Labels shall be received, handled, and stored in a manner that 
prevents label mixups and assures that the correct labels are used for 
the medicated feed. All deliveries of medicated feeds, whether bagged or 
in bulk, shall be adequately labeled to assure that the feed can be 
properly used.

[51 FR 7390, Mar. 3, 1986]



                            Subpart I_Records



Sec.  225.202  Formula, production, and distribution records.

    Records shall be maintained identifying the formulation, date of 
mixing, and if not for own use, date of shipment. The records shall be 
adequate to facilitate the recall of specific batches of medicated feed 
that have been distributed. Such records shall be retained on the 
premises for 1 year following the date of last distribution.

(Approved by the Office of Management and Budget under control number 
0910-0152)

[51 FR 7390, Mar. 3, 1986]



PART 226_CURRENT GOOD MANUFACTURING PRACTICE FOR TYPE A MEDICATED 
ARTICLES--Table of Contents



                      Subpart A_General Provisions

Sec.
226.1 Current good manufacturing practice.
226.10 Personnel.

   Subpart B_Construction and Maintenance of Facilities and Equipment

226.20 Buildings.
226.30 Equipment.

                    Subpart C_Product Quality Control

226.40 Production and control procedures.
226.42 Components.
226.58 Laboratory controls.

                    Subpart D_Packaging and Labeling

226.80 Packaging and labeling.

                      Subpart E_Records and Reports

226.102 Master-formula and batch-production records.
226.110 Distribution records.
226.115 Complaint files.

    Authority: 21 U.S.C. 351, 352, 360b, 371, 374.

    Source: 40 FR 14031, Mar. 27, 1975, unless otherwise noted.



                      Subpart A_General Provisions



Sec.  226.1  Current good manufacturing practice.

    (a) The criteria in Sec. Sec.  226.10 through 226.115, inclusive, 
shall apply in determining whether the methods used in, or the 
facilities and controls used for the manufacture, processing, packing, 
or holding of a Type A medicated article(s) conform to or are operated 
or administered in conformity with current good manufacturing practice 
to assure that a Type A medicated article(s) meets the requirements of 
the act as to safety, and has the identity and strength, and meets the 
quality and purity characteristics which it purports or is represented 
to possess, as required by section 501(a)(2)(B) of the act. The 
regulations in this part 226 permit the use of precision, automatic, 
mechanical, or electronic equipment in the production of a Type A 
medicated article(s) when adequate inspection

[[Page 198]]

and checking procedures or other quality control procedures are used to 
assure proper performance.
    (b) In addition to maintaining records and reports required in this 
part, Type A medicated articles requiring approved NADAs are subject to 
the requirements of Sec.  514.80 of this chapter. Similarly, Type A 
medicated articles listed in the index are subject to the requirements 
of Sec.  516.165 of this chapter.

[40 FR 14031, Mar. 27, 1975, as amended at 68 FR 15364, Mar. 31, 2003; 
72 FR 69120, Dec. 6, 2007]



Sec.  226.10  Personnel.

    The key personnel and any consultants involved in the manufacture 
and control of the Type A medicated article(s) shall have a background 
of appropriate education or appropriate experience or combination 
thereof for assuming responsibility to assure that the Type A medicated 
article(s) has the proper labeling and the safety, identity, strength, 
quality, and purity that it purports to possess.



   Subpart B_Construction and Maintenance of Facilities and Equipment



Sec.  226.20  Buildings.

    Buildings in which Type A medicated article(s) are manufactured, 
processed, packaged, labeled, or held shall be maintained in a clear and 
orderly manner and shall be of suitable size, construction and location 
in relation to surroundings to facilitate maintenance and operation for 
their intended purpose. The building shall:
    (a) Provide adequate space for the orderly placement of equipment 
and materials used in any of the following operations for which they are 
employed to minimize risk of mixups between different Type A medicated 
article(s), their components, packaging, or labeling:
    (1) The receipt, sampling, control, and storage of components.
    (2) Manufacturing and processing operations performed on the Type A 
medicated article(s).
    (3) Packaging and labeling operations.
    (4) Storage of containers, packaging materials, labeling, and 
finished products.
    (5) Control laboratory operations.
    (b) Provide adequate lighting and ventilation, and when necessary 
for the intended production or control purposes, adequate screening, 
dust and temperature controls, to avoid contamination of Type A 
medicated article(s), and to avoid other conditions unfavorable to the 
safety, identity, strength, quality, and purity of the raw materials and 
Type A medicated article(s) before, during, and after production.
    (c) Provide for adequate washing, cleaning, toilet, and locker 
facilities.

Work areas and equipment used for the production of Type A medicated 
article(s) or for the storage of the components of Type A medicated 
article(s) shall not be used for the production, mixing or storage of 
finished or unfinished insecticides, fungicides, rodenticides, or other 
pesticides or their components unless such materials are recognized as 
approved drugs intended for use in animal feeds.



Sec.  226.30  Equipment.

    Equipment used for the manufacture, processing, packaging, bulk 
shipment, labeling, holding, or control of Type A medicated article(s) 
or their components shall be maintained in a clean and orderly manner 
and shall be of suitable design, size, construction, and location to 
facilitate maintenance and operation for its intended purpose. The 
equipment shall:
    (a) Be so constructed that any surfaces that come into contact with 
Type A medicated article(s) are suitable, in that they are not reactive, 
additive, or absorptive to an extent that significantly affects the 
identity, strength, quality, or purity of the Type A medicated 
article(s) or its components.
    (b) Be so constructed that any substance required for the operation 
of the equipment, such as lubricants, coolants, etc., may be employed 
without hazard of becoming an unsafe additive to the Type A medicated 
article(s).
    (c) Be constructed to facilitate adjustment, cleaning, and 
maintenance, and to assure uniformity of production and reliability of 
control procedures

[[Page 199]]

and to assure the exclusion from Type A medicated article(s) of 
contamination, including cross-contamination from manufacturing 
operations.
    (d) Be suitably grounded electrically to prevent lack of uniform 
mixing due to electrically charged particles.
    (e) Be of suitable size and accuracy for use in any intended 
measuring, mixing, or weighing operations.



                    Subpart C_Product Quality Control



Sec.  226.40  Production and control procedures.

    Production and control procedures shall include all reasonable 
precautions, including the following, to assure that the Type A 
medicated article(s) produced have the identity, strength, quality, and 
purity they purport to possess:
    (a) Each critical step in the process, such as the selection, 
weighing, and measuring of components; the addition of drug components 
during the process; weighing and measuring during various stages of the 
processing; and the determination of the finished yield, shall be 
performed by one or more competent, responsible individuals. If such 
steps in the processing are controlled by precision, automatic, 
mechanical, or electronic equipment, their proper performance shall be 
adequately checked by one or more competent, responsible individuals.
    (b) All containers to be used for undiluted drugs, drug components, 
intermediate mixtures thereof, and Type A medicated article(s) shall be 
received, adequately identified, and properly stored and handled in a 
manner adequate to avoid mixups and contamination.
    (c) Equipment, including dust-control and other equipment, such as 
that used for holding and returning recovered or flush-out materials 
back into production, shall be maintained and operated in a manner to 
avoid contamination of the Type A medicated article(s) and to insure the 
integrity of the finished product.
    (d) Competent and responsible personnel shall check actual against 
theoretical yield of a batch of Type A medicated article(s), and, in the 
event of any significant discrepancies, key personnel shall prevent 
distribution of the batch in question and other associated batches of 
Type A medicated article(s) that may have been involved in a mixup with 
it.
    (e) Adequate procedures for cleaning of those parts of storage, 
mixing conveying and other equipment coming in contact with the drug 
component of the Type A medicated article(s) shall be used to avoid 
contamination of Type A medicated article(s).
    (f) If there is sequential production of batches of a Type A 
medicated article(s) containing the same drug component (or components) 
at the same or lower levels, there shall be sufficient safeguards to 
avoid any buildup above the specified levels of the drug components in 
any of the batches of the Type A medicated article(s).
    (g) Production and control procedures shall include provision for 
discontinuing distribution of any Type A medicated article(s) found by 
the assay procedures, or other controls performed to fail to conform to 
appropriate specifications. Distribution of subsequent production of 
such Type A medicated article(s) shall not begin until it has been 
determined that proper control procedures have been established.



Sec.  226.42  Components.

    (a) Drug components, including undiluted drugs and any intermediate 
mixes containing drugs used in the manufacture and processing of Type A 
medicated article(s), shall be received, examined or tested, stored, 
handled, and otherwise controlled in a manner to maintain the integrity 
and identification of such articles. Appropriate receipt and inventory 
records shall be maintained for 2 years, and such records shall show the 
origin of any drug components, the manufacturer's control number (if 
any), the dates and batches in which they were used, and the results of 
any testing of them.
    (b) Nondrug components shall be stored and otherwise handled in a 
manner to avoid contamination, including cross-contamination from 
manufacturing operations.

[[Page 200]]



Sec.  226.58  Laboratory controls.

    Laboratory controls shall include the establishment of adequate 
specifications and test procedures to assure that the drug components 
and the Type A medicated article(s) conform to appropriate standards of 
identity, strength, quality, and purity. Laboratory controls shall 
include:
    (a) The establishment of master records containing appropriate 
specifications and a description of the test procedures used to check 
them for each kind of drug component used in the manufacture of Type A 
medicated article(s). This may consist of the manufacturer's or 
supplier's statement of specifications and methods of analyses.
    (b) The establishment of specifications for Type A medicated 
article(s) and a description of necessary laboratory test procedures to 
check such specifications.
    (c) Assays which shall be made of representative samples of finished 
Type A medicated article(s) in accordance with the following schedule:
    (1) Each batch of a Type A medicated article(s) manufactured from an 
undiluted drug shall be assayed for its drug component(s).
    (2) In the case of Type A medicated article(s) which are 
manufactured by dilution of Type A medicated article(s) assayed in 
accordance with paragraph (c)(1) of this section, each batch shall be 
assayed for its drug component(s) with the first five consecutive 
batches assaying within the limitations, followed thereafter by assay of 
representative samples of not less than 5 percent of all batches 
produced. When any batch does not assay within limitations, each batch 
should again be assayed until five consecutive batches are within 
limitations.
    (d) A determination establishing that the drug components remain 
uniformly dispersed and stable in the Type A medicated article(s) under 
ordinary conditions of shipment, storage, and use. This may consist of a 
determination on a Type A medicated article(s) of substantially the same 
formula and characteristics. Suitable expiration dates shall appear on 
the labels of the Type A medicated article(s) to assure that the 
articles meet the appropriate standards of identity, strength, quality, 
and purity at the time of use.
    (e) Adequate provision to check the reliability, accuracy, and 
precision of any laboratory test procedure used. The official methods in 
``Methods of Analysis of the Association of Official Analytical 
Chemists,'' \1\ methods described in an official compendium, and any 
method submitted as a part of a food additive petition or new-drug 
application that has been accepted by the Food and Drug Administration 
shall be regarded as meeting this provision.
---------------------------------------------------------------------------

    \1\ Copies may be obtained from: AOAC INTERNATIONAL, 481 North 
Frederick Ave., suite 500, Gaithersburg, MD 20877.
---------------------------------------------------------------------------

    (f) Provisions for the maintenance of the results of any assays, 
including dates and endorsement of analysts. Such records shall be 
retained in the possession of the manufacturer and shall be maintained 
for a period of at least 2 years after distribution by the manufacturer 
of the Type A medicated article(s) has been completed.

[40 FR 14031, Mar. 27, 1975, as amended at 55 FR 11577, Mar. 29, 1990; 
55 FR 23703, June 12, 1990; 70 FR 40880, July 15, 2005; 70 FR 67651, 
Nov. 8, 2005]



                    Subpart D_Packaging and Labeling



Sec.  226.80  Packaging and labeling.

    (a) Packaging and labeling operations shall be adequately 
controlled:
    (1) To assure that only those Type A medicated article(s) that have 
met the specifications established in the master-formula records shall 
be distributed.
    (2) To prevent mixups during the packaging and labeling operations.
    (3) To assure that correct labeling is employed for each Type A 
medicated article(s).
    (4) To identify Type A medicated article(s) with lot or control 
numbers that permit determination of the history of the manufacture and 
control of the batch of Type A medicated article(s).
    (b) Packaging and labeling operations shall provide:
    (1) For storage of labeling in a manner to avoid mixups.

[[Page 201]]

    (2) For careful checking of labeling for identity and conformity to 
the labeling specified in the batch-production records.
    (3) For adequate control of the quantities of labeling issued for 
use with the Type A medicated article(s).
    (c) Type A medicated article(s) shall be distributed in suitable 
containers to insure the safety, identity, strength, and quality of the 
finished product.



                      Subpart E_Records and Reports



Sec.  226.102  Master-formula and batch-production records.

    (a) For each Type A medicated article(s) master-formula records 
shall be prepared, endorsed, and dated by a competent and responsible 
individual and shall be independently checked, reconciled, endorsed, and 
dated by a second competent and responsible individual. The record shall 
include:
    (1) The name of the Type A medicated article(s) and a specimen copy 
of its label.
    (2) The weight or measure of each ingredient, adequately identified, 
to be used in manufacturing a stated weight of the Type A medicated 
article(s).
    (3) A complete formula for each batch size, or of appropriate size 
in the case of continuous systems to be produced from the master-formula 
record, including a complete list of ingredients designated by names or 
codes sufficiently specific to indicate any special quality 
characteristics; an accurate statement of the weight or measure of each 
ingredient, except that reasonable variations may be permitted in the 
amount of ingredients necessary in the preparation of the Type A 
medicated article(s), provided that the variations are stated in the 
master formula; an appropriate statement concerning any calculated 
excess of an ingredient; and a statement of the theoretical yield.
    (4) Manufacturing instructions for each type of Type A medicated 
article(s) produced on a batch or continuous operation basis, including 
mixing steps and mixing times that have been determined to yield an 
adequately mixed Type A medicated article(s); and in the case of Type A 
medicated article(s) produced by continuous production run, any 
additional manufacturing directions including, when indicated, the 
settings of equipment that have been determined to yield an adequately 
mixed Type A medicated article(s) of the specified formula.
    (5) Control instructions, procedures, specifications, special 
notations, and precautions to be followed.
    (b) A separate batch-production and control record shall be prepared 
for each batch or run of Type A medicated article(s) produced and shall 
be retained for at least 2 years after distribution by the manufacturer 
has been completed. The batch-production and control record shall 
include:
    (1) Product identification, date of production, and endorsement by a 
competent and responsible individual.
    (2) Records of each step in the manufacturing, packaging, labeling, 
and controlling of the batch, including dates, specific identification 
of drug components used, weights or measures of all components, 
laboratory-control results, mixing times, and the endorsements of the 
individual actively performing or the individual actively supervising or 
checking each step in the operation.
    (3) A batch number that permits determination of all laboratory-
control procedures and results on the batch and all lot or control 
numbers appearing on the labels of the Type A medicated article(s).



Sec.  226.110  Distribution records.

    Complete records shall be maintained for each shipment of Type A 
medicated article(s) in a manner that will facilitate the recall, 
diversion, or destruction of the Type A medicated article(s), if 
necessary. Such records shall be retained for at least 2 years after the 
date of the shipment by the manufacturer and shall include the name and 
address of the consignee, the date and quantity shipped, and the 
manufacturing dates, control numbers, or marks identifying the Type A 
medicated article(s) shipped.



Sec.  226.115  Complaint files.

    Records shall be maintained for a period of 2 years of all written 
or verbal complaints concerning the safety or efficacy of each Type A 
medicated article(s). Complaints shall be evaluated

[[Page 202]]

by competent and responsible personnel and, where indicated, appropriate 
action shall be taken. The record shall indicate the evaluation and the 
action.



PART 250_SPECIAL REQUIREMENTS FOR SPECIFIC HUMAN DRUGS--Table of Contents



                 Subpart A_Drugs Regarded as Misbranded

Sec.
250.11 Thyroid-containing drug preparations intended for treatment of 
          obesity in humans.
250.12 Stramonium preparations labeled with directions for use in self-
          medication regarded as misbranded.

       Subpart B_New Drug or Prescription Status of Specific Drugs

250.100 Amyl nitrite inhalant as a prescription drug for human use.
250.101 Amphetamine and methamphetamine inhalers regarded as 
          prescription drugs.
250.102 Drug preparations intended for human use containing certain 
          ``coronary vasodilators''.
250.103-250.104 [Reserved]
250.105 Gelsemium-containing preparations regarded as prescription 
          drugs.
250.106-250.107 [Reserved]
250.108 Potassium permanganate preparations as prescription drugs.

               Subpart C_Requirements for Drugs and Foods

250.201 Preparations for the treatment of pernicious anemia.

             Subpart D_Requirements for Drugs and Cosmetics

250.250 Hexachlorophene, as a component of drug and cosmetic products.

    Authority: 21 U.S.C. 321, 336, 342, 352, 353, 355, 361(a), 362(a) 
and (c), 371, 375(b).

    Source: 40 FR 14033, Mar. 27, 1975, unless otherwise noted.



                 Subpart A_Drugs Regarded as Misbranded



Sec.  250.11  Thyroid-containing drug preparations intended for 
treatment of obesity in humans.

    (a) Investigation by the Food and Drug Administration has revealed 
that a large number of drug preparations containing thyroid or 
thyrogenic substances in combination with central nervous system 
stimulants, with or without one or more additional drug substances such 
as barbiturates or laxatives, are being marketed for or as adjuncts to 
the treatment, control, or management of obesity in humans. The 
Commissioner of Food and Drugs finds that the administration of such 
combinations for said purposes is without medical rationale except 
possibly in those relatively uncommon instances where the condition is 
directly related to hypothyroidism and there exists a concurrent need 
for appetite control (in such instances the safety and effectiveness of 
such combinations are not generally recognized). In particular, the 
Commissioner of Food and Drugs finds that neither the consensus of 
informed medical opinion nor clinical experience justifies any 
representation that such combinations are safe and effective in 
connection with the treatment, control, or management of obesity in 
patients having normal thyroid function.
    (b) Combinations of thyroid or other thyrogenic drugs with central 
nervous system stimulants with or without other drug substances when 
offered for or as adjuncts to the treatment, control, or management of 
obesity not related to hypothyroidism are regarded as misbranded. Such 
combinations when offered for obesity in humans directly attributable to 
established hypothyroidism are regarded as new drugs within the meaning 
of section 201(p) of the Federal Food, Drug, and Cosmetic Act.



Sec.  250.12  Stramonium preparations labeled with directions for use 
in self-medication regarded as misbranded.

    (a) Stramonium products for inhalation have been offered for use in 
the therapy of the acute attacks of bronchial asthma for many years 
although their reliability and effectiveness are questionable. Recently, 
a significantly increased number of reports have come to the attention 
of the Food and Drug Administration showing that such products have been 
subject to abuse and misuse on a fairly large scale, mostly by young 
people, through oral

[[Page 203]]

ingestion for the purpose of producing hallucinations. Reports of such 
use have been received from physicians and police and other law 
enforcement authorities. Reports have also appeared in the public press 
and in medical journals.
    (b) Labeling these products with a warning that they are not for 
oral ingestion has not been effective in protecting the public. Misuse 
of stramonium preparations can cause serious toxic effects including 
toxic delirium, visual disturbances, fever, and coma. A number of 
serious reactions have already occurred from the oral ingestion of such 
products.
    (c) On the basis of this information, the Commissioner of Food and 
Drugs has concluded that such articles have a potentiality for harmful 
effect through misuse and are not safe for use except under the 
supervision of a physician. In the interest of public health protection, 
therefore, the Food and Drug Administration adopts the following policy:
    (1) Preparations containing stramonium supplied from the leaves, 
seeds, or any other part of the plant in the form of a powder, pipe 
mixture, cigarette, or any other form, with or without admixture of 
other ingredients, will be regarded as misbranded if they are labeled 
with directions for use in self-medication.
    (2) The Food and Drug Administration will, on request, furnish 
comment on proposed labeling limiting any such preparation to 
prescription sale.
    (d) The labeling or dispensing of stramonium preparations contrary 
to this statement after 60 days following the date of its publication in 
the Federal Register may be made the subject of regulatory proceedings.



       Subpart B_New Drug or Prescription Status of Specific Drugs



Sec.  250.100  Amyl nitrite inhalant as a prescription drug for human
use.

    (a) Amyl nitrite inhalant has been available over-the-counter for 
emergency use by the patient in the management of angina pectoris for a 
number of years. As a result of a proposed policy statement published 
August 25, 1967 (32 FR 12404), the Commissioner of Food and Drugs 
received reports of the abuse of this drug by those who do not require 
it for medical purposes. Additionally, comment included a great deal of 
concern expressed by individual physicians, medical associations, 
pharmaceutical associations, manufacturers, and State and local health 
authorities. Based on the information available, it is the opinion of 
the Commissioner of Food and Drugs, concurred in by the Food and Drug 
Administration Medical Advisory Board, that amyl nitrite inhalant is a 
drug with a potentiality for harmful effect and that it should be 
removed from over-the-counter status and restricted to sale on the 
prescription of a practitioner licensed by law to administer such drug.
    (b) Therefore, amyl nitrite inhalant will be regarded as misbranded 
unless the labeling on or within the package from which the drug is to 
be dispensed bears adequate information for its safe and effective use 
by physicians, in accordance with Sec.  201.100(c) of this chapter, and 
its label bears the statement ``Rx only.''
    (c) Regulatory proceedings may be initiated with regard to the 
interstate shipment of amyl nitrite inhalant that is labeled, 
advertised, or dispensed contrary to this statement of policy if such 
act occurs after July 1, 1969.

[40 FR 14033, Mar. 27, 1975, as amended at 67 FR 4906, Feb. 1, 2002]



Sec.  250.101  Amphetamine and methamphetamine inhalers regarded as 
prescription drugs.

    (a) Recurring reports of abuse and misuse of methamphetamine (also 
known as desoxyephedrine) inhalers show that they have a potentiality 
for harmful effect and that they should not be freely available to the 
public through over-the-counter sale. From complaints by law-enforcement 
officials, health officials, individual physicians, parents, and others 
as well as from Food and Drug Administration investigations, it is 
evident that the wicks from these inhalers are being removed and the 
methamphetamine they contain is being used as a substitute for 
amphetamine tablets. Amphetamine tablets and amphetamine inhalers have 
been restricted to prescription

[[Page 204]]

sale because of their potentiality for harm to the user.
    (b) It is the considered opinion of the Food and Drug Administration 
that, in order to adequately protect the public health, inhalers 
containing methamphetamine or methamphetamine salts (d-desoxyephedrine, 
or dl-desoxyephedrine, or their salts), as well as amphetamine inhalers 
should be restricted to prescription sale and should be labeled with the 
statement ``Rx only.''

[40 FR 14033, Mar. 27, 1975, as amended at 67 FR 4906, Feb. 1, 2002]



Sec.  250.102  Drug preparations intended for human use containing
certain ``coronary vasodilators''.

    (a)(1) The Food and Drug Administration finds that the following 
``coronary vasodilators'' are extensively regarded by physicians as safe 
and useful as employed under medical supervision for the management of 
angina pectoris in some patients:

Amyl nitrite.
Erythrityl tetranitrate.
Mannitol hexanitrate.
Nitroglycerin.
Potassium nitrite.
Sodium nitrite.

    (2) Additionally, new-drug applications have been approved for 
products containing:

Inositol hexanitrate.
Isosorbide dinitrate.
Octyl nitrite.
Pentaerythritol tetranitrate.
Triethanolamine trinitrate biphosphate (trolnitrate phosphate).

    (b) The Food and Drug Administration also finds that there is 
neither substantial evidence of effectiveness nor a general recognition 
by qualified experts that such drugs are effective for any of the other 
purposes for which some such drugs are promoted to the medical 
profession in labeling and advertising. In particular, neither clinical 
investigations nor clinical experience justify any representations that 
such drugs are effective in the management of hypertension; in the 
management of coronary insufficiency or coronary artery disease, except 
for their anginal manifestations; or in the management of the post 
coronary state, except angina pectoris present after coronary occlusion 
and myocardial infarction.
    (c) Any preparation containing such drugs that is labeled or 
advertised for any use other than management of angina pectoris, or that 
is represented to be efficacious for any other purpose by reason of its 
containing such drug, will be regarded by the Food and Drug 
Administration as misbranded and subject to regulatory proceedings, 
unless such recommendations are covered by the approval of a new-drug 
application based on a showing of safety and effectiveness.
    (d) Any such drug in long-acting dosage form is regarded as a new 
drug that requires an approved new-drug application before marketing.
    (e) Any of the drugs listed in paragraph (a)(2) of this section is 
regarded as a new drug that requires an approved new-drug application. 
Articles for which new-drug approvals are now in effect should be 
covered by supplemental new-drug applications as necessary to provide 
for labeling revisions consistent with this policy statement.



Sec. Sec.  250.103-250.104  [Reserved]



Sec.  250.105  Gelsemium-containing preparations regarded as 
prescription drugs.

    It is the consensus of informed medical opinion that the margin of 
safety between the therapeutic and toxic concentration of gelsemium is 
narrow and it is difficult to predict the point at which the dose will 
be toxic. Very small doses may cause toxic symptoms. It is therefore the 
view of the Food and Drug Administration that gelsemium is not a proper 
ingredient in any product that is to be sold without prescription. 
Accordingly, any drug containing gelsemium will be regarded as 
misbranded under section 503(b)(4) of the Federal Food, Drug, and 
Cosmetic Act if its label fails to bear in a prominent and conspicuous 
fashion the statement ``Rx only.''

[40 FR 14033, Mar. 27, 1975, as amended at 67 FR 4906, Feb. 1, 2002]

[[Page 205]]



Sec. Sec.  250.106-250.107  [Reserved]



Sec.  250.108  Potassium permanganate preparations as prescription drugs.

    (a) There have been a number of reports in the medical literature of 
serious injuries to women resulting from the misuse of potassium 
permanganate in an effort to induce abortion. Reports from physicians 
who have treated such cases show that the injuries are commonly caused 
by introducing tablets or crystals of potassium permanganate into the 
vagina. Experience with these cases shows that such use of potassium 
permanganate is not effective in producing abortion, but that instead 
the drug produces serious and painful injury to the walls of the vagina, 
causing ulcers, massive hemorrhage, and infection. Such dangerous and 
useless employment of potassium permanganate is apparently encouraged 
among the misinformed by the mistaken idea that the vaginal bleeding 
caused by the corrosive action of the drug indicates a termination of 
pregnancy, which it does not.
    (b) Potassium permanganate is a strong oxidizing agent, a highly 
caustic, tissue-destroying chemical, and a poison. There are no 
circumstances under which crystals and tablets of potassium permanganate 
constitute safe dosage forms for use in self-medication. It is the 
consensus of informed medical opinion that the only dosage forms of 
potassium permanganate known to be safe for use in self-medication are 
aqueous solutions containing not more than 0.04 percent potassium 
permanganate. Such solutions are safe for use in self-medication only by 
external application to the skin.
    (c) In view of the very real potentiality for harmful effect, and 
the actual injuries caused by the misuse of potassium permanganate, the 
Food and Drug Administration believes that in order adequately to 
protect the public health:
    (1) Potassium permanganate and potassium permanganate tablets 
intended for human use are drugs subject to section 503(b)(1) of the 
Federal Food, Drug, and Cosmetic Act and should be restricted to 
prescription sale. Such drugs will be regarded as misbranded if at any 
time prior to dispensing the label fails to bear the statement ``Rx 
only.''
    (2) Potassium permanganate labeled for use as a prescription 
component in human drugs under the exemption provided in Sec.  201.120 
of this chapter or labeled for manufacturing use under the exemption 
provided in Sec.  201.122 of this chapter will be regarded as misbranded 
unless the label bears the statement, ``Rx only.''
    (3) These drugs will be regarded as misbranded when intended for 
veterinary use unless the label bears the legend, ``Caution: Federal law 
restricts this drug to sale by or on the order of a licensed 
veterinarian''; Provided, however, That this shall not apply to a drug 
labeled and marketed for veterinary use if such drug contains not more 
than 50 percent of potassium permanganate and includes other ingredients 
which make it unsuitable for human use and unlikely that the article 
would be used in an attempt to induce abortion.
    (4) Any preparation of potassium permanganate intended for over-the-
counter sale for human use internally or by application to any mucous 
membranes or for use in the vagina will be regarded as misbranded under 
the provisions of section 502(f) (1) and (2) and section 502(j) of the 
act.
    (5) Any other preparation of potassium permanganate intended for 
over-the-counter sale for human use will be regarded as misbranded under 
section 502(f) (1) and (2) and section 502(j) of the act unless, among 
other things, all of the following conditions are met:
    (i) It is an aqueous solution containing not more than 0.04 percent 
potassium permanganate.
    (ii) The label and labeling bear, in juxtaposition with adequate 
directions for use, clear warning statements designated as ``Warning,'' 
and to the effect: ``Warning--For external use on the skin only. Severe 
injury may result from use internally or as a douche. Avoid contact with 
mucous membranes.''
    (d) The labeling or dispensing of any potassium permanganate 
preparations intended for drug use within the jurisdiction of the 
Federal Food, Drug, and Cosmetic Act contrary to this statement after 60 
days from the date of its

[[Page 206]]

publication in the Federal Register may be made the subject of 
regulatory proceedings.

[40 FR 14033, Mar. 27, 1975, as amended at 67 FR 4906, Feb. 1, 2002]



               Subpart C_Requirements for Drugs and Foods



Sec.  250.201  Preparations for the treatment of pernicious anemia.

    (a) The ninth announcement of the Anti-anemia Preparations Advisory 
Board of the United States Pharmacopeia is concerned with the status of 
the treatment of pernicious anemia. It clearly presents the following 
facts:
    (1) The Sixteenth Revision of the Pharmacopeia of the United States, 
which became official on October 1, 1960, does not include preparations 
intended for the treatment of pernicious anemia by oral administration.
    (2) The U.S.P. unit for anti-anemia preparations no longer has any 
significance.
    (3) The U.S.P. Anti-anemia Preparations Advisory Board was 
disbanded.
    (b) On the basis of the scientific evidence and conclusions 
summarized in the statement of the U.S.P. Anti-anemia Preparations 
Advisory Board as well as pertinent information from other sources, the 
Commissioner of Food and Drugs finds it is the consensus of well 
informed medical opinion that:
    (1) The parenteral administration of cyanocobalamin or vitamin 
B12 is generally recognized as a fully effective treatment of 
pernicious anemia. Parenteral cyanocobalamin preparations have not been 
and are not authorized for use except by or on the prescription of a 
duly licensed medical practitioner.
    (2) Some patients afflicted with pernicious anemia do not respond to 
orally ingested products. There is no known way to predict which 
patients will fail to respond or will cease to respond to the treatment 
of pernicious anemia with orally ingested preparations.
    (3) The substitution of a possibly inadequate treatment, such as the 
ingestion of oral preparations of vitamin B12 with intrinsic 
factor concentrate, in place of parenteral vitamin B12 
products for a disease condition as serious as pernicious anemia cannot 
be regarded as safe in all cases.
    (4) The development of the classical symptoms of pernicious anemia 
that would cause a person to seek medical attention may in some cases be 
delayed by oral ingestion of intrinsic factor. Pernicious anemia is a 
disease that is associated, among other things, with a higher than 
normal incidence of cancer of the stomach and that for the safety of the 
patient, requires continuous expert medical supervision.
    (5) With inadequate treatment there may be markedly deleterious 
effects on the nervous system. It is well established that whereas the 
development of anemia is completely reversible with adequate treatment, 
the involvement of the nervous system may not be completely reversible 
and thus may result in permanent damage.
    (6) Some hematologists prescribe oral preparations of vitamin 
B12 in the treatment of pernicious-anemia patients.
    (7) Intrinsic factor and intrinsic factor concentrate serve no known 
useful therapeutic or nutritive purpose except to the extent that they 
do increase the gastrointestinal absorption of vitamin B12 in 
patients with a deficiency or absence of intrinsic factor, which may 
eventually lead to pernicious anemia. This conclusion does not apply to 
diagnostic procedures using radioactive cyanocobalamin.
    (8) Medical expertise is required for the diagnosis as well as the 
management of pernicious anemia.
    (c) The Eleventh Edition of The National Formulary and its first 
Interim Revision include monographs for oral preparations of vitamin 
B12 with intrinsic factor concentrate, establish a unit of 
vitamin B12 with intrinsic factor concentrate, and provide 
for a National Formulary Anti-anemia Preparations Advisory Board to 
assign the potency of such preparations. This provides for the 
availability of such oral preparations, standardized within the meaning 
of the broad limits characteristic of the evaluation of such 
preparations.
    (d) Any drug that is offered for or purports to contain intrinsic 
factor or

[[Page 207]]

intrinsic factor concentrate will be regarded as misbranded within the 
meaning of section 503(b) of the Federal Food, Drug, and Cosmetic Act 
unless it is labeled with the statement ``Rx only.''
    (e) Any drug for oral ingestion intended, represented, or advertised 
for the prevention or treatment of pernicious anemia or which purports 
to contain any substance or mixture of substances described in paragraph 
(d) of this section (other than diagnostic drugs containing radioactive 
cyanocobalamin) will be regarded as misbranded under sections 502 (f)(2) 
and (j) of the act unless its labeling bears a statement to the effect 
that some patients afflicted with pernicious anemia may not respond to 
the orally ingested product and that there is no known way to predict 
which patients will respond or which patients may cease to respond to 
the orally ingested products. The labeling shall also bear a statement 
that periodic examinations and laboratory studies of pernicious anemia 
patients are essential and recommended.
    (f) Under section 409 of the Federal Food, Drug, and Cosmetic Act, 
intrinsic factor and intrinsic factor concentrate are regarded as food 
additives. No food additive regulation nor existing extension of the 
effective date of section 409 of the act authorizes these additives in 
foods, including foods for special dietary uses. Any food containing 
added intrinsic factor or intrinsic factor concentrate will be regarded 
as adulterated within the meaning of section 402(a)(2)(C) of the act.
    (g) Regulatory action may be initiated with respect to any article 
shipped within the jurisdiction of the act contrary to the provisions of 
this policy statement after the 180th day following publication of this 
statement in the Federal Register.

[40 FR 14033, Mar. 27, 1975, as amended at 67 FR 4906, Feb. 1, 2002]



             Subpart D_Requirements for Drugs and Cosmetics



Sec.  250.250  Hexachlorophene, as a component of drug and cosmetic 
products.

    (a) Antibacterial component. The use of hexachlorophene as an 
antibacterial component in drug and cosmetic products has expanded 
widely in recent years. It is used in such products because of its 
bacteriostatic action against gram-positive organisms, especially 
against strains of staphylococcus; however, hexachlorophene offers no 
protection against gram-negative infections. In addition the 
antibacterial activity depends largely on repeated use. A notice 
published in the Federal Register of April 4, 1972 (37 FR 6775), invited 
data on OTC antimicrobial ingredients, including hexachlorophene, for 
review by an OTC Drug Advisory Review Panel to be convened under the 
procedures set forth in the Federal Register of May 11, 1972 (37 FR 
9464). This statement of policy will remain in effect unless and until 
replaced by a monograph resulting from the OTC Drug Advisory Review 
Panel.
    (b) Adverse effects. Though considered safe for many years, recent 
information has become available associating hexachlorophene with toxic 
effects, including deaths. Studies have shown that toxic amounts of 
hexachlorophene can be absorbed through the skin of humans, especially 
the skin of premature babies or damaged skin. Human toxicity reports 
include data on symptomatology, blood and tissue levels of 
hexachlorophene, and descriptions of neuropathologic lesions. Recent 
infant deaths due to use of baby powder accidentally contaminated with 6 
percent hexachlorophene have occurred. The accumulated evidence of 
toxicity is sufficient to require that continued marketing of 
hexachlorophene containing products be carefully defined in order to 
protect consumers.
    (c) Prescription drugs. (1) Because of their potential for harmful 
effect, drugs containing hexachlorophene, other than as a preservative 
as described below, are not considered to

[[Page 208]]

have been shown to be safe and effective, are regarded as new drugs 
requiring approved new drug applications, and would be misbranded for 
over-the-counter distribution. In the interest of public health 
protection, hexachlorophene containing drugs will be regarded as 
misbranded and subject to regulatory proceedings unless the label bears 
the statement ``Rx only,'' and the labeling on or within the package 
from which the drug is to be dispensed bears adequate information for 
its safe and effective use by practitioners, in accord with Sec.  
201.100(c) of this chapter.
    (2) The Food and Drug Administration recognizes that hexachlorophene 
is useful as a bacteriostatic skin cleanser. It further concludes that 
the margin of safety is such that products containing hexachlorophene 
may appropriately be used within clearly delineated conditions of use.
    (3) In order for such drugs to bear adequate information for safe 
and effective use the following statements are representative of the 
type of labeling for products shown to be effective bacteriostatic skin 
cleansers. Labeling for products other than bacteriostatic skin 
cleansers will be determined through the new drug procedures based on 
the available data.
    (i) In the labeling other than on the immediate container label.

                               Indications

    1. Bacteriostatic skin cleanser for surgical scrubbing or 
handwashing as part of patient care.
    2. For topical application to control an outbreak of gram-positive 
infection where other infection control procedures have been 
unsuccessful. Use only as long as necessary for infection control.

                            Contraindications

    1. Not for use on burned or denuded skin or on mucous membranes.
    2. Not for routine prophylactic total body bathing.

                                Warnings

    Rinse thoroughly after use. Patients should be closely monitored and 
use should be immediately discontinued at the first sign of any of the 
symptoms described below.
    Hexachlorophene is rapidly absorbed and may produce toxic blood 
levels when applied to skin lesions such as ichthyosis congenita or the 
dermatitis of Letterer-Siwe's syndrome or other generalized dermatologic 
conditions. Application to burns has also produced neurotoxicity and 
death.
    Infants have developed dermatitis, irritability, generalized clonic 
muscular contractions and decerebrate rigidity following application of 
a 6 percent hexachlorophene powder. Examination of brainstems of those 
infants revealed vacuolization like that which can be produced in 
newborn experimental animals following repeated topical application of 3 
percent hexachlorophene. Moreover, a study of histologic sections of 
premature infants who died of unrelated causes has shown a positive 
correlation between hexachlorophene baths and lesions in white matter of 
brains.

    (ii) On the immediate container label prominently displayed and in 
bold print:

    ``Special Warning: This compound may be toxic if used other than as 
directed. Rinse thoroughly after use. Monitor patients closely for 
toxicity symptoms.''

    (4) Marketing of products for the indications listed in paragraph 
(c)(3) of this section may be continued without an approved new drug 
application (or required supplement thereto) either until a notice of 
opportunity for hearing is issued on a proposal by the Director of the 
Center for Drug Evaluation and Research to refuse to approve such new 
drug application (or required supplement) or until January 31, 1978, 
whichever comes first, if all the following conditions were met after 
September 27, 1972:
    (i) The product is labeled with the statement ``Rx only'' and 
adequate information for safe and effective use as set forth in 
paragraph (c)(3) of this section.
    (ii) Within 30 days, or by (10-27-72) the holder of an approved new 
drug application submits a supplement to provide for the revised label 
and full disclosure labeling. As the label and labeling will have been 
put into use, the supplement should be submitted under the provision of 
Sec.  314.70(c)(6)(iii) of this chapter.
    (iii) Within 30 days, or by (10-27-72) the holder of an approved new 
drug application submits a supplement to provide for a revised 
formulation where appropriate to comply with this order.

[[Page 209]]

    (iv) Within 90 days, or by (12-26-72) the holder of an approved new 
drug application submits a supplement containing blood level data 
obtained from use of the drug as recommended, unless such information is 
a part of the new drug application file.
    (v) Within 90 days, or by (12-26-72), the manufacturer or 
distributor of such a drug for which a new drug approval is not in 
effect submits a new drug application in accord with Sec.  314.50 of the 
new drug regulations (21 CFR 314.50), including blood level data 
obtained from use of the drug as recommended.
    (5) Prescription drug products may contain hexachlorophene as part 
of an effective preservative system only under the conditions and 
limitations provided for under paragraph (d) of this section.
    (d) Over-the-counter (OTC) drugs. Over-the-counter drug products, 
other than those which in normal use may be applied to mucous membranes 
or which are intended to be used on mucous membranes, may contain 
hexachlorophene only as part of an effective preservative system, at a 
level that is no higher than necessary to achieve the intended 
preservative function, and in no event higher than 0.1 percent. Such use 
of hexachlorophene shall be limited to situations where an alternative 
preservative has not yet been shown to be as effective or where adequate 
integrity and stability data for the reformulated product are not yet 
available. This use of hexachlorophene will not, by itself, require an 
approved new drug application. Use of hexachlorophene as a preservative 
at a level higher than 0.1 percent is regarded as a new drug use 
requiring an approved new drug application, which must be submitted 
within the time set out in paragraph (c)(4) of this section.
    (e) Cosmetics. Hexachlorophene may be used as a preservative in 
cosmetic products other than those which in normal use may be applied to 
mucous membranes or which are intended to be used on mucous membranes, 
at a level that is no higher than necessary to achieve the intended 
preservative function, and in no event higher than 0.1 percent. Such use 
of hexachlorophene shall be limited to situations where an alternative 
preservative has not yet been shown to be as effective or where adequate 
integrity and stability data for the reformulated product are not yet 
available. The component of a preservative system whether 
hexachlorophene or other antimicrobial agent, should be selected on the 
basis of the effect on the total microbial ecology of the product, not 
merely on gram-positive bacteria.
    (1) Adequate safety data do not presently exist to justify wider use 
of hexachlorophene in cosmetics.
    (2) Antibacterial ingredients used as substitutes for 
hexachlorophene in cosmetic products, and finished cosmetic products 
containing such ingredients, shall be adequately tested for safety prior 
to marketing. Any such ingredient or product whose safety is not 
adequately substantiated prior to marketing may be adulterated and will 
in any event be deemed misbranded unless it contains a conspicuous front 
panel statement that the product has not been adequately tested for 
safety and may be hazardous.
    (f) Content statement. All reference to hexachlorophene limit in 
this order is on a weight-in-weight (w/w) basis. Quantitative 
declaration of hexachlorophene content on the labeling of the products, 
where required, shall be on a w/w basis.
    (g) Shipments of products. Shipments of products falling within the 
scope of paragraphs (c), (d), or (e) of this section which are not in 
compliance with the guidelines stated herein shall be the subject of 
regulatory proceedings after the effective date of the final order.
    (h) Prior notices. This order preempts any conditions for marketing 
products set forth in the following prior notices.

1. DESI No. 4749 (34 FR 15389, October 2, 1969), ``Certain OTC Drugs for 
Topical Use.''
2. DESI No. 2855 (35 FR 12423, August 4, 1970), ``Certain Mouthwash and 
Gargle Preparations.''
3. DESI No. 8940 (36 FR 14510, August 6, 1971), ``Topical Cream 
Containing Pyrilamine Maleate, Benzocaine, Hexachlorophene, and 
Cetrimonium Bromide.''
4. DESI No. 6615 (36 FR 18022, September 8, 1971), ``Deodorant/
Antiperspirant.''

[[Page 210]]

5. DESI No. 6270 (36 FR 23330, December 8, 1971), ``Certain Preparations 
Containing Hexachlorophene''.

[40 FR 14033, Mar. 27, 1975, as amended at 42 FR 63773, Dec. 20, 1977; 
55 FR 11577, Mar. 29, 1990; 67 FR 4906, Feb. 1, 2002; 69 FR 18763, Apr. 
8, 2004]



PART 251_SECTION 804 IMPORTATION PROGRAM--Table of Contents



                      Subpart A_General Provisions

Sec.
251.1 Scope of the part.
251.2 Definitions.

   Subpart B_Section 804 Importation Program Proposals and Pre-Import 
                                Requests

251.3 SIP proposal submission requirements.
251.4 Review and authorization of importation program proposals.
251.5 Pre-Import Request.
251.6 Termination of authorized importation programs.
251.7 Suspension and revocation of authorized importation programs.
251.8 Modification or extension of authorized importation programs.

   Subpart C_Certain Requirements for Section 804 Importation Programs

251.9 Registration of Foreign Sellers.
251.10 Reviewing and updating registration information for Foreign 
          Sellers.
251.11 Official contact and U.S. agent for Foreign Sellers.
251.12 Importer responsibilities.
251.13 Labeling of eligible prescription drugs.
251.14 Supply chain security requirements for eligible prescription 
          drugs.
251.15 Qualifying laboratory requirements.
251.16 Laboratory testing requirements.
251.17 Importation requirements.
251.18 Post-importation requirements.
251.19 Reports to FDA.
251.20 Severability.
251.21 Consequences for violations.

    Authority: 21 U.S.C. 351, 352, 353, 355, 360, 360eee-1, 371, 374, 
381, 384.

    Source: 85 FR 62126, Oct. 1, 2020, unless otherwise noted.



                      Subpart A_General Provisions



Sec.  251.1  Scope of the part.

    (a) This part sets forth the procedures that Section 804 Importation 
Program sponsors (SIP Sponsors) must follow when submitting plans to 
implement time-limited programs to begin importation of drugs from 
Canada under section 804 of the Federal Food, Drug, and Cosmetic Act. 
This part also sets forth certain requirements that are necessary for 
such programs to be authorized by the Food and Drug Administration 
(FDA). Additionally, this part sets forth requirements for eligible 
prescription drugs and requirements for entities that engage in 
importation of eligible prescription drugs.
    (b) This part includes provisions that exempt eligible prescription 
drugs that meet certain requirements from section 502(f)(1) of the 
Federal Food, Drug, and Cosmetic Act. This part also includes provisions 
that exempt certain transactions involving eligible prescription drugs 
from certain requirements in section 582 of the Federal Food, Drug, and 
Cosmetic Act.



Sec.  251.2  Definitions.

    The definitions of terms in section 804 of the Federal Food, Drug, 
and Cosmetic Act apply to the terms used in this part, if not otherwise 
defined in this section. The following definitions apply to this part:
    Active ingredient has the meaning set forth in Sec.  314.3 of this 
chapter.
    Adverse event means any untoward medical occurrence associated with 
the use of a drug product in humans, whether or not it is considered 
related to the drug product. An adverse event can occur in the course of 
the use of a drug product; from overdose of a drug product, whether 
accidental or intentional; from abuse of a drug product; from 
discontinuation of the drug product (e.g., physiological withdrawal); 
and it includes any failure of expected pharmacological action.
    Combination product has the meaning set forth in Sec.  3.2(e) of 
this chapter.
    Constituent part has the meaning set forth in Sec.  4.2 of this 
chapter.
    Disability means a substantial disruption of a person's ability to 
conduct normal life functions.
    Eligible prescription drug:
    (1) Means a drug subject to section 503(b) of the Federal Food, 
Drug, and Cosmetic Act that has been approved and has received a Notice 
of Compliance and a Drug Identification Number (DIN) from the Health 
Products and

[[Page 211]]

Food Branch of Health Canada (HPFB) and, but for the fact that it 
deviates from the required U.S. labeling, also meets the conditions in 
an FDA-approved new drug application (NDA) or abbreviated new drug 
application (ANDA) for a drug that is currently commercially marketed in 
the United States, including those relating to the drug substance, drug 
product, production process, quality controls, equipment, and 
facilities.
    (2) The term eligible prescription drug does not include:
    (i) A controlled substance (as defined in section 102 of the 
Controlled Substances Act (21 U.S.C. 802));
    (ii) A biological product (as defined in section 351(i)(1) of the 
Public Health Service Act (42 U.S.C. 262(i)(1)));
    (iii) An infused drug (including a peritoneal dialysis solution);
    (iv) An intravenously injected drug;
    (v) A drug that is inhaled during surgery;
    (vi) An intrathecally or intraocularly injected drug;
    (vii) A drug that is subject to a risk evaluation and mitigation 
strategy under section 505-1 of the Federal Food, Drug, and Cosmetic 
Act; or
    (viii) A drug that is not a ``product'' for purposes of section 582 
as defined in section 581(13) of the Federal Food, Drug, and Cosmetic 
Act.
    Entered (or entry) for consumption has the meaning set forth in 19 
CFR 141.0a(f).
    Entry means the information or data filed electronically in the 
Automated Commercial Environment (ACE) or any other U.S. Customs and 
Border Protection (CBP)-authorized electronic data interchange system to 
secure the release of imported merchandise from CBP, or the act of 
filing that information or data.
    Foreign Seller means an establishment within Canada engaged in the 
distribution of an eligible prescription drug that is imported or 
offered for importation into the United States. A Foreign Seller must 
have an active Drug Establishment License to wholesale drugs by Health 
Canada. A Foreign Seller must be registered with provincial regulatory 
authorities to distribute HPFB-approved drugs. A Foreign Seller must not 
be licensed by a provincial regulatory authority with an international 
pharmacy license that allows it to distribute drugs that are approved by 
countries other than Canada and that are not HPFB-approved for 
distribution in Canada. A Foreign Seller must also be registered with 
FDA under section 804 of the Federal Food, Drug, and Cosmetic Act in 
accordance with the requirements described in this part.
    Illegitimate foreign product means a drug purchased by a Foreign 
Seller from a manufacturer, and intended for sale to the Importer in the 
United States, where the Foreign Seller has credible evidence that shows 
that the product:
    (1) Is counterfeit, diverted, or stolen;
    (2) Is intentionally adulterated such that the product would result 
in serious adverse health consequences or death to humans;
    (3) Is the subject of a fraudulent transaction; or
    (4) Appears otherwise unfit for distribution such that the product 
would be reasonably likely to result in serious adverse health 
consequences or death to humans.
    Importer means a pharmacist or wholesaler. An Importer must be a 
State-licensed pharmacist, or a State- or FDA-licensed wholesale 
distributor, who is the U.S. owner of an eligible prescription drug at 
the time of entry into the United States. The Importer's pharmacist 
license or wholesale distributor license (if issued by a State and not 
FDA) must be issued by a State that is a SIP Sponsor or SIP Co-Sponsor. 
An Importer's pharmacist or wholesale distributor license must be in 
effect (i.e., not expired) and the Importer's license must be in good 
standing with the licensor.
    Individual case safety report (ICSR) means a description of an 
adverse event related to an individual patient or subject.
    ICSR attachments means any document related to the adverse event 
described in an ICSR, such as medical records, hospital discharge 
summaries, or other documentation.
    Life-threatening adverse event means any adverse event that places 
the patient, in the view of the initial reporter, at immediate risk of 
death from the adverse event as it occurred,

[[Page 212]]

i.e., it does not include an adverse event that, had it occurred in a 
more severe form, might have caused death.
    Manufacturer means an applicant, as defined in Sec.  314.3 of this 
chapter, or a person who owns or operates an establishment that 
manufactures an eligible prescription drug. Manufacturer also means a 
holder of a drug master file containing information necessary to conduct 
the Statutory Testing, prepare the manufacturer's attestation and 
information statement, or otherwise comply with section 804 of the 
Federal Food, Drug, and Cosmetic Act or this part.
    Minimum data set for an adverse event means the minimum four 
elements required for reporting an ICSR of an adverse event: An 
identifiable patient, an identifiable reporter, a suspect drug product, 
and an adverse event.
    Pharmacist means a person licensed by a State to practice pharmacy, 
including the dispensing and selling of prescription drugs.
    Pre-Import Request means a request made to FDA by an Importer that 
must be granted by FDA before the Importer can start importation under a 
Section 804 Importation Program.
    Qualifying laboratory means a laboratory in the United States that 
has been approved by FDA for the purposes of section 804 of the Federal 
Food, Drug, and Cosmetic Act.
    Relabel has the meaning set forth in Sec.  207.1 of this chapter.
    Relabeler has the meaning set forth in Sec.  207.1 of this chapter.
    Repack or repackage has the meaning set forth in Sec.  207.1 of this 
chapter.
    Responsible individual(s) means an individual or individuals who are 
designated in the Section 804 Importation Program compliance plan. Such 
individuals are responsible for ensuring compliance with the 
requirements of the Section 804 Importation Program under their 
oversight and with the applicable provisions of the Federal Food, Drug, 
and Cosmetic Act and this part.
    Section 804 Importation Program (``SIP'') means a program under 
section 804 of the Federal Food, Drug, and Cosmetic Act, and this part, 
that has been authorized by FDA for the importation of eligible 
prescription drugs from Canada.
    Section 804 Importation Program Sponsor (``SIP Sponsor'') means a 
State or Indian Tribe that regulates wholesale drug distribution and the 
practice of pharmacy that submits a proposal to FDA that describes a 
program to facilitate the importation of prescription drugs from Canada 
under section 804 of the Federal Food, Drug, and Cosmetic Act and is 
responsible for oversight of the implementation of the program. After an 
initial 2-year period beginning on the date of the first import entry 
under any SIP authorized under this part, the Secretary may determine, 
based on experience under the program, that there is a sufficient 
likelihood that a proposal that does not include a State or Indian Tribe 
as the SIP sponsor could provide the same level of assurance of safety 
as a proposal that does include such a sponsor, such that FDA may begin 
receiving, reviewing, and potentially authorizing applications for SIPs 
without such a sponsor. After the Secretary makes such a determination, 
a pharmacist or wholesaler may propose a SIP that does not include a 
State or Indian Tribe as a sponsor, and FDA may authorize such a SIP if 
the sponsor demonstrates that the SIP meets the criteria for 
authorization with the same level of assurance of safety as a proposal 
that includes a State or Indian Tribe as the SIP sponsor, which FDA 
shall evaluate consistent with any considerations described in the 
Secretary's determination, including by evaluating whether the 
application demonstrates that the proposed sponsor has sufficient 
relevant experience, such as participating in a SIP and demonstrating 
compliance with the requirements of the Federal Food, Drug, and Cosmetic 
Act and this part.
    Section 804 Importation Program Co-Sponsor (``SIP Co-Sponsor'') 
means any other State or Indian Tribe, or a pharmacist or a wholesale 
distributor that, with the SIP Sponsor, signs a proposal to FDA that 
describes a program to facilitate the importation of prescription drugs 
from Canada under section 804 of the Federal Food, Drug, and Cosmetic 
Act.
    Section 804 Serial Identifier (``SSI'') means a unique alphanumeric 
serial number of up to 20 characters that is

[[Page 213]]

assigned and placed on or affixed by the Foreign Seller to each package 
and homogenous case of the product that the Foreign Seller intends to 
sell to an Importer. For purposes of the SSI, ``package'' means the 
smallest individual saleable unit of product for distribution that is 
intended by the Foreign Seller for sale to an Importer located in the 
United States, and ``individual saleable unit'' means the smallest 
container of product sold by the Foreign Seller to the Importer.
    Serious adverse event means:
    (1) An adverse event is considered ``serious'' if it results in any 
of the following outcomes:
    (i) Death;
    (ii) A life-threatening adverse event;
    (iii) Inpatient hospitalization or prolongation of existing 
hospitalization;
    (iv) A persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions; and/or
    (v) A congenital anomaly/birth defect.
    (2) Other events that may be considered serious adverse events: 
Important medical events that may not result in one of the listed 
outcomes in this definition may be considered serious adverse events 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or study subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
Examples include: Allergic bronchospasm requiring intensive treatment in 
an emergency department or at home, blood dyscrasias or convulsions that 
do not result in inpatient hospitalization, or the development of 
product dependency or product abuse.
    Statutory Testing means the testing of an eligible prescription drug 
as required by section 804(d)(1)(J) and (L) and section 804(e) of the 
Federal Food, Drug, and Cosmetic Act, including for authenticity, for 
degradation, and to ensure that the prescription drug is in compliance 
with established specifications and standards.
    Suspect foreign product means a drug purchased by a Foreign Seller 
from a manufacturer, and intended for sale to an Importer in the United 
States, for which the Foreign Seller has reason to believe that such 
product:
    (1) Is potentially counterfeit, diverted, or stolen;
    (2) Is potentially intentionally adulterated such that the product 
would result in serious adverse health consequences or death to humans;
    (3) Is potentially the subject of a fraudulent transaction; or
    (4) Appears otherwise unfit for distribution such that the product 
would result in serious adverse health consequences or death to humans.
    Transaction means the transfer of product between persons in which a 
change of ownership occurs, in accordance with section 581(24) of the 
Federal Food, Drug, and Cosmetic Act. For the purposes of this part, 
``transaction'' includes the sale and transfer of product between the 
manufacturer and Foreign Seller. The sale and transfer of product 
between Foreign Seller and Importer also constitutes a ``transaction.''
    Unexpected adverse event means an adverse event that is not included 
in the current U.S. labeling for the drug product. Events that may be 
symptomatically or pathophysiologically related to an adverse event 
included in the labeling but differ from the labeled event because of 
greater severity or specificity would be considered unexpected. 
``Unexpected,'' as used in this definition, also refers to adverse 
events that are mentioned in the product labeling as occurring with a 
class of products or anticipated from the pharmacological properties of 
the product but are not specifically mentioned as occurring with the 
particular product.
    (1) Example of greater severity. Under this definition, hepatic 
necrosis would be unexpected if the labeling referred only to elevated 
hepatic enzymes or hepatitis.
    (2) Example of greater specificity. Cerebral thromboembolism and 
cerebral hemorrhage would be unexpected if the labeling included only 
cerebrovascular accidents.
    Unique facility identifier means the identifier required to be 
submitted by the registrant for drug establishment registration under 
section 510 of the Federal Food, Drug, and Cosmetic Act in accordance 
with Sec.  207.25 of this chapter. For Foreign Sellers registering

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under section 804 of the Federal Food, Drug, and Cosmetic Act, the term 
``unique facility identifier'' means the identifier required to be 
submitted under Sec.  251.9 in accordance with the system specified 
under section 510 of the Federal Food, Drug, and Cosmetic Act.
    Wholesaler means a person licensed as a wholesale distributor, as 
the terms ``licensed'' and ``wholesale distributor'' are defined in 
section 581(9)(A) and 581(29), respectively. The term ``wholesaler'' 
does not include a person authorized to import drugs under section 
801(d)(1).



   Subpart B_Section 804 Importation Program Proposals and Pre-Import 
                                Requests



Sec.  251.3  SIP proposal submission requirements.

    (a) A SIP Sponsor may delegate implementation activities to a SIP 
co-sponsor but the SIP Sponsor remains responsible for oversight of the 
implementation of the program.
    (b) A SIP Sponsor must only designate one Foreign Seller and one 
Importer per initial proposal. Additional Foreign Sellers and Importers 
may be added to an authorized SIP through a supplemental proposal under 
Sec.  251.8.
    (c) A SIP Sponsor that intends to implement a SIP under this part 
must submit a proposal to FDA in electronic format via FDA's Electronic 
Submissions Gateway (ESG) or to an alternative transmission point 
identified by FDA. The proposal must include:
    (1) A cover sheet containing the following:
    (i) Name or names of SIP Sponsor and co-sponsors, if any;
    (ii) Name and contact information for a person authorized to serve 
as the point of contact with FDA during its review of the proposal; and
    (iii) The signature of the SIP Sponsor and co-sponsors, if any, or 
authorized representative who is an employee or agent of the Sponsor or 
co-sponsor and has been authorized to sign the proposal for the Sponsor 
or co-sponsor. The signatory must reside or have a place of business 
within the United States, and the proposal cover sheet must contain the 
name, title, and business address of the signatory.
    (2) A table of contents;
    (3) An introductory statement that includes an overview of the SIP 
Sponsor's SIP Proposal; and
    (4) The SIP Sponsor's importation plan.
    (d) The overview of the SIP Proposal must include:
    (1) The name of the SIP, if any, and the name or names and address 
or addresses of the SIP Sponsor and co-sponsors, if any;
    (2) The name, email address, and telephone number of the responsible 
individual(s);
    (3) The name and DIN of each eligible prescription drug that the SIP 
Sponsor seeks to include in the SIP;
    (4) The name and address of the applicant that holds the approved 
NDA or ANDA for each eligible prescription drug's FDA-approved 
counterpart, and the approved NDA or ANDA number;
    (5) The name and address of the manufacturer of the finished dosage 
form of the eligible prescription drug, if known or reasonably known;
    (6) The name and address of the manufacturer of the active 
ingredient or ingredients of the eligible prescription drugs, if known 
or reasonably known;
    (7) The name and address of the Foreign Seller;
    (8) A copy of the Foreign Seller's Health Canada Drug Establishment 
License;
    (9) The name and address of the Importer;
    (10) The name and address of the FDA-registered repackager or 
relabeler, if different from the Importer, that will relabel the 
eligible prescription drugs (including any limited repackaging in 
accordance with the requirements in this part), along with adequate 
evidence of registration and of satisfactory resolution of any 
objectionable conditions or practices identified during its most recent 
FDA inspection, if applicable; and
    (11) A summary of how the SIP Sponsor will ensure that:
    (i) The imported eligible prescription drugs meet the Statutory 
Testing requirements;
    (ii) The supply chain is secure;

[[Page 215]]

    (iii) The labeling requirements of the Federal Food, Drug, and 
Cosmetic Act and this part are met;
    (iv) The post-importation pharmacovigilance and other requirements 
of the Federal Food, Drug, and Cosmetic Act and this part are met; and
    (v) The SIP will result in a significant reduction in the cost to 
the American consumer of the eligible prescription drugs that the SIP 
Sponsor seeks to import.
    (e) The SIP Sponsor's importation plan must:
    (1) Identify the SIP Sponsor, including any co-sponsors, identify 
the responsible individual(s), and identify the applicant that holds the 
approved NDA or ANDA for each eligible prescription drug's FDA-approved 
counterpart, the manufacturer(s) of the finished dosage form and the 
active ingredient or ingredients of each eligible prescription drug that 
the SIP Sponsor seeks to import, if known or reasonably known, the 
Foreign Seller, if known or reasonably known, and the Importer, and 
explain the legal relationship, if any, of each of these entities to the 
SIP Sponsor.
    (2) Include an attestation and information statement containing a 
complete disclosure of any past criminal convictions or violations of 
State, Federal, or Canadian laws regarding drugs or devices against or 
by the responsible individual(s), Foreign Seller, or Importer or an 
attestation that the responsible individual(s), Foreign Seller, or 
Importer has not been involved in, or convicted of, any such violations. 
Such attestation and information statement must include principals, any 
shareholder who owns 10 percent or more of outstanding stock in any non-
publicly held corporation, directors, officers, and any facility manager 
or designated representative of such manager.
    (3) Include a list of all disciplinary actions, to include the date 
of and parties to any action imposed against the responsible 
individual(s), Foreign Seller, or Importer by State, Federal, or 
Canadian regulatory bodies, including any such actions against the 
principals, owners, directors, officers, quality unit, or any facility 
manager or designated representative of such manager for the previous 7 
years prior to submission of the SIP Proposal.
    (4) Include:
    (i) The Health Canada inspectional history for the Foreign Seller 
for the previous 5 years or, if the Foreign Seller has been licensed for 
less than 5 years, for the duration of its period of licensure; and
    (ii) The State and Federal inspectional history for the Importer for 
the previous 5 years or, if the Importer has been licensed for less than 
5 years, for the duration of its period of licensure.
    (5) Include the proprietary name (if any), the established name, the 
approved application numbers, and the DIN and National Drug Code (NDC) 
for each eligible prescription drug that the SIP Sponsor seeks to import 
from Canada and for its FDA-approved counterpart. The SIP Sponsor's 
importation plan must also include as much of the information that is 
required by Sec.  251.5 about the HPFB-approved product and its FDA-
approved counterpart as is available, including the name and quantity of 
the active ingredient, the inactive ingredients, and the dosage form.
    (6) Provide adequate evidence that each HPFB-approved drug's FDA-
approved counterpart drug is currently commercially marketed in the 
United States.
    (7) Describe, to the extent possible, the testing that will be done 
to establish that the HPFB-approved drug meets the conditions in the NDA 
or ANDA for the HPFB-approved drug's FDA-approved counterpart. The SIP 
Sponsor's importation plan must also identify the qualifying laboratory 
that will conduct the Statutory Testing for the Importer, if the 
Importer is responsible for conducting the Statutory Testing, and it 
must establish that the laboratory is qualified in accordance with Sec.  
251.15 to conduct the tests.
    (8) Include a copy of the FDA-approved drug labeling for the FDA-
approved counterpart of the eligible prescription drug, a copy of the 
proposed labeling that will be used for the eligible prescription drug, 
and a side-by-side comparison of the FDA-approved

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labeling and the proposed labeling, including the Prescribing 
Information, carton and container labeling, and patient labeling (e.g., 
Medication Guide, Instructions for Use, patient package inserts), with 
all differences annotated and explained. The SIP Proposal must also 
include a copy of the HPFB-approved labeling.
    (9) Explain how the SIP Sponsor will ensure that the SIP will result 
in a significant reduction in the cost to the American consumer of the 
eligible prescription drugs that the SIP Sponsor seeks to import. The 
explanation must include any assumptions and uncertainty, and it must be 
sufficiently detailed to allow for a meaningful evaluation.
    (10) Explain how the SIP Sponsor will ensure that all the 
participants in the SIP comply with the requirements of section 804 of 
the Federal Food, Drug, and Cosmetic Act and this part.
    (11) Describe the procedures the SIP Sponsor will use to ensure that 
the requirements of this part are met, including the steps that will be 
taken to ensure that the:
    (i) Storage, handling, and distribution practices of supply chain 
participants, including transportation providers, meet the requirements 
of part 205 of this chapter and do not affect the quality or impinge on 
the security of the eligible prescription drugs;
    (ii) Supply chain is secure;
    (iii) Importer screens the eligible prescription drugs it imports 
for evidence that they are adulterated, counterfeit, damaged, tampered 
with, expired, suspect foreign product, or illegitimate foreign product; 
and
    (iv) Importer fulfills its responsibilities to submit adverse event, 
field alert, and other reports required by the SIP, the Federal Food, 
Drug, and Cosmetic Act, or this part.
    (12) Explain how the SIP Sponsor will educate pharmacists, 
healthcare providers, pharmacy benefit managers, health insurance 
issuers and plans, as appropriate, and patients about the eligible 
prescription drugs imported under its SIP.
    (13) Include the SIP's recall plan, including an explanation of how 
the SIP Sponsor will obtain recall or market withdrawal information and 
how it will ensure that recall or market withdrawal information is 
shared among the SIP Sponsor, the Foreign Seller, the Importer, and FDA 
and provided to the manufacturer.
    (14) Include the SIP's return plan, including an explanation of how 
the SIP Sponsor will ensure that product that is returned after 
distribution in the United States is properly dispositioned in the 
United States, if it is a non-saleable return, in order to protect 
patients from expired or unsafe drugs, and an explanation of how the SIP 
Sponsor will prevent the non-saleable returned eligible prescription 
drugs from being exported from the United States. In the event that a 
returned eligible prescription drug may be considered saleable, include 
an explanation for how the returned product will be determined to be 
saleable and under what circumstances such eligible prescription drugs 
may be re-distributed in the United States.
    (15) Include the SIP's compliance plan, which must include:
    (i) A description of the division of responsibilities among co-
sponsors, if any, which includes a plan for timely communication of any 
compliance issues to the SIP Sponsor;
    (ii) Identification of responsible individual(s) and a description 
of the respective area(s) of the SIP, the Federal Food, Drug, and 
Cosmetic Act, or this part that will be under each responsible 
individual's oversight;
    (iii) The creation of written compliance policies, procedures, and 
protocols;
    (iv) The provision of education and training to ensure that Foreign 
Sellers, Importers, qualifying laboratories, and their employees 
understand their compliance-related obligations;
    (v) The creation and maintenance of effective lines of 
communication, including a process to protect the anonymity of 
complainants and to protect whistleblowers; and
    (vi) The adoption of processes and procedures for uncovering and 
addressing noncompliance, misconduct, or conflicts of interest.
    (16) Explain how the SIP Sponsor will ensure that any information 
that the manufacturer supplies to authenticate a prescription drug being 
tested and

[[Page 217]]

confirm that the labeling of the prescription drug complies with 
labeling requirements under the Federal Food, Drug, and Cosmetic Act, 
and any trade secrets or commercial or financial information that is 
privileged or confidential that the manufacturer supplies for the 
purposes of testing or otherwise complying with the Federal Food, Drug, 
and Cosmetic Act and this part, are kept in strict confidence and used 
only for the purposes of testing or otherwise complying with the Federal 
Food, Drug, and Cosmetic Act and this part.



Sec.  251.4  Review and authorization of importation program proposals.

    Based on a review of a SIP Proposal or supplemental proposal 
submitted under this part, FDA may authorize a SIP, modify a SIP, or 
extend the authorization period of a SIP, that meets the requirements of 
this part. FDA may use a phased review process to review a SIP Proposal 
that does not identify a Foreign Seller in an initial submission, under 
which FDA may notify the Sponsor of such a SIP Proposal whether the 
Sponsor's SIP Proposal otherwise meets the requirements of this part. In 
such a case, the required information regarding importers, relabelers, 
and repackagers still must be included in the initial submission of the 
SIP Proposal, and the SIP Proposal will be denied if a Foreign Seller is 
not identified within 6 months of the initial submission date of the SIP 
Proposal.
    (a) FDA may deny a request for authorization, modification, or 
extension of a SIP, including if a SIP Proposal or supplemental proposal 
does not meet the requirements of this part. When a SIP Proposal or 
supplemental proposal meets the requirements of this part, FDA may 
nonetheless decide not to authorize the SIP Proposal or supplemental 
proposal. For example, FDA may decide not to authorize a SIP Proposal or 
supplemental proposal because of potential safety concerns with the SIP; 
because a Foreign Seller is not identified within 6 months of the 
initial submission of the SIP Proposal; because of the degree of 
uncertainty that the SIP Proposal or supplemental proposal would 
adequately ensure the protection of public health; because of, based on 
the recommendation of another Department of Health and Human Services 
(HHS) component as directed by the Secretary, the relative likelihood 
that the SIP Proposal or supplemental proposal would not result in 
significant cost savings to the American consumer; because of the 
potential for conflicts of interest; or in order to limit the number of 
authorized SIPs so FDA can effectively and efficiently carry out its 
responsibilities under section 804 of the Federal Food, Drug, and 
Cosmetic Act in light of the amount of resources allocated to carrying 
out such responsibilities.
    (b) FDA will notify a SIP Sponsor in writing when FDA receives the 
SIP Sponsor's SIP Proposal or supplemental proposal.
    (c) FDA will make a reasonable effort to promptly communicate to a 
SIP Sponsor about any information required by Sec.  251.3 that was not 
submitted in a SIP Proposal.
    (1) FDA may notify a SIP Sponsor if FDA believes additional 
information would help FDA's review of a SIP Proposal or supplemental 
proposal.
    (2) FDA will notify a SIP Sponsor in writing whether FDA has decided 
to authorize or not to authorize the SIP Sponsor's SIP Proposal or 
supplemental proposal.



Sec.  251.5  Pre-Import Request.

    (a) An eligible prescription drug may not be imported or offered for 
import under this part unless the Importer has filed a Pre-Import 
Request for that drug in accordance with this section and FDA has 
granted the Pre-Import Request.
    (b) The Importer must submit a complete Pre-Import Request in 
electronic format via the ESG, or to an alternative transmission point 
identified by FDA, at least 30 calendar days prior to the scheduled date 
of arrival or entry for consumption, whichever occurs first, of an 
eligible prescription drug covered under an authorized SIP.
    (c) A complete Pre-Import Request must include, at a minimum:
    (1) Identification of the Importer, including Importer name; 
business type (wholesale distributor or pharmacist); U.S. license 
number(s) and State(s) of

[[Page 218]]

license; business address; unique facility identifier if required to 
register with FDA as an establishment under section 510 of the Federal 
Food, Drug, and Cosmetic Act or FDA establishment identification number 
if not required to register under section 510 of the Federal Food, Drug, 
and Cosmetic Act; and the name, email address, and phone number of a 
contact person.
    (2) Identification of the FDA-authorized SIP, including the name of 
the SIP, if any; the name or names of the SIP Sponsor and co-sponsors, 
if any; business address; and the name, email address, and phone number 
of a contact person.
    (3) Identification of the Foreign Seller, including the name of the 
Foreign Seller; business address; unique facility identifier; any 
license numbers issued by Health Canada or a provincial regulatory body; 
and the name, email address, and phone number of a contact person.
    (4) Identification and description of each drug covered by the Pre-
Import Request, including, for each drug, the following information:
    (i) Established and proprietary name of the HPFB-approved drug, as 
applicable; DIN; and complete product description, including strength, 
description of dosage form, and route(s) of administration.
    (ii) Active pharmaceutical ingredient (API) information, including:
    (A) Name of API;
    (B) Manufacturer of API and its unique facility identifier; and
    (C) Amount of API and unit measure in the eligible prescription 
drug;
    (iii) Established name and proprietary name, as applicable, of the 
FDA-approved counterpart drug and NDA or ANDA number.
    (iv) Manufacturer of the eligible prescription drug with the 
business address and unique facility identifier.
    (v) Copies of the invoice and any other documents related to the 
manufacturer's sale of the drug to the Foreign Seller that was provided 
by the manufacturer to the Importer, and copies of the same documents 
provided by the Foreign Seller to the Importer.
    (vi) Quantity, listed separately by dosage form, strength, batch and 
lot or control number assigned by the manufacturer to the eligible 
prescription drug intended to be imported under this Pre-Import Request, 
compared to the quantity of each batch and lot or control number 
originally received by the Foreign Seller from the manufacturer, and the 
date of such receipt.
    (vii) Expiration date of the HFPB-approved drug, listed by lot or 
control number assigned by the manufacturer.
    (viii) Expiration date to be assigned to the eligible prescription 
drug when relabeled by the Importer with a complete description of how 
that expiration date was determined using the manufacturer's stability 
studies in accordance with the FDA-approved NDA or ANDA.
    (ix) NDC proposed for assignment by the Importer.
    (x) FDA product code for the eligible prescription drug(s) to be 
imported.
    (xi) Unless the manufacturer has notified the Importer that it 
intends to conduct the required testing as provided in Sec.  251.16(e), 
a Statutory Testing plan that includes:
    (A) A description of how the samples will be selected from a 
shipment for the Statutory Testing;
    (B) The name and location of the qualifying laboratory in the United 
States that will conduct the Statutory Testing; and
    (C) A description of the testing method(s) that will be used to 
conduct the Statutory Testing.
    (xii) Attestation and information statement from the manufacturer 
that establishes that the drug proposed for import, but for the fact 
that it bears the HPFB-approved labeling, meets the conditions in the 
FDA-approved NDA or ANDA, including any process-related or other 
requirements for which compliance cannot be established through 
laboratory testing. Accordingly, the attestation and information 
statement must include, at a minimum:
    (A) Confirmation that the HPFB-approved drug has the active 
ingredient(s), active ingredient source(s) (including manufacturing 
facility or facilities), inactive ingredient(s), dosage form, 
strength(s), and route(s) of administration described in the FDA-
approved drug's NDA or ANDA.

[[Page 219]]

    (B) Confirmation that the HPFB-approved drug conforms to the 
specifications in the FDA-approved drug's NDA or ANDA regarding the 
quality of the drug substance(s), drug product, intermediates, raw 
materials, reagents, components, in-process materials, container closure 
systems, and other materials used in the production of the drug.
    (C) Confirmation that the HPFB-approved drug was manufactured in 
accordance with the conditions described in the FDA-approved drug's NDA 
or ANDA, including with regard to the facilities and manufacturing lines 
that are used, and in compliance with current good manufacturing 
practice requirements set forth in section 501 of the Federal Food, 
Drug, and Cosmetic Act and parts 4 (if a combination product), 210, and 
211 of this chapter.
    (D) Original date of manufacture or the date used to calculate the 
labeled expiration date based on the HPFB-approved or scientifically 
validated expiration period, the expiration period set forth in the FDA-
approved drug's NDA or ANDA, and any other information needed to label 
the drug with an expiration date within the expiration dating period 
determined by stability studies in the FDA-approved NDA or ANDA.
    (E) Information needed to confirm that the labeling of the 
prescription drug complies with labeling requirements under the Federal 
Food, Drug, and Cosmetic Act.
    (xiii) Information related to the importation, including:
    (A) Location of the eligible prescription drugs in Canada and 
anticipated date of shipment (date the eligible prescription drug(s) 
leave their location in Canada);
    (B) Name, address, email address, and telephone number of the 
Foreign Seller;
    (C) Anticipated date of export from Canada and Canadian port of 
exportation;
    (D) Anticipated date and approximate time of arrival at the port 
authorized by FDA to import eligible prescription drugs under section 
804 of the Federal Food, Drug, and Cosmetic Act;
    (E) The name, address, unique facility identifier or FDA 
establishment identification number, and telephone number of the secured 
warehouse, location within a specific foreign trade zone, or other 
secure distribution facility controlled by or under contract with the 
Importer where the eligible prescription drug will be stored pending 
testing, relabeling, and FDA determination of admissibility;
    (F) Information regarding the facility where the relabeling and any 
repackaging allowed under the authorized SIP will occur for the eligible 
prescription drug, including:
    (1) The facility's unique facility identifier;
    (2) The facility's name, address, and FDA establishment identifier 
number;
    (3) The anticipated date the relabeling and any limited repackaging 
will be completed; and
    (4) Information about where the relabeled drug will be stored 
pending distribution, including the FDA establishment identification 
number of the storage facility, if available.
    (d) The manufacturer must provide the attestation and information 
statement described in paragraph (c)(4)(xii) of this section to the 
Importer within 30 calendar days of receiving the Importer's request. If 
the manufacturer cannot provide the attestation and information 
statement, it must notify FDA and the Importer of its inability to 
provide the attestation and information statement and articulate with 
specificity the reason(s) why it cannot provide the attestation and 
information statement.
    (e)(1) The Importer must provide the executed batch record, 
including the certificate of analysis, for at least one recently 
manufactured, commercial-scale batch of the HPFB-approved drug, and at 
least one recently manufactured, commercial-scale batch of the FDA-
approved drug that was produced for and released for distribution to the 
U.S. market under an NDA or ANDA.
    (2) The manufacturer must provide these records to the Importer, 
within 30 calendar days of receiving the Importer's request, for each 
manufacturing line that the manufacturer used to produce either or both 
of the drugs.

[[Page 220]]



Sec.  251.6  Termination of authorized importation programs.

    (a) Unless an extension is granted under this part, authorization 
for a SIP automatically terminates after 2 years, or a shorter period of 
time if a shorter period of time is specified in the authorization for 
the SIP.
    (b) The authorization period for a SIP begins when the Importer, or 
its authorized customs broker, files an electronic import entry for 
consumption for its first shipment of drugs under the SIP.
    (c) Notwithstanding paragraph (a) of this section, authorization for 
a SIP terminates if the Importer, or its authorized customs broker, does 
not file an electronic import entry for consumption for a shipment of 
eligible prescription drugs under the SIP within 1 year of the date that 
the SIP was authorized.
    (d) FDA will terminate authorization of a SIP upon request from the 
SIP Sponsor.
    (e) An eligible prescription drug cannot be shipped into the United 
States under this part, and is subject to refusal of admission into the 
United States, if the authorization of the SIP has terminated.



Sec.  251.7  Suspension and revocation of authorized importation programs.

    (a) FDA may suspend a SIP under any of the circumstances set forth 
in Sec.  251.18, or under any other circumstances in FDA's discretion. 
An eligible prescription drug cannot be shipped into the United States 
under this part, and is subject to refusal of admission into the United 
States, if FDA has suspended the SIP or revoked its authorization.
    (b) SIP Sponsors and other SIP participants must agree to submit to 
audits of their books and records and inspections of their facilities as 
a condition of participation in a SIP. If a SIP Sponsor, manufacturer, 
Foreign Seller, Importer, qualifying laboratory, or other participant in 
the supply chain delays, denies, or limits an inspection, or refuses to 
permit entry, inspection, or audit of its facility or its records, FDA 
may suspend the SIP, in whole or in part, immediately.
    (c) FDA may revoke authorization of a SIP, in whole or in part, 
including with respect to one or more drugs in the SIP, at any time if 
FDA determines that:
    (1) The SIP Proposal contained an untrue statement of material fact;
    (2) The SIP Proposal omitted material information;
    (3) The SIP no longer meets the requirements of section 804 of the 
Federal Food, Drug, and Cosmetic Act, this part, or the SIP, including, 
among other things, if FDA finds that the manufacturer, the Foreign 
Seller, the Importer, or any other supply chain participant is found to 
be not compliant with section 501(a)(2)(A) or (B) of the Federal Food, 
Drug, and Cosmetic Act;
    (4) Continued implementation of the SIP is reasonably likely to pose 
additional risk to the public's health and safety;
    (5) Confidential manufacturer information was disclosed in violation 
of Sec.  251.16;
    (6) Continued implementation of the SIP is not reasonably likely to 
result in a significant reduction in the cost of the drugs covered by 
the SIP to the American consumer;
    (7) Continued monitoring of the SIP imposes too much of a burden on 
FDA or HHS resources for carrying out this part or is inconsistent with 
FDA or HHS prioritization of resources;
    (8) Continued implementation of the SIP is otherwise inappropriate; 
or
    (9) Grounds exist for suspension under paragraph (a) or (b) of this 
section and FDA determines it should revoke, either instead of, or 
after, suspension.



Sec.  251.8  Modification or extension of authorized importation programs.

    (a) A supplemental proposal to modify or extend an authorized SIP 
must be submitted in electronic format via the ESG, or to an alternative 
transmission point identified by FDA, for FDA's consideration.
    (b) FDA's review and authorization of a supplemental proposal to 
modify or extend an authorized SIP is governed by this part. In 
reviewing a supplemental proposal, FDA may take into

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account information learned subsequent to authorization of the SIP.
    (c) FDA may authorize a supplemental proposal from a SIP Sponsor to 
add additional Foreign Sellers or additional Importers to an authorized 
SIP if FDA determines the SIP Sponsor has adequately demonstrated that 
the SIP has consistently imported eligible prescription drugs in 
accordance with section 804 of the Federal Food, Drug, and Cosmetic Act 
and this part. Each supply chain under a SIP must be limited to one 
manufacturer, one Foreign Seller, and one Importer.
    (d) If FDA authorizes changes to a SIP, the Importer must submit a 
new Pre-Import Request in accordance with Sec.  251.5.
    (e) A SIP Sponsor must not make any changes or permit any changes to 
be made to a SIP without first securing FDA's authorization.
    (f) A SIP Sponsor may request that FDA extend the authorization 
period of an authorized SIP. Such a request must be submitted at least 
90 calendar days before the SIP's authorization period will expire. To 
be eligible for an extension of the authorized SIP, a SIP must be up to 
date on all of the information and records-related requirements of 
section 804 of the Federal Food, Drug, and Cosmetic Act and this part. 
FDA may extend the authorization period for up to 2 years at a time.



   Subpart C_Certain Requirements for Section 804 Importation Programs



Sec.  251.9  Registration of Foreign Sellers.

    (a) Any Foreign Seller(s) designated in a SIP Proposal must be 
registered with FDA before FDA will authorize the SIP Proposal.
    (b) To register, a Foreign Seller must provide the following 
information:
    (1) Name of the owner or operator; if a partnership, the name of 
each partner; if a corporation, the name of each corporate officer and 
director, and the place of incorporation;
    (2) All names of the Foreign Seller, including names under which the 
Foreign Seller conducts business or names by which the Foreign Seller is 
known;
    (3) Physical address and telephone number(s) of the Foreign Seller;
    (4) Registration number, if previously assigned by FDA;
    (5) A unique facility identifier in accordance with the system 
specified under section 510 of the Federal Food, Drug, and Cosmetic Act;
    (6) All types of operations performed by the Foreign Seller;
    (7) Name, mailing address, telephone number, and email address of 
the official contact for the establishment; and
    (8) Name, mailing address, telephone number, and email address of:
    (i) The U.S. agent;
    (ii) The Importer to which the Foreign Seller plans to sell eligible 
prescription drugs; and
    (iii) Each SIP Sponsor with which the Foreign Seller works.



Sec.  251.10  Reviewing and updating registration information for
Foreign Sellers.

    (a) Expedited updates. A Foreign Seller must update its registration 
information no later than 30 calendar days after:
    (1) Closing or being sold;
    (2) Changing its name or physical address; or
    (3) Changing the name, mailing address, telephone number, or email 
address of the official contact or the U.S. agent. A Foreign Seller, 
official contact, or U.S. agent may notify FDA about a change of 
information for the designated official contact or U.S. agent, but only 
a Foreign Seller is permitted to designate a new official contact or 
U.S. agent.
    (b) Annual review and update of registration information. A Foreign 
Seller must review and update all registration information required 
under Sec.  251.9.
    (1) The first review and update must occur during the period 
beginning on October 1 and ending December 31 of the year of initial 
registration, if the initial registration occurs prior to October 1. 
Subsequent reviews and updates must occur annually, during the period 
beginning on October 1 and ending December 31 of each calendar year.
    (2) The updates must reflect new changes not previously required to 
be reported, along with a summary of the registration updates that were 
provided to FDA as required during the calendar year.

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    (3) If no changes have occurred since the last registration, a 
Foreign Seller must certify that no changes have occurred.



Sec.  251.11  Official contact and U.S. agent for Foreign Sellers.

    (a) Official contact. A Foreign Seller subject to the registration 
requirements of this part must designate an official contact. The 
official contact is responsible for:
    (1) Ensuring the accuracy of registration information as required by 
Sec.  251.9; and
    (2) Reviewing, disseminating, routing, and responding to all 
communications from FDA, including emergency communications.
    (b) U.S. agent. (1) A Foreign Seller must designate a single U.S. 
agent. The U.S. agent must reside or maintain a place of business in the 
United States and may not be a mailbox, answering machine or service, or 
other place where a person acting as the U.S. agent is not physically 
present. The U.S. agent is responsible for:
    (i) Reviewing, disseminating, routing, and responding to all 
communications from FDA, including emergency communications;
    (ii) Responding to questions concerning those drugs that are 
imported or offered for import to the United States; and
    (iii) Assisting FDA in scheduling inspections.
    (2) FDA may provide certain information and/or documents to the U.S. 
agent. The provision of information and/or documents by FDA to the U.S. 
agent is equivalent to providing the same information and/or documents 
to the Foreign Seller.



Sec.  251.12  Importer responsibilities.

    (a) The Importer is responsible for:
    (1) In accordance with the procedures set forth in Sec.  207.33 of 
this chapter, proposing an NDC for assignment for each eligible 
prescription drug imported pursuant to this part;
    (2) Examining the Canadian labeling of a sample of each shipment of 
eligible prescription drugs to verify that the labeling is that of the 
HPFB-approved drug, and attesting that such examination has been 
conducted through reports to FDA required under this part;
    (3) Screening eligible prescription drugs for evidence that they are 
adulterated, counterfeit, damaged, tampered with, expired, suspect 
foreign product, or illegitimate foreign product;
    (4) Ensuring the eligible prescription drug is relabeled with the 
required U.S. labeling, including the container and carton labeling; 
Prescribing Information; and patient labeling, such as Medication 
Guides, Instruction for Use documents, and patient package inserts, in 
accordance with Sec. Sec.  251.13 and 251.14(d);
    (5) Arranging for an entry to be submitted in accordance with Sec.  
251.17;
    (6) Collecting and submitting the information and documentation to 
FDA about the imported drug(s) pursuant to section 804(d) of the Federal 
Food, Drug, and Cosmetic Act, in addition to information about the 
Foreign Seller, as set forth in Sec.  251.19; and
    (7) Submitting the adverse event, field alert, and other reports, 
and complying with drug recalls, in accordance with Sec.  251.18.
    (b) If the Importer is also relabeling the eligible prescription 
drug, the Importer must also:
    (1) Register with FDA as a repackager or relabeler under section 
510(b) of the Federal Food, Drug, and Cosmetic Act, in accordance with 
Sec.  207.25 of this chapter;
    (2) Obtain a labeler code from FDA and propose an NDC for each 
eligible prescription drug pursuant to Sec.  207.33 of this chapter; and
    (3) List each eligible prescription drug pursuant to Sec.  207.53 of 
this chapter.
    (c) If the Importer is not itself relabeling the eligible 
prescription drug, the Importer must:
    (1) Obtain its own labeler code from FDA under Sec.  207.33(c) of 
this chapter;
    (2) Ensure that the eligible prescription drug incorporates the NDC 
the Importer proposed for assignment, which must include the Importer's 
labeler code; and
    (3) Ensure that the entity relabeling an eligible prescription drug 
on its behalf proposes an NDC pursuant to

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Sec.  207.33 of this chapter and lists each eligible prescription drug 
pursuant to Sec.  207.53 of this chapter.



Sec.  251.13  Labeling of eligible prescription drugs.

    (a) Upon the request of a SIP Sponsor or Importer, the manufacturer 
of an eligible prescription drug must provide an Importer written 
authorization for the Importer to use, at no cost, the FDA-approved 
labeling for the drug. If the manufacturer fails to do so within 30 
calendar days of receiving the Importer's request, FDA may deem this 
authorization to have been given.
    (b) In addition to the exemption provided in subpart D of part 201 
of this chapter, an eligible prescription drug imported for purposes of 
this part is exempt from section 502(f)(1) of the Federal Food, Drug, 
and Cosmetic Act if all the following conditions are met:
    (1) The Importer or the manufacturer certifies that the drug meets 
all labeling requirements under the Federal Food, Drug, and Cosmetic 
Act, including the requirements of this part. The Importer of an 
eligible prescription drug must either:
    (i) Propose an NDC for the drug following the procedures in Sec.  
207.33 of this chapter and list the drug following the procedures in 
Sec.  207.53 of this chapter; or
    (ii) Take responsibility to ensure that the entity performing 
relabeling on its behalf lists each eligible prescription drug and 
incorporates the NDC the Importer proposed for assignment in accordance 
with the applicable requirements of part 207 of this chapter.
    (2) The drug must be:
    (i) In the possession of a person (or his or her agents or 
employees), including Foreign Sellers and Importers, regularly and 
lawfully engaged in the manufacture, transportation, storage, or 
wholesale distribution of prescription drugs;
    (ii) In the possession of a retail, hospital, or clinic pharmacy, or 
a public health agency, regularly and lawfully engaged in dispensing 
prescription drugs; or
    (iii) In the possession of a practitioner licensed by law to 
administer or prescribe such drugs.
    (3) The drug is to be dispensed in accordance with section 503(b) of 
the Federal Food, Drug, and Cosmetic Act.
    (4) At the time the drug is sold or dispensed, the labeling of the 
drug must be the same as the FDA-approved labeling under the applicable 
NDA or ANDA, except that the labeling must bear conspicuously:
    (i) The Importer's NDC for the eligible prescription drug, and such 
NDC must replace any other NDC otherwise appearing on the label of the 
FDA-approved drug;
    (ii) The lot number assigned by the manufacturer of the eligible 
prescription drug, on the carton labeling and on the container label;
    (iii) The name and place of business of the Importer;
    (iv) The statement: ``[This drug was/These drugs were] imported from 
Canada without the authorization of [Name of Applicant] under the [Name 
of SIP Sponsor] Section 804 Importation Program.'' If the SIP maintains 
a website, the statement could also include the website address. This 
statement must appear in the HOW SUPPLIED/STORAGE AND HANDLING section 
for products subject to Sec. Sec.  201.56(d) and 201.57 of this chapter, 
or in the HOW SUPPLIED section for products subject to Sec. Sec.  
201.56(e) and 201.80 of this chapter. The statement also must be 
included on the immediate container label and outside package;
    (v) For products subject to Sec. Sec.  201.56(d) and 
201.57(c)(17)(iii) of this chapter, the NDC(s) assigned to the eligible 
prescription drug in accordance with the procedures in Sec.  207.33 of 
this chapter must be included in the HOW SUPPLIED/STORAGE AND HANDLING 
section in place of the NDC(s) assigned to the FDA-approved versions of 
the drug. The NDC(s) also must be included on the immediate container 
label and outside package;
    (vi) For products subject to Sec. Sec.  201.56(d) and 
201.57(a)(11)(ii) of this chapter, the Adverse Reaction Contact 
Reporting Statement under the Adverse Reactions heading in the 
Highlights of Prescribing Information. This statement must include the 
Importer's name and the telephone number of the

[[Page 224]]

firm to provide a structured process for reporting suspected adverse 
events; and
    (vii) For products subject to Sec. Sec.  201.56(e) and 201.80(k)(3) 
of this chapter, the NDC(s) assigned to the eligible prescription drug 
in accordance with the procedures in Sec.  207.33 of this chapter. The 
NDC(s) must be included in the HOW SUPPLIED section in place of the 
NDC(s) assigned to the FDA-approved versions of the drug. The NDC(s) 
also must be included on the immediate container label and outside 
package.
    (c) The Importer is responsible for relabeling the drug, or 
arranging for it to be relabeled, to meet the requirements of this part. 
The relabeling and associated limited repackaging activities must meet 
applicable requirements, including applicable current good manufacturing 
practice requirements under parts 210 and 211 of this chapter. Except 
for repackaging that is necessary to perform the relabeling described in 
this part, further repackaging of drugs imported pursuant to a SIP is 
prohibited. Repackaging the container closure of a drug is not permitted 
under this part.
    (d) The Importer may submit to FDA, in electronic format via the ESG 
or to an alternative transmission point identified by FDA, under Sec.  
251.8, a supplemental proposal to modify the labeling of an eligible 
prescription drug, for example if the eligible prescription drug's 
container is too small to fit the additional information required by 
this section.



Sec.  251.14  Supply chain security requirements for eligible 
prescription drugs.

    (a) SIP Sponsor. A sponsor of an authorized SIP must ensure that:
    (1) Each drug imported under the SIP is HPFB-approved and labeled 
for sale in Canada by the manufacturer before it reaches the Foreign 
Seller;
    (2) For each drug that is imported under the SIP and that is 
manufactured outside Canada, the drug was authorized for import into 
Canada by the manufacturer and was not transshipped through Canada for 
sale in another country;
    (3) For each drug imported under the SIP, the drug was sold by the 
manufacturer directly to a Foreign Seller;
    (4) For each drug imported under the SIP, the Foreign Seller ships 
the drug directly to the Importer in the United States;
    (5) For each drug imported under the SIP, the Foreign Seller 
identified in the SIP meets applicable supply chain security 
requirements of this part;
    (6) The Importer identified in the SIP meets the applicable 
requirements of this part and in sections 582(c) and (d) of the Federal 
Food, Drug, and Cosmetic Act; and
    (7) Returned eligible prescription drugs are properly dispositioned 
in, and not exported from, the United States.
    (b) Manufacturer. For each transaction of the eligible prescription 
drug, the manufacturer must provide to the Importer, within 30 calendar 
days of receiving the Importer's request, a copy of all transaction 
documents that were provided from the manufacturer to the Foreign 
Seller.
    (c) Foreign Seller. (1) A Foreign Seller must have systems in place 
to:
    (i) Determine whether a drug in its possession or control that it 
intends to sell to the Importer under a SIP is a suspect foreign 
product. Upon making a determination that a drug in its possession or 
control is a suspect foreign product, or upon receiving a request for 
verification from FDA that the Foreign Seller has determined that a 
product within its possession or control is a suspect foreign product, a 
Foreign Seller must:
    (A) Quarantine such product within its possession or control until 
such product is cleared or dispositioned;
    (B) Promptly conduct an investigation, in coordination with the 
Importer and the manufacturer, as applicable, to determine whether the 
product is an illegitimate foreign product, and verify the product at 
the package level, including the SSI; and
    (C) If the Foreign Seller makes the determination that a suspect 
foreign product is not an illegitimate foreign product, promptly notify 
FDA of such determination for those products that FDA has requested 
verification.
    (ii) Determine whether a drug in its possession or control that it 
intends to sell to the Importer under a SIP is an illegitimate foreign 
product. Upon making a determination that a drug in

[[Page 225]]

its possession or control is an illegitimate foreign product, the 
Foreign Seller must:
    (A) Quarantine such product within the possession or control of the 
Foreign Seller from product intended for distribution until such product 
is dispositioned;
    (B) Disposition the illegitimate foreign product within the 
possession or control of the Foreign Seller;
    (C) Take reasonable and appropriate steps to assist a manufacturer 
or Importer to disposition an illegitimate product not in the possession 
or control of the Foreign Seller; and
    (D) Retain a sample of the product for further physical examination 
or laboratory analysis of the product by the manufacturer or FDA (or 
other appropriate Federal or State official) upon request by FDA (or 
other appropriate Federal or State official), as necessary and 
appropriate.
    (2)(i) Upon determining that a product in the possession or control 
of the Foreign Seller is an illegitimate foreign product, the Foreign 
Seller must notify FDA and the Importer that the Foreign Seller received 
such illegitimate product not later than 24 hours after making such 
determination.
    (ii) Upon the receipt of a notification from the manufacturer, FDA, 
the Importer or other wholesale distributor, or dispenser that a 
determination has been made that a product that had been sold by the 
Foreign Seller is an illegitimate foreign product, a Foreign Seller must 
identify all illegitimate foreign product subject to such notification 
that is in the possession or control of the Foreign Seller, including 
any product that is subsequently received, and perform the activities to 
investigate the product described in paragraph (c)(1) of this section.
    (iii) Upon making a determination, in consultation with FDA, that a 
notification is no longer necessary, a Foreign Seller must promptly 
notify the Importer and person who sent the notification that the 
notification is terminated.
    (iv) A Foreign Seller must keep records of the disposition of an 
illegitimate foreign product for not less than 6 years after the 
conclusion of the disposition.
    (3) Upon request by FDA, or other appropriate Federal or State 
official, in the event of a recall or for purposes of investigating a 
suspect foreign product or an illegitimate foreign product, a Foreign 
Seller must promptly provide the official with information about its 
transactions with the manufacturer and the Importer.
    (4) A Foreign Seller, upon receiving a shipment of eligible 
prescription drugs from the manufacturer, must:
    (i) Separate the portion of drugs intended for sale to the Importer 
located in the United States, and store such portion separately from 
that portion of product intended for sale in the Canadian market;
    (ii) Assign an SSI to each package and homogenous case intended for 
sale to the Importer in the United States, unless each such package and 
homogenous case displayed a manufacturer-affixed or imprinted product 
identifier, as such term is defined in section 581(14) of the Federal 
Food, Drug, and Cosmetic Act, at the time of receipt by the Foreign 
Seller;
    (iii) Affix or imprint the SSI on each package and homogenous case 
intended for sale to the Importer in the United States. Such SSI must be 
located on blank space on the package or homogenous case and must not 
obscure any labeling for the Canadian market, including the DIN; and
    (iv) Keep records associating the SSI with the DIN and all the 
records the Foreign Seller received from the manufacturer upon receipt 
of the original shipment intended for the Canadian market for not less 
than 6 years.
    (5) Upon receiving a request for verification from the Importer or 
other authorized repackager, wholesale distributor, or dispenser that is 
in possession or control of a product such person believes to be 
distributed by such Foreign Seller, a Foreign Seller must, not later 
than 24 hours after receiving the request for verification, or in such 
other reasonable time as determined by the FDA based on the 
circumstances of the request, notify the person making the request 
whether the SSI that is the subject of the request corresponds to the 
SSI affixed or imprinted by the Foreign Seller. If a Foreign Seller 
responding to a request for verification

[[Page 226]]

identifies an SSI that does not correspond to that SSI affixed or 
imprinted by the Foreign Seller, the Foreign Seller must treat such 
product as suspect foreign product and conduct an investigation as 
described in paragraph (c)(1) of this section. If the Foreign Seller 
determines the product is an illegitimate foreign product, the Foreign 
Seller must advise the person making the request of such determination 
at the time such Foreign Seller responds to the request for 
verification.
    (6) For each transaction between the Foreign Seller and the Importer 
for an eligible prescription drug, the Foreign Seller must provide:
    (i) A statement that the Foreign Seller purchased the product 
directly from the manufacturer;
    (ii) The proprietary name (if any) and the established name of the 
product;
    (iii) The strength and dosage form of the product;
    (iv) The container size;
    (v) The number of containers;
    (vi) The lot number of the product assigned by the manufacturer;
    (vii) The date of the transaction;
    (viii) The date of the shipment, if more than 24 hours after the 
date of the transaction;
    (ix) The business name and address of the person associated with the 
Foreign Seller from whom ownership is being transferred;
    (x) The business name and address of the person associated with the 
Importer to whom ownership is being transferred;
    (xi) The SSI for each package and homogenous case of product; and
    (xii) The Canadian DIN for each product transferred.
    (7) Upon a request by FDA, or other appropriate Federal or State 
official, in the event of a recall or for purposes of investigating a 
suspect foreign product or an illegitimate foreign product, the Foreign 
Seller must promptly provide the official with information about its 
transactions with the manufacturer and the Importer.
    (d) Importers. (1) An Importer of an eligible prescription drug must 
purchase the drug directly from a Foreign Seller in Canada.
    (2) Upon receipt of an eligible prescription drug in a transaction 
from the Foreign Seller, an Importer must facilitate the affixation or 
imprinting of a product identifier, as defined in section 581(14) of the 
Federal Food, Drug, and Cosmetic Act, for all eligible prescription 
drugs. The Importer must ensure that such affixation or imprinting 
occurs at the same time the product is relabeled with the required U.S.-
approved labeling for the drug product and, except for repackaging 
necessary to perform the relabeling described in this part, cannot 
otherwise relabel or repackage the product. The Importer may affix or 
imprint the product identifier, or the Importer may contract with an 
entity registered with FDA under part 207 of this chapter to accomplish 
such relabeling, provided that the entity does not otherwise relabel or 
repackage the product, except for repackaging that is necessary to 
perform the relabeling described in this part. Any entity with which the 
Importer contracts to accomplish such labeling must, even if not engaged 
in a repackaging operation with respect to the eligible prescription 
drug, have systems and processes in place to meet applicable 
requirements of a ``repackager'' under section 582(e) of the Federal 
Food, Drug, and Cosmetic Act for any transaction involving the eligible 
prescription drug.
    (3) The repackager that affixes or imprints the product identifier 
on each package and homogenous case of an eligible prescription drug in 
accordance with section 582 of the Federal Food, Drug, and Cosmetic Act, 
which may be the Importer or the Importer's authorized repackager--
    (i) May affix or imprint a product identifier only on a package of 
an eligible prescription drug that has a serial number that was assigned 
and affixed by the Foreign Seller;
    (ii) Must maintain the product identifier information for such drug 
for not less than 6 years; and
    (iii) Must maintain records for not less than 6 years that associate 
the product identifier the repackager affixes or imprints with the 
serial number assigned by the Foreign Seller and the Canadian DIN.
    (4) An Importer must retain records, for not less than 6 years, that 
allow the

[[Page 227]]

Importer to associate the product identifier affixed or imprinted on 
each package or homogenous case of product it received from the Foreign 
Seller, with the SSI that had been assigned by the Foreign Seller, and 
the Canadian DIN that was on the package when the Foreign Seller 
received the product from the manufacturer.
    (5) An Importer must, upon receipt of an eligible prescription drug 
and records from a Foreign Seller, compare such information with 
information the Importer received from the manufacturer, including 
relevant documentation about the transaction that the manufacturer 
provided to the Foreign Seller upon its transfer of ownership of the 
product for the Canadian market.
    (6) An Importer must comply with all applicable requirements of 
section 582 of the Federal Food, Drug, and Cosmetic Act, including 
requirements that apply to subsequent transactions with trading 
partners, unless a waiver, exception, or exemption applies.
    (7) For transactions of eligible prescription drugs between 
Importers and Foreign Sellers under a SIP, an Importer is exempt from 
the following specific supply chain security requirements that are 
otherwise applicable:
    (i) An Importer is exempt from the prohibition on receiving a 
product for which the previous owner did not provide the transaction 
history, transaction information, and transaction statement, under 
sections 582(c)(1)(A) or (d)(1)(A) of the Federal Food, Drug, and 
Cosmetic Act, as applicable, provided that the Importer receives from 
the Foreign Seller the information required under paragraph (c) of this 
section.
    (ii) An Importer is exempt from the prohibition on receiving a 
product that is not encoded with a product identifier, under sections 
582(c)(2) or (d)(2) of the Federal Food, Drug, and Cosmetic Act, as 
applicable, provided that the product the Importer received from the 
Foreign Seller has an SSI.
    (iii) An Importer is exempt from the prohibition on conducting a 
transaction with an entity that is not an ``authorized trading 
partner,'' under sections 582(c)(3) or (d)(3) of the Federal Food, Drug, 
and Cosmetic Act, as applicable.
    (iv) An Importer is exempt from the requirement to verify that a 
product in the Importer's possession or control contains a 
``standardized numerical identifier'' at the package level, under 
sections 582(c)(4)(A)(i)(II) or (d)(4)(A)(ii)(II) of the Federal Food, 
Drug, and Cosmetic Act as applicable, provided that the Importer 
verifies that each package and homogenous case of the product includes 
the SSI affixed or imprinted by the Foreign Seller.



Sec.  251.15  Qualifying laboratory requirements.

    (a) To be considered a qualifying laboratory for purposes of section 
804 of the Federal Food, Drug, and Cosmetic Act and this part, a 
laboratory must have ISO 17025 accreditation.
    (b) To be considered a qualifying laboratory for purposes of section 
804 of the Federal Food, Drug, and Cosmetic Act and this part, a 
laboratory must have an FDA inspection history and it must have 
satisfactorily addressed any objectionable conditions or practices 
identified during its most recent FDA inspection, if applicable.
    (c) To be considered a qualifying laboratory for purposes of section 
804 of the Federal Food, Drug, and Cosmetic Act and this part, a 
laboratory must comply with the applicable current good manufacturing 
practice requirements, including provisions regarding laboratory 
controls in Sec.  211.160 of this chapter and laboratory records in 
Sec.  211.194 of this chapter.



Sec.  251.16  Laboratory testing requirements.

    (a) The manufacturer or the Importer must arrange for drugs imported 
under an authorized SIP to be tested by a qualifying laboratory.
    (b) Unless the manufacturer conducts the Statutory Testing, in 
accordance with this part, the manufacturer of the drugs imported under 
an authorized SIP must supply to the Importer, within 30 calendar days 
of receiving the Importer's request, all information needed to conduct 
the Statutory Testing, including any testing protocols, Certificate of 
Analysis, and samples of analytical reference standards that the

[[Page 228]]

manufacturer has developed. The manufacturer must also provide the 
Importer, within 30 calendar days of receiving the Importer's request, 
with formulation information about the HPFB-approved drug, a stability-
indicating assay, and the FDA-approved drug to facilitate 
authentication.
    (c) Testing done on a statistically valid sample of the batch or 
shipment, as applicable, must be sufficiently thorough to establish, in 
conjunction with data and information from the manufacturer, that the 
batch or shipment is eligible for importation under a SIP. The size of 
the sample must be large enough to enable a statistically valid 
statement to be made regarding the authenticity and stability of the 
quantity of the batch in the shipment or the entire shipment, as 
applicable.
    (d) The statistically valid sample of the HPFB-approved drug must be 
subjected to testing to confirm that the HPFB-approved drug meets the 
FDA-approved drug's specifications and standards, which include the 
analytical procedures and methods and the acceptance criteria. In 
addition, to test for degradation, a stability-indicating assay provided 
by the manufacturer must be conducted on the sample of the drug that is 
proposed for import.
    (e) If the manufacturer performs the Statutory Testing at a 
qualifying laboratory, the testing results, a complete set of laboratory 
records, a detailed description of the selection method for the samples, 
the testing methods used, complete data derived from all tests necessary 
to ensure that the eligible prescription drug meets the specifications 
and standards of the FDA-approved drug that are established in the NDA 
or ANDA, a Certificate of Analysis, and any other documentation 
demonstrating that the testing meets the requirements under section 804 
must be submitted in electronic format directly to FDA via the ESG or to 
an alternative transmission point identified by FDA. The manufacturer 
must notify the Importer and FDA of the manufacturer's intent to perform 
the Statutory Testing, and identify the qualifying laboratory for FDA 
review and approval pursuant to section 804 of the Federal Food, Drug, 
and Cosmetic Act, within 30 calendar days of receipt of the request from 
the Importer described in paragraph (b) of this section.
    (f) Regardless of whether testing under this section is performed by 
the manufacturer or Importer, the sample of a batch or shipment of drugs 
must be randomly selected for testing or, in the alternative, the sample 
must be selected to be representative of the quantity of the batch in a 
shipment or of a shipment, as applicable.
    (g) Information supplied by the manufacturer to authenticate the 
prescription drug being tested and confirm that the labeling of the 
prescription drug complies with labeling requirements under the Federal 
Food, Drug, and Cosmetic Act, and any trade secrets or commercial or 
financial information that is privileged or confidential that the 
manufacturer supplies for the purposes of testing or otherwise complying 
with the Federal Food, Drug, and Cosmetic Act and this part, must be 
kept in strict confidence and used only for the purposes of testing or 
otherwise complying with the Federal Food, Drug, and Cosmetic Act and 
this part.
    (h) To ensure that the information described in paragraph (g) of 
this section is protected:
    (1) The information that the manufacturer supplies about a 
prescription drug must not be disseminated except for the purpose of 
testing or otherwise complying with the Federal Food, Drug, and Cosmetic 
Act and this part; and
    (2) The SIP Sponsor must take all of the steps set out in the 
authorized SIP Proposal to ensure that the information is kept in strict 
confidence and used only for the purpose of testing or otherwise 
complying with the Federal Food, Drug, and Cosmetic Act and this part.



Sec.  251.17  Importation requirements.

    (a) Importers must ensure that each shipment of eligible 
prescription drugs imported or offered for import pursuant to this part 
is accompanied by an import entry for consumption filed electronically 
as a formal entry in ACE, or another CBP-authorized electronic data 
interchange system, and designated in such a system as a drug imported 
pursuant to this part.

[[Page 229]]

    (b) The Importer may make entry for consumption and arrival of 
shipments containing eligible prescription drugs only at the CBP port of 
entry authorized by FDA to import eligible prescription drugs under 
section 804 of the Federal Food, Drug, and Cosmetic Act. The Importer 
must keep the product at a secured warehouse, location within a specific 
foreign trade zone, or other secure distribution facility controlled by 
or under contract with the Importer, and under appropriate environmental 
conditions to maintain the integrity of the products, until FDA issues 
an admissibility decision. The secured warehouse or other secure 
distribution facility must be within 30 miles of the authorized Port of 
Entry for examination.
    (c) If the entry for consumption is filed in ACE before the testing 
and relabeling of the eligible prescription drug, the Importer must 
submit an application to bring the drug into compliance and must relabel 
and test the drug in accordance with the plan approved by FDA pursuant 
to Sec. Sec.  1.95 and 1.96 of this chapter.
    (d) Upon arrival in the United States of an initial shipment that 
contains a batch of an eligible prescription drug identified in a Pre-
Import Request that has been granted by FDA, the Importer must select a 
statistically valid sample of that batch to send to a qualifying 
laboratory for Statutory Testing, unless the manufacturer conducts the 
Statutory Testing at a qualifying laboratory.
    (1) In the case of any subsequent shipment composed entirely of a 
batch of an eligible prescription drug that has already been tested in 
accordance with this part, the Importer must select a statistically 
valid sample of the shipment to send to a qualifying laboratory for 
Statutory Testing.
    (2) The Importer must send three sets of the samples sent to the 
qualifying laboratory in accordance with Sec.  251.16 to the FDA field 
lab identified by FDA when the Agency granted the Pre-Import Request.
    (3) The Importer must submit to FDA a complete set of laboratory 
records, a detailed description of the sampling method used to select 
the sample of the eligible prescription drug sent to the qualifying 
laboratory, the testing protocols used, complete data derived from all 
tests necessary to ensure that the eligible prescription drug meets the 
specifications of the FDA-approved drug that are established in the NDA 
or ANDA, a Certificate of Analysis, and all relevant documentation 
demonstrating that the testing meets the requirements under section 
804(e)(1) of the Federal Food, Drug, and Cosmetic Act, as well as any 
additional information FDA deems necessary to evaluate whether the drug 
meets manufacturing, quality, and safety standards.
    (e) If the manufacturer conducts the Statutory Testing, upon arrival 
in the United States of an initial shipment that contains a batch of an 
eligible prescription drug identified in a Pre-Import Request that has 
been granted by FDA, a statistically valid sample of that batch must be 
selected to send to a qualifying laboratory for the Statutory Testing.
    (1) In the case of any subsequent shipment composed entirely of a 
batch or batches of an eligible prescription drug that has already been 
tested in accordance with this part, the manufacturer must select a 
statistically valid sample of that shipment to send to a qualifying 
laboratory for that Statutory Testing.
    (2) The manufacturer must send three sets of the samples the 
manufacturer sent to the qualifying laboratory in accordance with Sec.  
251.16 to the FDA field lab identified by FDA when the Agency granted 
the Pre-Import Request.
    (3) The manufacturer must submit to FDA, directly in electronic form 
to the ESG or to an alternative transmission point identified by FDA, a 
complete set of laboratory records, a detailed description of the 
selection method for the sample of the eligible prescription drug sent 
to the qualifying laboratory, the testing methods used, complete data 
derived from all tests necessary to ensure that the eligible 
prescription drug meets the conditions in the FDA-approved drug's NDA or 
ANDA, a Certificate of Analysis, and all relevant documentation 
demonstrating that the testing meets the requirements under section 
804(e)(1) of the Federal Food, Drug, and Cosmetic Act, as well as any

[[Page 230]]

additional information FDA deems necessary to evaluate whether the drug 
meets manufacturing, quality, and safety standards.
    (f) After FDA has reviewed the testing results provided by the 
Importer or manufacturer and determined that they are acceptable, FDA 
will notify the Importer and then the Importer must cause the eligible 
prescription drug to be relabeled with the required U.S. labeling.
    (g) After the eligible prescription drug has been shown by testing 
and relabeling to meet the requirements of section 804 of the Federal 
Food, Drug, and Cosmetic Act and this part, the Importer or the 
manufacturer must provide to FDA the written certification described in 
section 804(d)(1)(K) of the Federal Food, Drug, and Cosmetic Act in 
electronic format via the ESG or to an alternative transmission point 
identified by FDA.



Sec.  251.18  Post-importation requirements.

    (a) Stopping importation. If at any point a SIP Sponsor determines 
that a drug, manufacturer, Foreign Seller, Importer, qualifying 
laboratory, or other participant in or element of the supply chain in 
the authorized SIP does not meet all applicable requirements of the 
Federal Food, Drug, and Cosmetic Act, FDA regulations, and the 
authorized SIP, the SIP Sponsor must immediately stop importation of all 
drugs under the SIP, notify FDA, and demonstrate to FDA that importation 
has in fact been stopped.
    (b) Field alert reports. Importers must submit NDA and ANDA field 
alert reports, as described in Sec. Sec.  314.81(b)(1) and 314.98 of 
this chapter, to the manufacturer and to FDA.
    (c) Additional reporting requirements for combination products. For 
combination products containing a device constituent part, Importers 
must submit the reports to the manufacturer and to FDA described in 
Sec.  4.102(c)(1) of this chapter and maintain the records described in 
Sec. Sec.  4.102(c)(1) and 4.105(b) of this chapter.
    (d) Adverse event reports--(1) Scope. An Importer must establish and 
maintain records and submit to FDA and the manufacturer reports of all 
adverse events associated with the use of its drug products imported 
under this part.
    (2) Review of safety information. The Importer must promptly review 
all domestic safety information for the eligible prescription drugs 
obtained or otherwise received by the Importer.
    (3) Expedited ICSRs. The Importer must submit expedited ICSRs for 
each domestic adverse event to FDA and the manufacturer as soon as 
possible but no later than 15 calendar days from the date when the 
Importer has both met the reporting criteria described in this paragraph 
(d) and acquired a minimum data set for that adverse event.
    (i) Serious, unexpected adverse events. The Importer must submit 
expedited ICSRs for domestic adverse events reported to the Importer 
spontaneously (such as reports initiated by a patient, consumer, or 
healthcare professional) that are both serious and unexpected, whether 
or not the Importer believes the events are related to the product.
    (ii) Other adverse event reports to be expedited upon notification 
by FDA. Upon notification by FDA, the Importer must submit as expedited 
ICSRs any adverse event reports that do not qualify for expedited 
reporting under paragraph (d)(3)(i) of this section. The notice will 
specify the adverse events to be reported and the reason for requiring 
the expedited reports.
    (4) Followup reports for expedited ICSRs. The Importer must actively 
seek any missing data elements under paragraph (d)(7) of this section or 
updated information for any previously submitted expedited ICSR under 
paragraph (d)(3) of this section. The Importer must also investigate any 
new information it obtains or otherwise receives about previously 
submitted expedited ICSRs. The Importer must submit followup reports for 
expedited ICSRs to FDA and the manufacturer as soon as possible but no 
later than 15 calendar days after obtaining the new information. The 
Importer must document and maintain records of its efforts to obtain 
missing or incomplete information.

[[Page 231]]

    (5) Nonexpedited ICSRs. The Importer must submit to FDA and the 
manufacturer an ICSR for each domestic adverse event not reported under 
paragraph (d)(3)(i) of this section (all serious, expected adverse 
events and nonserious adverse events) within 90 calendar days from the 
date when the Importer has both met the reporting criteria described in 
this paragraph (d) and acquired a minimum data set for that adverse 
event.
    (6) Completing and submitting safety reports. This paragraph (d)(6) 
describes how to complete and submit ICSRs required under this section. 
Additionally, upon written notice, FDA may require the Importer to 
submit any of this section's adverse event reports at a different time 
period than identified in paragraphs (d)(1) through (5) and (7) through 
(11) of this section.
    (i) Electronic format for submissions. (A) ICSR and ICSR attachments 
must be submitted in an electronic format that FDA can process, review, 
and archive, as described in Sec.  314.80(g)(1) of this chapter.
    (B) The Importer may request, in writing, a temporary waiver of the 
requirements in paragraph (d)(6)(i)(A) of this section, as described in 
Sec.  314.80(g)(2) of this chapter. These waivers will be granted on a 
limited basis for good cause shown.
    (ii) Completing and submitting ICSRs--(A) Single submission. Submit 
each ICSR only once.
    (B) Separate ICSR. The Importer must submit a separate ICSR for each 
patient who experiences an adverse event reportable under paragraph 
(d)(3)(i) or (ii) or (d)(4) or (5) of this section.
    (C) Coding terms. The adverse event terms described in the ICSR must 
be coded using standardized medical terminology.
    (D) Minimum data set. All ICSRs submitted under this section must 
contain at least the minimum data set for an adverse event. The Importer 
must actively seek the minimum data set in a manner consistent with its 
written procedures under paragraph (d)(9) of this section. The Importer 
must document and maintain records of its efforts to obtain the minimum 
data set.
    (E) ICSR elements. The Importer must complete all available elements 
of an ICSR as specified in paragraph (d)(7) of this section.
    (1) The Importer must actively seek any information needed to 
complete all applicable elements, consistent with its written procedures 
under paragraph (d)(9) of this section.
    (2) The Importer must document and maintain records of its efforts 
to obtain the missing information.
    (F) Supporting documentation. When submitting supporting 
documentation for expedited ICSRs of adverse events, the Importer must:
    (1) Submit for each ICSR for a domestic adverse event, if available, 
a copy of the autopsy report if the patient died, or a copy of the 
hospital discharge summary if the patient was hospitalized. The Importer 
must submit each document as an ICSR attachment. The ICSR attachment 
must be submitted either with the initial ICSR or no later than 15 
calendar days after obtaining the document.
    (2) Include in the ICSR a list of available, relevant documents 
(such as medical records, laboratory results, death certificates) that 
are held in its drug product safety files. Upon written notice from FDA, 
the Importer must submit a copy of these documents within 5 calendar 
days of the FDA notice.
    (7) Information reported on ICSRs. ICSRs must include the following 
information:
    (i) Patient information, which includes:
    (A) Patient identification code;
    (B) Patient age at the time of adverse event, or date of birth;
    (C) Patient gender; and
    (D) Patient weight.
    (ii) Adverse event, which includes:
    (A) Outcome attributed to adverse event;
    (B) Date of adverse event;
    (C) Date of ICSR submission;
    (D) Description of adverse event (including a concise medical 
narrative);
    (E) Adverse drug event term(s);
    (F) Description of relevant tests, including dates and laboratory 
data; and
    (G) Other relevant patient history, including preexisting medical 
conditions.
    (iii) Suspect medical product(s), which includes:
    (A) Name;

[[Page 232]]

    (B) Dose, frequency, and route of administration used;
    (C) Therapy dates;
    (D) Diagnosis for use (indication);
    (E) Whether the product is a combination product;
    (F) Whether adverse event abated after drug use stopped or dose 
reduced;
    (G) Whether adverse event reappeared after reintroduction of drug;
    (H) Lot number;
    (I) Expiration date;
    (J) NDC; and
    (K) Concomitant medical products and therapy dates.
    (iv) Initial reporter information, which includes:
    (A) Name, address, and telephone number;
    (B) Whether the initial reporter is a healthcare professional; and
    (C) Occupation, if a healthcare professional.
    (v) Importer information, which includes:
    (A) Importer name and contact office address;
    (B) Importer telephone number;
    (C) Date the report was received by the Importer;
    (D) Whether the ICSR is an expedited report;
    (E) Whether the ICSR is an initial report or followup report; and
    (F) Unique case identification number, which must be the same in the 
initial report and any subsequent followup report(s).
    (8) Recordkeeping. (i) For a period of 10 years from the initial 
receipt of information, the Importer must maintain records of 
information relating to adverse event reports under this section, 
whether or not submitted to FDA.
    (ii) These records must include raw data, correspondence, and any 
other information relating to the evaluation and reporting of adverse 
event information that is obtained by the Importer.
    (iii) Upon written notice by FDA, the Importer must submit any or 
all of these records to FDA within 5 calendar days after receipt of the 
notice. The Importer must permit any authorized FDA employee, at 
reasonable times, to access, copy, and verify its established and 
maintained records described in this section.
    (9) Written procedures. The Importer must develop written procedures 
needed to fulfill the requirements in this section for the surveillance, 
receipt, evaluation, and reporting to FDA and the manufacturer of 
adverse event information, including procedures for employee training, 
and for obtaining and processing safety information from the Foreign 
Seller.
    (10) Patient privacy. The Importer must not include in reports under 
this section the names and addresses of individual patients; instead, 
the Importer must assign a unique code for identification of the 
patient. The Importer must include the name of the reporter from whom 
the information was received as part of the initial reporter 
information, even when the reporter is the patient. As set forth in 
FDA's public information regulations in part 20 of this chapter, FDA 
generally may not disclose the names of patients, individual reporters, 
healthcare professionals, hospitals, and geographical identifiers 
submitted to FDA in adverse event reports.
    (11) Safety reporting disclaimer. (i) A report or information 
submitted by the Importer under this section (and any release by FDA of 
that report or information) does not necessarily reflect a conclusion by 
the Importer or by FDA that the report or information constitutes an 
admission that the eligible prescription drug imported under section 804 
of the Federal Food, Drug, and Cosmetic Act caused or contributed to an 
adverse event.
    (ii) The Importer need not admit, and may deny, that the report or 
information submitted as described in this section constitutes an 
admission that the drug product caused or contributed to an adverse 
event.
    (e) Drug recalls. (1) The SIP Sponsor must establish a procedure to 
track the public announcements of the manufacturer of each drug it 
imports under section 804 of the Federal Food, Drug, and Cosmetic Act, 
and the SIP Sponsor must also monitor FDA's recall website for recall or 
market withdrawal information relevant to the drugs that it imports 
under section 804.
    (2) If FDA, the SIP Sponsor, the Foreign Seller, the Importer, or 
the manufacturer determines that a recall is

[[Page 233]]

warranted, the SIP Sponsor must effectuate the recall in accordance with 
its written recall plan under paragraph (e)(3) of this section.
    (3) A SIP must have a written recall plan that describes the 
procedures to perform a recall of the product and specifies who will be 
responsible for performing the procedures. The recall plan must cover 
recalls mandated or requested by FDA and recalls initiated by the SIP 
Sponsor, the Foreign Seller, the Importer, or the manufacturer. The 
recall plan must include sufficient procedures for the SIP Sponsor to:
    (i) Immediately cease distribution of the drugs affected by the 
recall;
    (ii) Directly notify consignees of the drug(s) included in the 
recall, including how to return or dispose of the recalled drugs;
    (iii) Specify the depth to which the recall will extend (e.g., 
wholesale, intermediate wholesale, retail or consumer level) if not 
specified by FDA;
    (iv) Notify the public about any hazard(s) presented by the recalled 
drug when appropriate to protect the public health;
    (v) Conduct effectiveness checks to verify that all consignees at 
the specified recall depth have received notification about the recall 
and have taken appropriate action;
    (vi) Appropriately dispose of recalled product; and
    (vii) Notify FDA of the recall.
    (4) In the event of a recall, the Importer must, upon request by 
FDA, provide transaction history, information, and statement (as these 
terms are defined in sections 581(25), 581(26), and 581(27) of the 
Federal Food, Drug, and Cosmetic Act), in accordance with applicable 
requirements under sections 582(c)(1)(C) and 582(d)(1)(D).
    (i) The Importer must also provide to FDA, upon request, information 
given by the manufacturer under Sec.  251.14(a)(6), including 
transaction documents that were provided from the manufacturer to the 
Foreign Seller.
    (ii) The Foreign Seller must provide to FDA, upon request, 
information about its transactions of the recalled drug with the 
manufacturer and the Importer.
    (5) The Foreign Seller and Importer must cooperate with any recalls, 
including recalls initiated by the SIP Sponsor, FDA, the Foreign Seller, 
the Importer, or the drug's manufacturer.



Sec.  251.19  Reports to FDA.

    (a) A SIP Sponsor must submit a report to FDA each quarter in 
electronic format via the ESG or to an alternative transmission point 
identified by FDA containing the information set forth in this section, 
beginning after the SIP Sponsor files an electronic import entry for 
consumption for its first shipment of drugs under the SIP. If the SIP 
Sponsor specifies in such report that the information contained in the 
report is being transmitted on behalf of the Importer and in order to 
fulfill the Importer's obligation under Sec.  251.12, the Importer need 
not separately submit such information to FDA.
    (b) The report in paragraph (a) of this section must contain the 
following information:
    (1) The name, address, telephone number, and professional license 
number (if any) of the Importer;
    (2) The name and quantity of the active ingredient of the imported 
eligible prescription drug(s);
    (3) A description of the dosage form of the eligible prescription 
drug(s);
    (4) The date(s) on which the eligible prescription drug(s) were 
shipped;
    (5) The quantity of the eligible prescription drug(s) that was 
shipped;
    (6) The lot or control number assigned to the eligible prescription 
drug(s) by the manufacturer of the eligible prescription drug(s);
    (7) The point of origin (i.e., the manufacturer) and the destination 
(i.e., the wholesaler, pharmacy, or patient to whom the Importer sells 
the drug) of the eligible prescription drug(s);
    (8) The per unit price paid by the Importer for the prescription 
drug(s) in U.S. dollars; and
    (9) Any other information that FDA determines is necessary for the 
protection of the public health.
    (c) The Importer must also confirm as part of the report in 
paragraph (a) of this section that the eligible prescription drug(s) 
were bought directly from the manufacturer by the Foreign Seller and 
that the Foreign Seller sold the eligible prescription drug(s) directly 
to the Importer.

[[Page 234]]

    (d) The report in paragraph (a) of this section must include the 
following documentation:
    (1) Documentation from the Foreign Seller specifying the 
manufacturer of each eligible prescription drug and the quantity of each 
lot of the eligible prescription drug(s) received by the Foreign Seller 
from that manufacturer;
    (2) Documentation demonstrating that the eligible prescription drug 
was received by the Foreign Seller from the manufacturer and 
subsequently shipped by the Foreign Seller to the Importer;
    (3) Documentation of the quantity of each lot of the eligible 
prescription drug(s) received by the Foreign Seller, demonstrating that 
the quantity being imported into the United States is not more than the 
quantity that was received by the Foreign Seller; and
    (4) Documentation demonstrating that the sampling and testing 
requirements described in section 804(d)(1)(J)(i)(III) of the Federal 
Food, Drug, and Cosmetic Act were met for each shipment of each eligible 
prescription drug.
    (e) The report in paragraph (a) of this section must include 
certifications from the Importer for each shipment of each eligible 
prescription drug that the drug is approved for marketing in the United 
States and is not adulterated or misbranded and meets all labeling 
requirements under the Federal Food, Drug, and Cosmetic Act. This 
certification must include:
    (1) That there is an authorized SIP;
    (2) That the imported drug is covered by the authorized SIP;
    (3) That the drug is an eligible prescription drug as defined in 
this part;
    (4) That the FDA-approved counterpart of the drug is currently 
commercially marketed in the United States;
    (5) That the drug is approved for marketing in Canada; and
    (6) That the drug is not adulterated or misbranded and meets all 
labeling requirements under the Federal Food, Drug, and Cosmetic Act.
    (f) The report in paragraph (a) of this section must include 
laboratory records, including complete data derived from all tests 
necessary to ensure that each eligible prescription drug is in 
compliance with established specifications and standards, and 
documentation demonstrating that the Statutory Testing was conducted at 
a qualifying laboratory, unless the manufacturer conducted the testing 
and submitted this information directly to FDA.
    (g) The report in paragraph (a) of this section must include data, 
information, and analysis on the SIP's cost savings to the American 
consumer for the drugs imported under the SIP.
    (h) A SIP Sponsor must submit a report to FDA within 10 calendar 
days, in electronic format via the ESG or to an alternative transmission 
point identified by FDA, regarding any applicable criminal conviction, 
violation of law, or disciplinary action as described in Sec.  
251.3(e)(2) and (3).



Sec.  251.20  Severability.

    The provisions of this part are not separate and are not severable 
from one another. If any provision is stayed or determined to be invalid 
or unenforceable, the remaining provisions shall not continue in effect.



Sec.  251.21  Consequences for violations.

    (a) An article that is imported or offered for import into the 
United States in violation of section 804 of the Federal Food, Drug, and 
Cosmetic Act or this part is subject to refusal under section 801 of the 
Federal Food, Drug, and Cosmetic Act.
    (b) The importation of a prescription drug in violation of section 
804 of the Federal Food, Drug, and Cosmetic Act; the falsification of 
any record required to be maintained or provided to FDA under section 
804; or any other violation of this part is a prohibited act under 
section 301(aa) of the Federal Food, Drug, and Cosmetic Act.



PART 290_CONTROLLED DRUGS--Table of Contents



                      Subpart A_General Provisions

Sec.
290.1 Controlled substances.
290.2 Exemption from prescription requirements.
290.5 Drugs; statement of required warning.
290.6 Spanish-language version of required warning.
290.10 Definition of emergency situation.

[[Page 235]]

Subpart B [Reserved]

Subpart C--Requirements for Specific Controlled Drugs [Reserved]

    Authority: 21 U.S.C. 352, 353, 355, 371.

    Source: 40 FR 14040, Mar. 27, 1975, unless otherwise noted.



                      Subpart A_General Provisions



Sec.  290.1  Controlled substances.

    Any drug that is a controlled substance listed in schedule II, III, 
IV, or V of the Federal Controlled Substances Act or implementing 
regulations must be dispensed by prescription only as required by 
section 503(b)(1) of the Federal Food, Drug, and Cosmetic Act unless 
specifically exempted in Sec.  290.2.

[67 FR 4906, Feb. 1, 2002]



Sec.  290.2  Exemption from prescription requirements.

    The prescription-dispensing requirements of section 503(b)(1) of the 
Federal Food, Drug, and Cosmetic Act are not necessary for the 
protection of the public health with respect to a compound, mixture, or 
preparation containing not more than 200 milligrams of codeine per 100 
milliliters or per 100 grams that also includes one or more nonnarcotic 
active medicinal ingredients in sufficient proportion to confer upon the 
compound, mixture, or preparation valuable medicinal qualities other 
than those possessed by codeine alone.

[67 FR 4907, Feb. 1, 2002]



Sec.  290.5  Drugs; statement of required warning.

    The label of any drug listed as a ``controlled substance'' in 
schedule II, III, or IV of the Federal Controlled Substances Act shall, 
when dispensed to or for a patient, contain the following warning: 
``Caution: Federal law prohibits the transfer of this drug to any person 
other than the patient for whom it was prescribed.'' This statement is 
not required to appear on the label of a controlled substance dispensed 
for use in clinical investigations which are ``blind.''



Sec.  290.6  Spanish-language version of required warning.

    By direction of section 305(c) of the Federal Controlled Substances 
Act, Sec.  290.5, promulgated under section 503(b) of the Federal Food, 
Drug, and Cosmetic Act, requires the following warning on the label of 
certain drugs when dispensed to or for a patient: ``Caution: Federal law 
prohibits the transfer of this drug to any person other than the patient 
for whom it was prescribed.'' The Spanish version of this is: 
``Precaucion: La ley Federal prohibe el transferir de esta droga a otra 
persona que no sea el paciente para quien fue recetada.''



Sec.  290.10  Definition of emergency situation.

    For the purposes of authorizing an oral prescription of a controlled 
substance listed in schedule II of the Federal Controlled Substances 
Act, the term emergency situation means those situations in which the 
prescribing practitioner determines:
    (a) That immediate administration of the controlled substance is 
necessary, for proper treatment of the intended ultimate user; and
    (b) That no appropriate alternative treatment is available, 
including administration of a drug which is not a controlled substance 
under schedule II of the Act, and
    (c) That it is not reasonably possible for the prescribing 
practitioner to provide a written prescription to be presented to the 
person dispensing the substance, prior to the dispensing.

Subpart B [Reserved]

Subpart C--Requirements for Specific Controlled Drugs [Reserved]



PART 299_DRUGS; OFFICIAL NAMES AND ESTABLISHED NAMES--Table of Contents



                      Subpart A_General Provisions

Sec.
299.3 Definitions and interpretations.
299.4 Established names for drugs.
299.5 Drugs; compendial name.


[[Page 236]]


    Authority: 21 U.S.C. 331, 351, 352, 355, 358, 360b, 371.

    Source: 40 FR 14041, Mar. 27, 1975, unless otherwise noted.



                      Subpart A_General Provisions



Sec.  299.3  Definitions and interpretations.

    (a) As used in this part 299, act means the Federal Food, Drug, and 
Cosmetic Act, sections 201-902, 52 Stat. 1040 (21 U.S.C. 321-392), with 
all amendments thereto.
    (b) The definitions and interpretations contained in section 201 of 
the act shall be applicable to such terms when used in this part 299.
    (c) The term official name means, with respect to a drug or 
ingredient thereof, the name designated in this part 299 under section 
508 of the act as the official name.



Sec.  299.4  Established names for drugs.

    (a) Section 508 of the Federal Food, Drug, and Cosmetic Act (added 
by the Kefauver-Harris Drug Amendments of 1962; Pub. L. 87-781) 
authorizes the Commissioner of Food and Drugs to designate an official 
name for any drug if he determines that such action is necessary or 
desirable in the interest of usefulness and simplicity. Section 502(e) 
of the act (as amended by said Drug Amendments) prescribes that the 
labeling of a drug must bear its established name, if there is one, to 
the exclusion of any other nonproprietary name (except the applicable 
systematic chemical name or the chemical formula) and, if the drug is 
fabricated from two or more ingredients, the established name of each 
active ingredient.
    (b) The term established name is defined in section 502(e)(3) of the 
act as (1) an official name designated pursuant to section 508 of the 
act; (2) if no such official name has been designated for the drug and 
the drug is an article recognized in an official compendium, then the 
official title thereof in such compendium; and (3) if neither paragraphs 
(b) (1) or (2) of this section applies, then the common or usual name of 
the drug.
    (c) The Food and Drug Administration recognizes the skill and 
experience of the U.S. Adopted Names Council (USAN) in deriving names 
for drugs. The U.S. Adopted Names Council is a private organization 
sponsored by the American Medical Association, the United States 
Pharmacopeia, and the American Pharmaceutical Association, and has been 
engaged in the assignment of names to drugs since January 1964. The 
Council negotiates with manufacturing firms in the selection of 
nonproprietary names for drugs.
    (d) The Food and Drug Administration cooperates with and is 
represented on the USAN Council. In addition, the Food and Drug 
Administration agrees with ``Guiding Principles for Coining U.S. Adopted 
Names for Drugs,'' published in USAN and the USP Dictionary of Drug 
Names (USAN 1985 ed., 1961-1984 cumulative list), which is incorporated 
by reference. Copies are available from: U.S. Pharmacopeial Convention, 
Inc., 12601 Twinbrook Parkway, Rockville, MD 20852, or are available for 
inspection at the National Archives and Records Administration (NARA). 
For information on the availability of this material at NARA, call 202-
741-6030, or go to: http://www.archives.gov/federal_register/
code_of_federal_regulations/ibr_locations.html. All applicants for new-
drug applications and sponsors for ``Investigational New Drug 
Applications'' (IND's) are encouraged to contact the USAN Council for 
assistance in selection of a simple and useful name for a new chemical 
entity. Approval of a new-drug application providing for the use of a 
new drug substance may be delayed if a simple and useful nonproprietary 
name does not exist for the substance and if one is not proposed in the 
application that meets the above-cited guidelines. Prior use of a name 
in the medical literature or otherwise will not commit the Food and Drug 
Administration to adopting such terminology as official.
    (e) The Food and Drug Administration will not routinely designate 
official names under section 508 of the act. As a result, the 
established name under section 502(e) of the act will ordinarily be 
either the compendial name of the drug or, if there is no compendial 
name, the common and usual name of the drug. Interested persons, in the 
absence of the designation by the food and Drug Administration of an 
official

[[Page 237]]

name, may rely on as the established name for any drug the current 
compendial name or the USAN adopted name listed in USAN and the USP 
Dictionary of Drug Names. The Food and Drug Administration, however, 
will continue to publish official names under the provisions of section 
508 of the act when the agency determines that:
    (1) The USAN or other official or common or usual name is unduly 
complex or is not useful for any other reason;
    (2) Two or more official names have been applied to a single drug, 
or to two or more drugs that are identical in chemical structure and 
pharmacological action and that are substantially identical in strength, 
quality, and purity; or
    (3) No USAN or other official or common or usual name has been 
applied to a medically useful drug. Any official name published under 
section 508 of the act will be the established name of the drug.
    (f) A cumulative list of U.S. adopted names selected and released 
since June 15, 1961, is published yearly by the U.S. Pharmacopeial 
Convention, Inc., in USAN and the USP Dictionary of Drug Names. Copies 
may be purchased from the U.S. Pharmacopeial Convention, Inc., 12601 
Twinbrook Parkway, Rockville, MD 20852.

[40 FR 14041, Mar. 27, 1975, as amended at 49 FR 37575, Sept. 25, 1984; 
53 FR 5369, Feb. 24, 1988; 55 FR 11577, Mar. 29, 1990; 64 FR 401, Jan. 
5, 1999; 69 FR 18803, Apr. 9, 2004]



Sec.  299.5  Drugs; compendial name.

    (a) The name by which a drug is designated shall be clearly 
distinguishing and differentiating from any name recognized in an 
official compendium unless such drug complies in identity with the 
identity prescribed in an official compendium under such recognized 
name.
    (b) The term drug defined in an official compendium means a drug 
having the identity prescribed for a drug in an official compendium.
    (c) A statement that a drug defined in an official compendium 
differs in strength, quality, or purity from the standard of strength, 
quality, or purity set forth for such drug in an official compendium 
shall show all the respects in which such drug so differs, and the 
extent of each such difference.

[[Page 239]]



                              FINDING AIDS




  --------------------------------------------------------------------

  A list of CFR titles, subtitles, chapters, subchapters and parts and 
an alphabetical list of agencies publishing in the CFR are included in 
the CFR Index and Finding Aids volume to the Code of Federal Regulations 
which is published separately and revised annually.

  Table of CFR Titles and Chapters
  Alphabetical List of Agencies Appearing in the CFR
  List of CFR Sections Affected

[[Page 241]]



                    Table of CFR Titles and Chapters




                      (Revised as of April 1, 2024)

                      Title 1--General Provisions

         I  Administrative Committee of the Federal Register 
                (Parts 1--49)
        II  Office of the Federal Register (Parts 50--299)
       III  Administrative Conference of the United States (Parts 
                300--399)
        IV  Miscellaneous Agencies (Parts 400--599)
        VI  National Capital Planning Commission (Parts 600--699)

                    Title 2--Grants and Agreements

            Subtitle A--Office of Management and Budget Guidance 
                for Grants and Agreements
         I  Office of Management and Budget Governmentwide 
                Guidance for Grants and Agreements (Parts 2--199)
        II  Office of Management and Budget Guidance (Parts 200--
                299)
            Subtitle B--Federal Agency Regulations for Grants and 
                Agreements
       III  Department of Health and Human Services (Parts 300--
                399)
        IV  Department of Agriculture (Parts 400--499)
        VI  Department of State (Parts 600--699)
       VII  Agency for International Development (Parts 700--799)
      VIII  Department of Veterans Affairs (Parts 800--899)
        IX  Department of Energy (Parts 900--999)
         X  Department of the Treasury (Parts 1000--1099)
        XI  Department of Defense (Parts 1100--1199)
       XII  Department of Transportation (Parts 1200--1299)
      XIII  Department of Commerce (Parts 1300--1399)
       XIV  Department of the Interior (Parts 1400--1499)
        XV  Environmental Protection Agency (Parts 1500--1599)
     XVIII  National Aeronautics and Space Administration (Parts 
                1800--1899)
        XX  United States Nuclear Regulatory Commission (Parts 
                2000--2099)
      XXII  Corporation for National and Community Service (Parts 
                2200--2299)
     XXIII  Social Security Administration (Parts 2300--2399)
      XXIV  Department of Housing and Urban Development (Parts 
                2400--2499)
       XXV  National Science Foundation (Parts 2500--2599)
      XXVI  National Archives and Records Administration (Parts 
                2600--2699)

[[Page 242]]

     XXVII  Small Business Administration (Parts 2700--2799)
    XXVIII  Department of Justice (Parts 2800--2899)
      XXIX  Department of Labor (Parts 2900--2999)
       XXX  Department of Homeland Security (Parts 3000--3099)
      XXXI  Institute of Museum and Library Services (Parts 3100--
                3199)
     XXXII  National Endowment for the Arts (Parts 3200--3299)
    XXXIII  National Endowment for the Humanities (Parts 3300--
                3399)
     XXXIV  Department of Education (Parts 3400--3499)
      XXXV  Export-Import Bank of the United States (Parts 3500--
                3599)
     XXXVI  Office of National Drug Control Policy, Executive 
                Office of the President (Parts 3600--3699)
    XXXVII  Peace Corps (Parts 3700--3799)
     LVIII  Election Assistance Commission (Parts 5800--5899)
       LIX  Gulf Coast Ecosystem Restoration Council (Parts 5900--
                5999)
        LX  Federal Communications Commission (Parts 6000--6099)

                        Title 3--The President

         I  Executive Office of the President (Parts 100--199)

                           Title 4--Accounts

         I  Government Accountability Office (Parts 1--199)

                   Title 5--Administrative Personnel

         I  Office of Personnel Management (Parts 1--1199)
        II  Merit Systems Protection Board (Parts 1200--1299)
       III  Office of Management and Budget (Parts 1300--1399)
        IV  Office of Personnel Management and Office of the 
                Director of National Intelligence (Parts 1400--
                1499)
         V  The International Organizations Employees Loyalty 
                Board (Parts 1500--1599)
        VI  Federal Retirement Thrift Investment Board (Parts 
                1600--1699)
      VIII  Office of Special Counsel (Parts 1800--1899)
        IX  Appalachian Regional Commission (Parts 1900--1999)
        XI  Armed Forces Retirement Home (Parts 2100--2199)
       XIV  Federal Labor Relations Authority, General Counsel of 
                the Federal Labor Relations Authority and Federal 
                Service Impasses Panel (Parts 2400--2499)
       XVI  Office of Government Ethics (Parts 2600--2699)
       XXI  Department of the Treasury (Parts 3100--3199)
      XXII  Federal Deposit Insurance Corporation (Parts 3200--
                3299)
     XXIII  Department of Energy (Parts 3300--3399)
      XXIV  Federal Energy Regulatory Commission (Parts 3400--
                3499)
       XXV  Department of the Interior (Parts 3500--3599)

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      XXVI  Department of Defense (Parts 3600--3699)
    XXVIII  Department of Justice (Parts 3800--3899)
      XXIX  Federal Communications Commission (Parts 3900--3999)
       XXX  Farm Credit System Insurance Corporation (Parts 4000--
                4099)
      XXXI  Farm Credit Administration (Parts 4100--4199)
    XXXIII  U.S. International Development Finance Corporation 
                (Parts 4300--4399)
     XXXIV  Securities and Exchange Commission (Parts 4400--4499)
      XXXV  Office of Personnel Management (Parts 4500--4599)
     XXXVI  Department of Homeland Security (Parts 4600--4699)
    XXXVII  Federal Election Commission (Parts 4700--4799)
        XL  Interstate Commerce Commission (Parts 5000--5099)
       XLI  Commodity Futures Trading Commission (Parts 5100--
                5199)
      XLII  Department of Labor (Parts 5200--5299)
     XLIII  National Science Foundation (Parts 5300--5399)
       XLV  Department of Health and Human Services (Parts 5500--
                5599)
      XLVI  Postal Rate Commission (Parts 5600--5699)
     XLVII  Federal Trade Commission (Parts 5700--5799)
    XLVIII  Nuclear Regulatory Commission (Parts 5800--5899)
      XLIX  Federal Labor Relations Authority (Parts 5900--5999)
         L  Department of Transportation (Parts 6000--6099)
       LII  Export-Import Bank of the United States (Parts 6200--
                6299)
      LIII  Department of Education (Parts 6300--6399)
       LIV  Environmental Protection Agency (Parts 6400--6499)
        LV  National Endowment for the Arts (Parts 6500--6599)
       LVI  National Endowment for the Humanities (Parts 6600--
                6699)
      LVII  General Services Administration (Parts 6700--6799)
     LVIII  Board of Governors of the Federal Reserve System 
                (Parts 6800--6899)
       LIX  National Aeronautics and Space Administration (Parts 
                6900--6999)
        LX  United States Postal Service (Parts 7000--7099)
       LXI  National Labor Relations Board (Parts 7100--7199)
      LXII  Equal Employment Opportunity Commission (Parts 7200--
                7299)
     LXIII  Inter-American Foundation (Parts 7300--7399)
      LXIV  Merit Systems Protection Board (Parts 7400--7499)
       LXV  Department of Housing and Urban Development (Parts 
                7500--7599)
      LXVI  National Archives and Records Administration (Parts 
                7600--7699)
     LXVII  Institute of Museum and Library Services (Parts 7700--
                7799)
    LXVIII  Commission on Civil Rights (Parts 7800--7899)
      LXIX  Tennessee Valley Authority (Parts 7900--7999)
       LXX  Court Services and Offender Supervision Agency for the 
                District of Columbia (Parts 8000--8099)
      LXXI  Consumer Product Safety Commission (Parts 8100--8199)

[[Page 244]]

    LXXIII  Department of Agriculture (Parts 8300--8399)
     LXXIV  Federal Mine Safety and Health Review Commission 
                (Parts 8400--8499)
     LXXVI  Federal Retirement Thrift Investment Board (Parts 
                8600--8699)
    LXXVII  Office of Management and Budget (Parts 8700--8799)
      LXXX  Federal Housing Finance Agency (Parts 9000--9099)
   LXXXIII  Special Inspector General for Afghanistan 
                Reconstruction (Parts 9300--9399)
    LXXXIV  Bureau of Consumer Financial Protection (Parts 9400--
                9499)
    LXXXVI  National Credit Union Administration (Parts 9600--
                9699)
     XCVII  Department of Homeland Security Human Resources 
                Management System (Department of Homeland 
                Security--Office of Personnel Management) (Parts 
                9700--9799)
    XCVIII  Council of the Inspectors General on Integrity and 
                Efficiency (Parts 9800--9899)
      XCIX  Military Compensation and Retirement Modernization 
                Commission (Parts 9900--9999)
         C  National Council on Disability (Parts 10000--10049)
        CI  National Mediation Board (Parts 10100--10199)
       CII  U.S. Office of Special Counsel (Parts 10200--10299)
      CIII  Federal Mediation and Conciliation Service (Parts 
                10300--10399)
       CIV  Office of the Intellectual Property Enforcement 
                Coordinator (Part 10400--10499)

                      Title 6--Domestic Security

         I  Department of Homeland Security, Office of the 
                Secretary (Parts 1--199)
         X  Privacy and Civil Liberties Oversight Board (Parts 
                1000--1099)

                         Title 7--Agriculture

            Subtitle A--Office of the Secretary of Agriculture 
                (Parts 0--26)
            Subtitle B--Regulations of the Department of 
                Agriculture
         I  Agricultural Marketing Service (Standards, 
                Inspections, Marketing Practices), Department of 
                Agriculture (Parts 27--209)
        II  Food and Nutrition Service, Department of Agriculture 
                (Parts 210--299)
       III  Animal and Plant Health Inspection Service, Department 
                of Agriculture (Parts 300--399)
        IV  Federal Crop Insurance Corporation, Department of 
                Agriculture (Parts 400--499)
         V  Agricultural Research Service, Department of 
                Agriculture (Parts 500--599)
        VI  Natural Resources Conservation Service, Department of 
                Agriculture (Parts 600--699)
       VII  Farm Service Agency, Department of Agriculture (Parts 
                700--799)

[[Page 245]]

      VIII  Agricultural Marketing Service (Federal Grain 
                Inspection Service, Fair Trade Practices Program), 
                Department of Agriculture (Parts 800--899)
        IX  Agricultural Marketing Service (Marketing Agreements 
                and Orders; Fruits, Vegetables, Nuts), Department 
                of Agriculture (Parts 900--999)
         X  Agricultural Marketing Service (Marketing Agreements 
                and Orders; Milk), Department of Agriculture 
                (Parts 1000--1199)
        XI  Agricultural Marketing Service (Marketing Agreements 
                and Orders; Miscellaneous Commodities), Department 
                of Agriculture (Parts 1200--1299)
       XIV  Commodity Credit Corporation, Department of 
                Agriculture (Parts 1400--1499)
        XV  Foreign Agricultural Service, Department of 
                Agriculture (Parts 1500--1599)
       XVI  [Reserved]
      XVII  Rural Utilities Service, Department of Agriculture 
                (Parts 1700--1799)
     XVIII  Rural Housing Service, Rural Business-Cooperative 
                Service, Rural Utilities Service, and Farm Service 
                Agency, Department of Agriculture (Parts 1800--
                2099)
        XX  [Reserved]
       XXV  Office of Advocacy and Outreach, Department of 
                Agriculture (Parts 2500--2599)
      XXVI  Office of Inspector General, Department of Agriculture 
                (Parts 2600--2699)
     XXVII  Office of Information Resources Management, Department 
                of Agriculture (Parts 2700--2799)
    XXVIII  Office of Operations, Department of Agriculture (Parts 
                2800--2899)
      XXIX  Office of Energy Policy and New Uses, Department of 
                Agriculture (Parts 2900--2999)
       XXX  Office of the Chief Financial Officer, Department of 
                Agriculture (Parts 3000--3099)
      XXXI  Office of Environmental Quality, Department of 
                Agriculture (Parts 3100--3199)
     XXXII  Office of Procurement and Property Management, 
                Department of Agriculture (Parts 3200--3299)
    XXXIII  Office of Transportation, Department of Agriculture 
                (Parts 3300--3399)
     XXXIV  National Institute of Food and Agriculture (Parts 
                3400--3499)
      XXXV  Rural Housing Service, Department of Agriculture 
                (Parts 3500--3599)
     XXXVI  National Agricultural Statistics Service, Department 
                of Agriculture (Parts 3600--3699)
    XXXVII  Economic Research Service, Department of Agriculture 
                (Parts 3700--3799)
   XXXVIII  World Agricultural Outlook Board, Department of 
                Agriculture (Parts 3800--3899)
       XLI  [Reserved]

[[Page 246]]

      XLII  Rural Business-Cooperative Service, Department of 
                Agriculture (Parts 4200--4299)
         L  Rural Business-Cooperative Service, Rural Housing 
                Service, and Rural Utilities Service, Department 
                of Agriculture (Parts 5000--5099)

                    Title 8--Aliens and Nationality

         I  Department of Homeland Security (Parts 1--499)
         V  Executive Office for Immigration Review, Department of 
                Justice (Parts 1000--1399)

                 Title 9--Animals and Animal Products

         I  Animal and Plant Health Inspection Service, Department 
                of Agriculture (Parts 1--199)
        II  Agricultural Marketing Service (Fair Trade Practices 
                Program), Department of Agriculture (Parts 200--
                299)
       III  Food Safety and Inspection Service, Department of 
                Agriculture (Parts 300--599)

                           Title 10--Energy

         I  Nuclear Regulatory Commission (Parts 0--199)
        II  Department of Energy (Parts 200--699)
       III  Department of Energy (Parts 700--999)
         X  Department of Energy (General Provisions) (Parts 
                1000--1099)
      XIII  Nuclear Waste Technical Review Board (Parts 1300--
                1399)
      XVII  Defense Nuclear Facilities Safety Board (Parts 1700--
                1799)
     XVIII  Northeast Interstate Low-Level Radioactive Waste 
                Commission (Parts 1800--1899)

                      Title 11--Federal Elections

         I  Federal Election Commission (Parts 1--9099)
        II  Election Assistance Commission (Parts 9400--9499)

                      Title 12--Banks and Banking

         I  Comptroller of the Currency, Department of the 
                Treasury (Parts 1--199)
        II  Federal Reserve System (Parts 200--299)
       III  Federal Deposit Insurance Corporation (Parts 300--399)
        IV  Export-Import Bank of the United States (Parts 400--
                499)
         V  (Parts 500--599) [Reserved]
        VI  Farm Credit Administration (Parts 600--699)
       VII  National Credit Union Administration (Parts 700--799)
      VIII  Federal Financing Bank (Parts 800--899)

[[Page 247]]

        IX  (Parts 900--999)[Reserved]
         X  Consumer Financial Protection Bureau (Parts 1000--
                1099)
        XI  Federal Financial Institutions Examination Council 
                (Parts 1100--1199)
       XII  Federal Housing Finance Agency (Parts 1200--1299)
      XIII  Financial Stability Oversight Council (Parts 1300--
                1399)
       XIV  Farm Credit System Insurance Corporation (Parts 1400--
                1499)
        XV  Department of the Treasury (Parts 1500--1599)
       XVI  Office of Financial Research, Department of the 
                Treasury (Parts 1600--1699)
      XVII  Office of Federal Housing Enterprise Oversight, 
                Department of Housing and Urban Development (Parts 
                1700--1799)
     XVIII  Community Development Financial Institutions Fund, 
                Department of the Treasury (Parts 1800--1899)

               Title 13--Business Credit and Assistance

         I  Small Business Administration (Parts 1--199)
       III  Economic Development Administration, Department of 
                Commerce (Parts 300--399)
        IV  Emergency Steel Guarantee Loan Board (Parts 400--499)
         V  Emergency Oil and Gas Guaranteed Loan Board (Parts 
                500--599)

                    Title 14--Aeronautics and Space

         I  Federal Aviation Administration, Department of 
                Transportation (Parts 1--199)
        II  Office of the Secretary, Department of Transportation 
                (Aviation Proceedings) (Parts 200--399)
       III  Commercial Space Transportation, Federal Aviation 
                Administration, Department of Transportation 
                (Parts 400--1199)
         V  National Aeronautics and Space Administration (Parts 
                1200--1299)
        VI  Air Transportation System Stabilization (Parts 1300--
                1399)

                 Title 15--Commerce and Foreign Trade

            Subtitle A--Office of the Secretary of Commerce (Parts 
                0--29)
            Subtitle B--Regulations Relating to Commerce and 
                Foreign Trade
         I  Bureau of the Census, Department of Commerce (Parts 
                30--199)
        II  National Institute of Standards and Technology, 
                Department of Commerce (Parts 200--299)
       III  International Trade Administration, Department of 
                Commerce (Parts 300--399)
        IV  Foreign-Trade Zones Board, Department of Commerce 
                (Parts 400--499)

[[Page 248]]

       VII  Bureau of Industry and Security, Department of 
                Commerce (Parts 700--799)
      VIII  Bureau of Economic Analysis, Department of Commerce 
                (Parts 800--899)
        IX  National Oceanic and Atmospheric Administration, 
                Department of Commerce (Parts 900--999)
        XI  National Technical Information Service, Department of 
                Commerce (Parts 1100--1199)
      XIII  East-West Foreign Trade Board (Parts 1300--1399)
       XIV  Minority Business Development Agency (Parts 1400--
                1499)
        XV  Office of the Under-Secretary for Economic Affairs, 
                Department of Commerce (Parts 1500--1599)
            Subtitle C--Regulations Relating to Foreign Trade 
                Agreements
        XX  Office of the United States Trade Representative 
                (Parts 2000--2099)
            Subtitle D--Regulations Relating to Telecommunications 
                and Information
     XXIII  National Telecommunications and Information 
                Administration, Department of Commerce (Parts 
                2300--2399) [Reserved]

                    Title 16--Commercial Practices

         I  Federal Trade Commission (Parts 0--999)
        II  Consumer Product Safety Commission (Parts 1000--1799)

             Title 17--Commodity and Securities Exchanges

         I  Commodity Futures Trading Commission (Parts 1--199)
        II  Securities and Exchange Commission (Parts 200--399)
        IV  Department of the Treasury (Parts 400--499)

          Title 18--Conservation of Power and Water Resources

         I  Federal Energy Regulatory Commission, Department of 
                Energy (Parts 1--399)
       III  Delaware River Basin Commission (Parts 400--499)
        VI  Water Resources Council (Parts 700--799)
      VIII  Susquehanna River Basin Commission (Parts 800--899)
      XIII  Tennessee Valley Authority (Parts 1300--1399)

                       Title 19--Customs Duties

         I  U.S. Customs and Border Protection, Department of 
                Homeland Security; Department of the Treasury 
                (Parts 0--199)
        II  United States International Trade Commission (Parts 
                200--299)
       III  International Trade Administration, Department of 
                Commerce (Parts 300--399)

[[Page 249]]

        IV  U.S. Immigration and Customs Enforcement, Department 
                of Homeland Security (Parts 400--599) [Reserved]

                     Title 20--Employees' Benefits

         I  Office of Workers' Compensation Programs, Department 
                of Labor (Parts 1--199)
        II  Railroad Retirement Board (Parts 200--399)
       III  Social Security Administration (Parts 400--499)
        IV  Employees' Compensation Appeals Board, Department of 
                Labor (Parts 500--599)
         V  Employment and Training Administration, Department of 
                Labor (Parts 600--699)
        VI  Office of Workers' Compensation Programs, Department 
                of Labor (Parts 700--799)
       VII  Benefits Review Board, Department of Labor (Parts 
                800--899)
      VIII  Joint Board for the Enrollment of Actuaries (Parts 
                900--999)
        IX  Office of the Assistant Secretary for Veterans' 
                Employment and Training Service, Department of 
                Labor (Parts 1000--1099)

                       Title 21--Food and Drugs

         I  Food and Drug Administration, Department of Health and 
                Human Services (Parts 1--1299)
        II  Drug Enforcement Administration, Department of Justice 
                (Parts 1300--1399)
       III  Office of National Drug Control Policy (Parts 1400--
                1499)

                      Title 22--Foreign Relations

         I  Department of State (Parts 1--199)
        II  Agency for International Development (Parts 200--299)
       III  Peace Corps (Parts 300--399)
        IV  International Joint Commission, United States and 
                Canada (Parts 400--499)
         V  United States Agency for Global Media (Parts 500--599)
       VII  U.S. International Development Finance Corporation 
                (Parts 700--799)
        IX  Foreign Service Grievance Board (Parts 900--999)
         X  Inter-American Foundation (Parts 1000--1099)
        XI  International Boundary and Water Commission, United 
                States and Mexico, United States Section (Parts 
                1100--1199)
       XII  United States International Development Cooperation 
                Agency (Parts 1200--1299)
      XIII  Millennium Challenge Corporation (Parts 1300--1399)
       XIV  Foreign Service Labor Relations Board; Federal Labor 
                Relations Authority; General Counsel of the 
                Federal Labor Relations Authority; and the Foreign 
                Service Impasse Disputes Panel (Parts 1400--1499)

[[Page 250]]

        XV  African Development Foundation (Parts 1500--1599)
       XVI  Japan-United States Friendship Commission (Parts 
                1600--1699)
      XVII  United States Institute of Peace (Parts 1700--1799)

                          Title 23--Highways

         I  Federal Highway Administration, Department of 
                Transportation (Parts 1--999)
        II  National Highway Traffic Safety Administration and 
                Federal Highway Administration, Department of 
                Transportation (Parts 1200--1299)
       III  National Highway Traffic Safety Administration, 
                Department of Transportation (Parts 1300--1399)

                Title 24--Housing and Urban Development

            Subtitle A--Office of the Secretary, Department of 
                Housing and Urban Development (Parts 0--99)
            Subtitle B--Regulations Relating to Housing and Urban 
                Development
         I  Office of Assistant Secretary for Equal Opportunity, 
                Department of Housing and Urban Development (Parts 
                100--199)
        II  Office of Assistant Secretary for Housing-Federal 
                Housing Commissioner, Department of Housing and 
                Urban Development (Parts 200--299)
       III  Government National Mortgage Association, Department 
                of Housing and Urban Development (Parts 300--399)
        IV  Office of Housing and Office of Multifamily Housing 
                Assistance Restructuring, Department of Housing 
                and Urban Development (Parts 400--499)
         V  Office of Assistant Secretary for Community Planning 
                and Development, Department of Housing and Urban 
                Development (Parts 500--599)
        VI  Office of Assistant Secretary for Community Planning 
                and Development, Department of Housing and Urban 
                Development (Parts 600--699) [Reserved]
       VII  Office of the Secretary, Department of Housing and 
                Urban Development (Housing Assistance Programs and 
                Public and Indian Housing Programs) (Parts 700--
                799)
      VIII  Office of the Assistant Secretary for Housing--Federal 
                Housing Commissioner, Department of Housing and 
                Urban Development (Section 8 Housing Assistance 
                Programs, Section 202 Direct Loan Program, Section 
                202 Supportive Housing for the Elderly Program and 
                Section 811 Supportive Housing for Persons With 
                Disabilities Program) (Parts 800--899)
        IX  Office of Assistant Secretary for Public and Indian 
                Housing, Department of Housing and Urban 
                Development (Parts 900--1699)
         X  Office of Assistant Secretary for Housing--Federal 
                Housing Commissioner, Department of Housing and 
                Urban Development (Interstate Land Sales 
                Registration Program) (Parts 1700--1799) 
                [Reserved]

[[Page 251]]

       XII  Office of Inspector General, Department of Housing and 
                Urban Development (Parts 2000--2099)
        XV  Emergency Mortgage Insurance and Loan Programs, 
                Department of Housing and Urban Development (Parts 
                2700--2799) [Reserved]
        XX  Office of Assistant Secretary for Housing--Federal 
                Housing Commissioner, Department of Housing and 
                Urban Development (Parts 3200--3899)
      XXIV  Board of Directors of the HOPE for Homeowners Program 
                (Parts 4000--4099) [Reserved]
       XXV  Neighborhood Reinvestment Corporation (Parts 4100--
                4199)

                           Title 25--Indians

         I  Bureau of Indian Affairs, Department of the Interior 
                (Parts 1--299)
        II  Indian Arts and Crafts Board, Department of the 
                Interior (Parts 300--399)
       III  National Indian Gaming Commission, Department of the 
                Interior (Parts 500--599)
        IV  Office of Navajo and Hopi Indian Relocation (Parts 
                700--899)
         V  Bureau of Indian Affairs, Department of the Interior, 
                and Indian Health Service, Department of Health 
                and Human Services (Part 900--999)
        VI  Office of the Assistant Secretary, Indian Affairs, 
                Department of the Interior (Parts 1000--1199)
       VII  Office of the Special Trustee for American Indians, 
                Department of the Interior (Parts 1200--1299)

                      Title 26--Internal Revenue

         I  Internal Revenue Service, Department of the Treasury 
                (Parts 1--End)

           Title 27--Alcohol, Tobacco Products and Firearms

         I  Alcohol and Tobacco Tax and Trade Bureau, Department 
                of the Treasury (Parts 1--399)
        II  Bureau of Alcohol, Tobacco, Firearms, and Explosives, 
                Department of Justice (Parts 400--799)

                   Title 28--Judicial Administration

         I  Department of Justice (Parts 0--299)
       III  Federal Prison Industries, Inc., Department of Justice 
                (Parts 300--399)
         V  Bureau of Prisons, Department of Justice (Parts 500--
                599)
        VI  Offices of Independent Counsel, Department of Justice 
                (Parts 600--699)
       VII  Office of Independent Counsel (Parts 700--799)

[[Page 252]]

      VIII  Court Services and Offender Supervision Agency for the 
                District of Columbia (Parts 800--899)
        IX  National Crime Prevention and Privacy Compact Council 
                (Parts 900--999)
        XI  Department of Justice and Department of State (Parts 
                1100--1199)

                            Title 29--Labor

            Subtitle A--Office of the Secretary of Labor (Parts 
                0--99)
            Subtitle B--Regulations Relating to Labor
         I  National Labor Relations Board (Parts 100--199)
        II  Office of Labor-Management Standards, Department of 
                Labor (Parts 200--299)
       III  National Railroad Adjustment Board (Parts 300--399)
        IV  Office of Labor-Management Standards, Department of 
                Labor (Parts 400--499)
         V  Wage and Hour Division, Department of Labor (Parts 
                500--899)
        IX  Construction Industry Collective Bargaining Commission 
                (Parts 900--999)
         X  National Mediation Board (Parts 1200--1299)
       XII  Federal Mediation and Conciliation Service (Parts 
                1400--1499)
       XIV  Equal Employment Opportunity Commission (Parts 1600--
                1699)
      XVII  Occupational Safety and Health Administration, 
                Department of Labor (Parts 1900--1999)
        XX  Occupational Safety and Health Review Commission 
                (Parts 2200--2499)
       XXV  Employee Benefits Security Administration, Department 
                of Labor (Parts 2500--2599)
     XXVII  Federal Mine Safety and Health Review Commission 
                (Parts 2700--2799)
        XL  Pension Benefit Guaranty Corporation (Parts 4000--
                4999)

                      Title 30--Mineral Resources

         I  Mine Safety and Health Administration, Department of 
                Labor (Parts 1--199)
        II  Bureau of Safety and Environmental Enforcement, 
                Department of the Interior (Parts 200--299)
        IV  Geological Survey, Department of the Interior (Parts 
                400--499)
         V  Bureau of Ocean Energy Management, Department of the 
                Interior (Parts 500--599)
       VII  Office of Surface Mining Reclamation and Enforcement, 
                Department of the Interior (Parts 700--999)
       XII  Office of Natural Resources Revenue, Department of the 
                Interior (Parts 1200--1299)

[[Page 253]]

                 Title 31--Money and Finance: Treasury

            Subtitle A--Office of the Secretary of the Treasury 
                (Parts 0--50)
            Subtitle B--Regulations Relating to Money and Finance
         I  Monetary Offices, Department of the Treasury (Parts 
                51--199)
        II  Fiscal Service, Department of the Treasury (Parts 
                200--399)
        IV  Secret Service, Department of the Treasury (Parts 
                400--499)
         V  Office of Foreign Assets Control, Department of the 
                Treasury (Parts 500--599)
        VI  Bureau of Engraving and Printing, Department of the 
                Treasury (Parts 600--699)
       VII  Federal Law Enforcement Training Center, Department of 
                the Treasury (Parts 700--799)
      VIII  Office of Investment Security, Department of the 
                Treasury (Parts 800--899)
        IX  Federal Claims Collection Standards (Department of the 
                Treasury--Department of Justice) (Parts 900--999)
         X  Financial Crimes Enforcement Network, Department of 
                the Treasury (Parts 1000--1099)

                      Title 32--National Defense

            Subtitle A--Department of Defense
         I  Office of the Secretary of Defense (Parts 1--399)
         V  Department of the Army (Parts 400--699)
        VI  Department of the Navy (Parts 700--799)
       VII  Department of the Air Force (Parts 800--1099)
            Subtitle B--Other Regulations Relating to National 
                Defense
       XII  Department of Defense, Defense Logistics Agency (Parts 
                1200--1299)
       XVI  Selective Service System (Parts 1600--1699)
      XVII  Office of the Director of National Intelligence (Parts 
                1700--1799)
     XVIII  National Counterintelligence Center (Parts 1800--1899)
       XIX  Central Intelligence Agency (Parts 1900--1999)
        XX  Information Security Oversight Office, National 
                Archives and Records Administration (Parts 2000--
                2099)
       XXI  National Security Council (Parts 2100--2199)
      XXIV  Office of Science and Technology Policy (Parts 2400--
                2499)
     XXVII  Office for Micronesian Status Negotiations (Parts 
                2700--2799)
    XXVIII  Office of the Vice President of the United States 
                (Parts 2800--2899)

               Title 33--Navigation and Navigable Waters

         I  Coast Guard, Department of Homeland Security (Parts 
                1--199)
        II  Corps of Engineers, Department of the Army, Department 
                of Defense (Parts 200--399)

[[Page 254]]

        IV  Great Lakes St. Lawrence Seaway Development 
                Corporation, Department of Transportation (Parts 
                400--499)

                          Title 34--Education

            Subtitle A--Office of the Secretary, Department of 
                Education (Parts 1--99)
            Subtitle B--Regulations of the Offices of the 
                Department of Education
         I  Office for Civil Rights, Department of Education 
                (Parts 100--199)
        II  Office of Elementary and Secondary Education, 
                Department of Education (Parts 200--299)
       III  Office of Special Education and Rehabilitative 
                Services, Department of Education (Parts 300--399)
        IV  Office of Career, Technical, and Adult Education, 
                Department of Education (Parts 400--499)
         V  Office of Bilingual Education and Minority Languages 
                Affairs, Department of Education (Parts 500--599) 
                [Reserved]
        VI  Office of Postsecondary Education, Department of 
                Education (Parts 600--699)
       VII  Office of Educational Research and Improvement, 
                Department of Education (Parts 700--799) 
                [Reserved]
            Subtitle C--Regulations Relating to Education
        XI  [Reserved]
       XII  National Council on Disability (Parts 1200--1299)

                          Title 35 [Reserved]

             Title 36--Parks, Forests, and Public Property

         I  National Park Service, Department of the Interior 
                (Parts 1--199)
        II  Forest Service, Department of Agriculture (Parts 200--
                299)
       III  Corps of Engineers, Department of the Army (Parts 
                300--399)
        IV  American Battle Monuments Commission (Parts 400--499)
         V  Smithsonian Institution (Parts 500--599)
        VI  [Reserved]
       VII  Library of Congress (Parts 700--799)
      VIII  Advisory Council on Historic Preservation (Parts 800--
                899)
        IX  Pennsylvania Avenue Development Corporation (Parts 
                900--999)
         X  Presidio Trust (Parts 1000--1099)
        XI  Architectural and Transportation Barriers Compliance 
                Board (Parts 1100--1199)
       XII  National Archives and Records Administration (Parts 
                1200--1299)
        XV  Oklahoma City National Memorial Trust (Parts 1500--
                1599)
       XVI  Morris K. Udall Scholarship and Excellence in National 
                Environmental Policy Foundation (Parts 1600--1699)

[[Page 255]]

             Title 37--Patents, Trademarks, and Copyrights

         I  United States Patent and Trademark Office, Department 
                of Commerce (Parts 1--199)
        II  U.S. Copyright Office, Library of Congress (Parts 
                200--299)
       III  Copyright Royalty Board, Library of Congress (Parts 
                300--399)
        IV  National Institute of Standards and Technology, 
                Department of Commerce (Parts 400--599)

           Title 38--Pensions, Bonuses, and Veterans' Relief

         I  Department of Veterans Affairs (Parts 0--199)
        II  Armed Forces Retirement Home (Parts 200--299)

                       Title 39--Postal Service

         I  United States Postal Service (Parts 1--999)
       III  Postal Regulatory Commission (Parts 3000--3099)

                  Title 40--Protection of Environment

         I  Environmental Protection Agency (Parts 1--1099)
        IV  Environmental Protection Agency and Department of 
                Justice (Parts 1400--1499)
         V  Council on Environmental Quality (Parts 1500--1599)
        VI  Chemical Safety and Hazard Investigation Board (Parts 
                1600--1699)
       VII  Environmental Protection Agency and Department of 
                Defense; Uniform National Discharge Standards for 
                Vessels of the Armed Forces (Parts 1700--1799)
      VIII  Gulf Coast Ecosystem Restoration Council (Parts 1800--
                1899)
        IX  Federal Permitting Improvement Steering Council (Part 
                1900)

          Title 41--Public Contracts and Property Management

            Subtitle A--Federal Procurement Regulations System 
                [Note]
            Subtitle B--Other Provisions Relating to Public 
                Contracts
        50  Public Contracts, Department of Labor (Parts 50-1--50-
                999)
        51  Committee for Purchase From People Who Are Blind or 
                Severely Disabled (Parts 51-1--51-99)
        60  Office of Federal Contract Compliance Programs, Equal 
                Employment Opportunity, Department of Labor (Parts 
                60-1--60-999)
        61  Office of the Assistant Secretary for Veterans' 
                Employment and Training Service, Department of 
                Labor (Parts 61-1--61-999)
   62--100  [Reserved]
            Subtitle C--Federal Property Management Regulations 
                System
       101  Federal Property Management Regulations (Parts 101-1--
                101-99)
       102  Federal Management Regulation (Parts 102-1--102-299)

[[Page 256]]

  103--104  [Reserved]
       105  General Services Administration (Parts 105-1--105-999)
       109  Department of Energy Property Management Regulations 
                (Parts 109-1--109-99)
       114  Department of the Interior (Parts 114-1--114-99)
       115  Environmental Protection Agency (Parts 115-1--115-99)
       128  Department of Justice (Parts 128-1--128-99)
  129--200  [Reserved]
            Subtitle D--Federal Acquisition Supply Chain Security
       201  Federal Acquisition Security Council (Parts 201-1--
                201-99)
            Subtitle E [Reserved]
            Subtitle F--Federal Travel Regulation System
       300  General (Parts 300-1--300-99)
       301  Temporary Duty (TDY) Travel Allowances (Parts 301-1--
                301-99)
       302  Relocation Allowances (Parts 302-1--302-99)
       303  Payment of Expenses Connected with the Death of 
                Certain Employees (Part 303-1--303-99)
       304  Payment of Travel Expenses from a Non-Federal Source 
                (Parts 304-1--304-99)

                        Title 42--Public Health

         I  Public Health Service, Department of Health and Human 
                Services (Parts 1--199)
   II--III  [Reserved]
        IV  Centers for Medicare & Medicaid Services, Department 
                of Health and Human Services (Parts 400--699)
         V  Office of Inspector General-Health Care, Department of 
                Health and Human Services (Parts 1000--1099)

                   Title 43--Public Lands: Interior

            Subtitle A--Office of the Secretary of the Interior 
                (Parts 1--199)
            Subtitle B--Regulations Relating to Public Lands
         I  Bureau of Reclamation, Department of the Interior 
                (Parts 400--999)
        II  Bureau of Land Management, Department of the Interior 
                (Parts 1000--9999)
       III  Utah Reclamation Mitigation and Conservation 
                Commission (Parts 10000--10099)

             Title 44--Emergency Management and Assistance

         I  Federal Emergency Management Agency, Department of 
                Homeland Security (Parts 0--399)
        IV  Department of Commerce and Department of 
                Transportation (Parts 400--499)

[[Page 257]]

                       Title 45--Public Welfare

            Subtitle A--Department of Health and Human Services 
                (Parts 1--199)
            Subtitle B--Regulations Relating to Public Welfare
        II  Office of Family Assistance (Assistance Programs), 
                Administration for Children and Families, 
                Department of Health and Human Services (Parts 
                200--299)
       III  Office of Child Support Services, Administration of 
                Families and Services, Department of Health and 
                Human Services (Parts 300--399)
        IV  Office of Refugee Resettlement, Administration for 
                Children and Families, Department of Health and 
                Human Services (Parts 400--499)
         V  Foreign Claims Settlement Commission of the United 
                States, Department of Justice (Parts 500--599)
        VI  National Science Foundation (Parts 600--699)
       VII  Commission on Civil Rights (Parts 700--799)
      VIII  Office of Personnel Management (Parts 800--899)
        IX  Denali Commission (Parts 900--999)
         X  Office of Community Services, Administration for 
                Children and Families, Department of Health and 
                Human Services (Parts 1000--1099)
        XI  National Foundation on the Arts and the Humanities 
                (Parts 1100--1199)
       XII  Corporation for National and Community Service (Parts 
                1200--1299)
      XIII  Administration for Children and Families, Department 
                of Health and Human Services (Parts 1300--1399)
       XVI  Legal Services Corporation (Parts 1600--1699)
      XVII  National Commission on Libraries and Information 
                Science (Parts 1700--1799)
     XVIII  Harry S. Truman Scholarship Foundation (Parts 1800--
                1899)
       XXI  Commission of Fine Arts (Parts 2100--2199)
     XXIII  Arctic Research Commission (Parts 2300--2399)
      XXIV  James Madison Memorial Fellowship Foundation (Parts 
                2400--2499)
       XXV  Corporation for National and Community Service (Parts 
                2500--2599)

                          Title 46--Shipping

         I  Coast Guard, Department of Homeland Security (Parts 
                1--199)
        II  Maritime Administration, Department of Transportation 
                (Parts 200--399)
       III  Coast Guard (Great Lakes Pilotage), Department of 
                Homeland Security (Parts 400--499)
        IV  Federal Maritime Commission (Parts 500--599)

[[Page 258]]

                      Title 47--Telecommunication

         I  Federal Communications Commission (Parts 0--199)
        II  Office of Science and Technology Policy and National 
                Security Council (Parts 200--299)
       III  National Telecommunications and Information 
                Administration, Department of Commerce (Parts 
                300--399)
        IV  National Telecommunications and Information 
                Administration, Department of Commerce, and 
                National Highway Traffic Safety Administration, 
                Department of Transportation (Parts 400--499)
         V  The First Responder Network Authority (Parts 500--599)

           Title 48--Federal Acquisition Regulations System

         1  Federal Acquisition Regulation (Parts 1--99)
         2  Defense Acquisition Regulations System, Department of 
                Defense (Parts 200--299)
         3  Health and Human Services (Parts 300--399)
         4  Department of Agriculture (Parts 400--499)
         5  General Services Administration (Parts 500--599)
         6  Department of State (Parts 600--699)
         7  Agency for International Development (Parts 700--799)
         8  Department of Veterans Affairs (Parts 800--899)
         9  Department of Energy (Parts 900--999)
        10  Department of the Treasury (Parts 1000--1099)
        12  Department of Transportation (Parts 1200--1299)
        13  Department of Commerce (Parts 1300--1399)
        14  Department of the Interior (Parts 1400--1499)
        15  Environmental Protection Agency (Parts 1500--1599)
        16  Office of Personnel Management, Federal Employees 
                Health Benefits Acquisition Regulation (Parts 
                1600--1699)
        17  Office of Personnel Management (Parts 1700--1799)
        18  National Aeronautics and Space Administration (Parts 
                1800--1899)
        19  Broadcasting Board of Governors (Parts 1900--1999)
        20  Nuclear Regulatory Commission (Parts 2000--2099)
        21  Office of Personnel Management, Federal Employees 
                Group Life Insurance Federal Acquisition 
                Regulation (Parts 2100--2199)
        23  Social Security Administration (Parts 2300--2399)
        24  Department of Housing and Urban Development (Parts 
                2400--2499)
        25  National Science Foundation (Parts 2500--2599)
        28  Department of Justice (Parts 2800--2899)
        29  Department of Labor (Parts 2900--2999)
        30  Department of Homeland Security, Homeland Security 
                Acquisition Regulation (HSAR) (Parts 3000--3099)
        34  Department of Education Acquisition Regulation (Parts 
                3400--3499)

[[Page 259]]

        51  Department of the Army Acquisition Regulations (Parts 
                5100--5199) [Reserved]
        52  Department of the Navy Acquisition Regulations (Parts 
                5200--5299)
        53  Department of the Air Force Federal Acquisition 
                Regulation Supplement (Parts 5300--5399) 
                [Reserved]
        54  Defense Logistics Agency, Department of Defense (Parts 
                5400--5499)
        57  African Development Foundation (Parts 5700--5799)
        61  Civilian Board of Contract Appeals, General Services 
                Administration (Parts 6100--6199)
        99  Cost Accounting Standards Board, Office of Federal 
                Procurement Policy, Office of Management and 
                Budget (Parts 9900--9999)

                       Title 49--Transportation

            Subtitle A--Office of the Secretary of Transportation 
                (Parts 1--99)
            Subtitle B--Other Regulations Relating to 
                Transportation
         I  Pipeline and Hazardous Materials Safety 
                Administration, Department of Transportation 
                (Parts 100--199)
        II  Federal Railroad Administration, Department of 
                Transportation (Parts 200--299)
       III  Federal Motor Carrier Safety Administration, 
                Department of Transportation (Parts 300--399)
        IV  Coast Guard, Department of Homeland Security (Parts 
                400--499)
         V  National Highway Traffic Safety Administration, 
                Department of Transportation (Parts 500--599)
        VI  Federal Transit Administration, Department of 
                Transportation (Parts 600--699)
       VII  National Railroad Passenger Corporation (AMTRAK) 
                (Parts 700--799)
      VIII  National Transportation Safety Board (Parts 800--999)
         X  Surface Transportation Board (Parts 1000--1399)
        XI  Research and Innovative Technology Administration, 
                Department of Transportation (Parts 1400--1499) 
                [Reserved]
       XII  Transportation Security Administration, Department of 
                Homeland Security (Parts 1500--1699)

                   Title 50--Wildlife and Fisheries

         I  United States Fish and Wildlife Service, Department of 
                the Interior (Parts 1--199)
        II  National Marine Fisheries Service, National Oceanic 
                and Atmospheric Administration, Department of 
                Commerce (Parts 200--299)
       III  International Fishing and Related Activities (Parts 
                300--399)

[[Page 260]]

        IV  Joint Regulations (United States Fish and Wildlife 
                Service, Department of the Interior and National 
                Marine Fisheries Service, National Oceanic and 
                Atmospheric Administration, Department of 
                Commerce); Endangered Species Committee 
                Regulations (Parts 400--499)
         V  Marine Mammal Commission (Parts 500--599)
        VI  Fishery Conservation and Management, National Oceanic 
                and Atmospheric Administration, Department of 
                Commerce (Parts 600--699)

[[Page 261]]





           Alphabetical List of Agencies Appearing in the CFR




                      (Revised as of April 1, 2024)

                                                  CFR Title, Subtitle or 
                     Agency                               Chapter

Administrative Conference of the United States    1, III
Advisory Council on Historic Preservation         36, VIII
Advocacy and Outreach, Office of                  7, XXV
Afghanistan Reconstruction, Special Inspector     5, LXXXIII
     General for
African Development Foundation                    22, XV
  Federal Acquisition Regulation                  48, 57
Agency for International Development              2, VII; 22, II
  Federal Acquisition Regulation                  48, 7
Agricultural Marketing Service                    7, I, VIII, IX, X, XI; 9, 
                                                  II
Agricultural Research Service                     7, V
Agriculture, Department of                        2, IV; 5, LXXIII
  Advocacy and Outreach, Office of                7, XXV
  Agricultural Marketing Service                  7, I, VIII, IX, X, XI; 9, 
                                                  II
  Agricultural Research Service                   7, V
  Animal and Plant Health Inspection Service      7, III; 9, I
  Chief Financial Officer, Office of              7, XXX
  Commodity Credit Corporation                    7, XIV
  Economic Research Service                       7, XXXVII
  Energy Policy and New Uses, Office of           2, IX; 7, XXIX
  Environmental Quality, Office of                7, XXXI
  Farm Service Agency                             7, VII, XVIII
  Federal Acquisition Regulation                  48, 4
  Federal Crop Insurance Corporation              7, IV
  Food and Nutrition Service                      7, II
  Food Safety and Inspection Service              9, III
  Foreign Agricultural Service                    7, XV
  Forest Service                                  36, II
  Information Resources Management, Office of     7, XXVII
  Inspector General, Office of                    7, XXVI
  National Agricultural Library                   7, XLI
  National Agricultural Statistics Service        7, XXXVI
  National Institute of Food and Agriculture      7, XXXIV
  Natural Resources Conservation Service          7, VI
  Operations, Office of                           7, XXVIII
  Procurement and Property Management, Office of  7, XXXII
  Rural Business-Cooperative Service              7, XVIII, XLII
  Rural Development Administration                7, XLII
  Rural Housing Service                           7, XVIII, XXXV
  Rural Utilities Service                         7, XVII, XVIII, XLII
  Secretary of Agriculture, Office of             7, Subtitle A
  Transportation, Office of                       7, XXXIII
  World Agricultural Outlook Board                7, XXXVIII
Air Force, Department of                          32, VII
  Federal Acquisition Regulation Supplement       48, 53
Air Transportation Stabilization Board            14, VI
Alcohol and Tobacco Tax and Trade Bureau          27, I
Alcohol, Tobacco, Firearms, and Explosives,       27, II
     Bureau of
AMTRAK                                            49, VII
American Battle Monuments Commission              36, IV
American Indians, Office of the Special Trustee   25, VII
Animal and Plant Health Inspection Service        7, III; 9, I
Appalachian Regional Commission                   5, IX
Architectural and Transportation Barriers         36, XI
   Compliance Board
[[Page 262]]

Arctic Research Commission                        45, XXIII
Armed Forces Retirement Home                      5, XI; 38, II
Army, Department of                               32, V
  Engineers, Corps of                             33, II; 36, III
  Federal Acquisition Regulation                  48, 51
Benefits Review Board                             20, VII
Bilingual Education and Minority Languages        34, V
     Affairs, Office of
Blind or Severely Disabled, Committee for         41, 51
     Purchase from People Who Are
  Federal Acquisition Regulation                  48, 19
Career, Technical, and Adult Education, Office    34, IV
     of
Census Bureau                                     15, I
Centers for Medicare & Medicaid Services          42, IV
Central Intelligence Agency                       32, XIX
Chemical Safety and Hazard Investigation Board    40, VI
Chief Financial Officer, Office of                7, XXX
Child Support Services, Office of                 45, III
Children and Families, Administration for         45, II, IV, X, XIII
Civil Rights, Commission on                       5, LXVIII; 45, VII
Civil Rights, Office for                          34, I
Coast Guard                                       33, I; 46, I; 49, IV
Coast Guard (Great Lakes Pilotage)                46, III
Commerce, Department of                           2, XIII; 44, IV; 50, VI
  Census Bureau                                   15, I
  Economic Affairs, Office of the Under-          15, XV
       Secretary for
  Economic Analysis, Bureau of                    15, VIII
  Economic Development Administration             13, III
  Emergency Management and Assistance             44, IV
  Federal Acquisition Regulation                  48, 13
  Foreign-Trade Zones Board                       15, IV
  Industry and Security, Bureau of                15, VII
  International Trade Administration              15, III; 19, III
  National Institute of Standards and Technology  15, II; 37, IV
  National Marine Fisheries Service               50, II, IV
  National Oceanic and Atmospheric                15, IX; 50, II, III, IV, 
       Administration                             VI
  National Technical Information Service          15, XI
  National Telecommunications and Information     15, XXIII; 47, III, IV
       Administration
  National Weather Service                        15, IX
  Patent and Trademark Office, United States      37, I
  Secretary of Commerce, Office of                15, Subtitle A
Commercial Space Transportation                   14, III
Commodity Credit Corporation                      7, XIV
Commodity Futures Trading Commission              5, XLI; 17, I
Community Planning and Development, Office of     24, V, VI
     Assistant Secretary for
Community Services, Office of                     45, X
Comptroller of the Currency                       12, I
Construction Industry Collective Bargaining       29, IX
     Commission
Consumer Financial Protection Bureau              5, LXXXIV; 12, X
Consumer Product Safety Commission                5, LXXI; 16, II
Copyright Royalty Board                           37, III
Corporation for National and Community Service    2, XXII; 45, XII, XXV
Cost Accounting Standards Board                   48, 99
Council on Environmental Quality                  40, V
Council of the Inspectors General on Integrity    5, XCVIII
     and Efficiency
Court Services and Offender Supervision Agency    5, LXX; 28, VIII
     for the District of Columbia
Customs and Border Protection                     19, I
Defense, Department of                            2, XI; 5, XXVI; 32, 
                                                  Subtitle A; 40, VII
  Advanced Research Projects Agency               32, I
  Air Force Department                            32, VII
  Army Department                                 32, V; 33, II; 36, III; 
                                                  48, 51
  Defense Acquisition Regulations System          48, 2
  Defense Intelligence Agency                     32, I

[[Page 263]]

  Defense Logistics Agency                        32, I, XII; 48, 54
  Engineers, Corps of                             33, II; 36, III
  National Imagery and Mapping Agency             32, I
  Navy, Department of                             32, VI; 48, 52
  Secretary of Defense, Office of                 2, XI; 32, I
Defense Contract Audit Agency                     32, I
Defense Intelligence Agency                       32, I
Defense Logistics Agency                          32, XII; 48, 54
Defense Nuclear Facilities Safety Board           10, XVII
Delaware River Basin Commission                   18, III
Denali Commission                                 45, IX
Disability, National Council on                   5, C; 34, XII
District of Columbia, Court Services and          5, LXX; 28, VIII
     Offender Supervision Agency for the
Drug Enforcement Administration                   21, II
East-West Foreign Trade Board                     15, XIII
Economic Affairs, Office of the Under-Secretary   15, XV
     for
Economic Analysis, Bureau of                      15, VIII
Economic Development Administration               13, III
Economic Research Service                         7, XXXVII
Education, Department of                          2, XXXIV; 5, LIII
  Bilingual Education and Minority Languages      34, V
       Affairs, Office of
  Career, Technical, and Adult Education, Office  34, IV
       of
  Civil Rights, Office for                        34, I
  Educational Research and Improvement, Office    34, VII
       of
  Elementary and Secondary Education, Office of   34, II
  Federal Acquisition Regulation                  48, 34
  Postsecondary Education, Office of              34, VI
  Secretary of Education, Office of               34, Subtitle A
  Special Education and Rehabilitative Services,  34, III
       Office of
Educational Research and Improvement, Office of   34, VII
Election Assistance Commission                    2, LVIII; 11, II
Elementary and Secondary Education, Office of     34, II
Emergency Oil and Gas Guaranteed Loan Board       13, V
Emergency Steel Guarantee Loan Board              13, IV
Employee Benefits Security Administration         29, XXV
Employees' Compensation Appeals Board             20, IV
Employees Loyalty Board                           5, V
Employment and Training Administration            20, V
Employment Policy, National Commission for        1, IV
Employment Standards Administration               20, VI
Endangered Species Committee                      50, IV
Energy, Department of                             2, IX; 5, XXIII; 10, II, 
                                                  III, X
  Federal Acquisition Regulation                  48, 9
  Federal Energy Regulatory Commission            5, XXIV; 18, I
  Property Management Regulations                 41, 109
Energy, Office of                                 7, XXIX
Engineers, Corps of                               33, II; 36, III
Engraving and Printing, Bureau of                 31, VI
Environmental Protection Agency                   2, XV; 5, LIV; 40, I, IV, 
                                                  VII
  Federal Acquisition Regulation                  48, 15
  Property Management Regulations                 41, 115
Environmental Quality, Office of                  7, XXXI
Equal Employment Opportunity Commission           5, LXII; 29, XIV
Equal Opportunity, Office of Assistant Secretary  24, I
     for
Executive Office of the President                 3, I
  Environmental Quality, Council on               40, V
  Management and Budget, Office of                2, Subtitle A; 5, III, 
                                                  LXXVII; 14, VI; 48, 99
  National Drug Control Policy, Office of         2, XXXVI; 21, III
  National Security Council                       32, XXI; 47, II
  Presidential Documents                          3
  Science and Technology Policy, Office of        32, XXIV; 47, II
  Trade Representative, Office of the United      15, XX
     States
[[Page 264]]

Export-Import Bank of the United States           2, XXXV; 5, LII; 12, IV
Families and Services, Administration of          45, III
Family Assistance, Office of                      45, II
Farm Credit Administration                        5, XXXI; 12, VI
Farm Credit System Insurance Corporation          5, XXX; 12, XIV
Farm Service Agency                               7, VII, XVIII
Federal Acquisition Regulation                    48, 1
Federal Acquisition Security Council              41, 201
Federal Aviation Administration                   14, I
  Commercial Space Transportation                 14, III
Federal Claims Collection Standards               31, IX
Federal Communications Commission                 2, LX; 5, XXIX; 47, I
Federal Contract Compliance Programs, Office of   41, 60
Federal Crop Insurance Corporation                7, IV
Federal Deposit Insurance Corporation             5, XXII; 12, III
Federal Election Commission                       5, XXXVII; 11, I
Federal Emergency Management Agency               44, I
Federal Employees Group Life Insurance Federal    48, 21
     Acquisition Regulation
Federal Employees Health Benefits Acquisition     48, 16
     Regulation
Federal Energy Regulatory Commission              5, XXIV; 18, I
Federal Financial Institutions Examination        12, XI
     Council
Federal Financing Bank                            12, VIII
Federal Highway Administration                    23, I, II
Federal Home Loan Mortgage Corporation            1, IV
Federal Housing Enterprise Oversight Office       12, XVII
Federal Housing Finance Agency                    5, LXXX; 12, XII
Federal Labor Relations Authority                 5, XIV, XLIX; 22, XIV
Federal Law Enforcement Training Center           31, VII
Federal Management Regulation                     41, 102
Federal Maritime Commission                       46, IV
Federal Mediation and Conciliation Service        5, CIII; 29, XII
Federal Mine Safety and Health Review Commission  5, LXXIV; 29, XXVII
Federal Motor Carrier Safety Administration       49, III
Federal Permitting Improvement Steering Council   40, IX
Federal Prison Industries, Inc.                   28, III
Federal Procurement Policy Office                 48, 99
Federal Property Management Regulations           41, 101
Federal Railroad Administration                   49, II
Federal Register, Administrative Committee of     1, I
Federal Register, Office of                       1, II
Federal Reserve System                            12, II
  Board of Governors                              5, LVIII
Federal Retirement Thrift Investment Board        5, VI, LXXVI
Federal Service Impasses Panel                    5, XIV
Federal Trade Commission                          5, XLVII; 16, I
Federal Transit Administration                    49, VI
Federal Travel Regulation System                  41, Subtitle F
Financial Crimes Enforcement Network              31, X
Financial Research Office                         12, XVI
Financial Stability Oversight Council             12, XIII
Fine Arts, Commission of                          45, XXI
Fiscal Service                                    31, II
Fish and Wildlife Service, United States          50, I, IV
Food and Drug Administration                      21, I
Food and Nutrition Service                        7, II
Food Safety and Inspection Service                9, III
Foreign Agricultural Service                      7, XV
Foreign Assets Control, Office of                 31, V
Foreign Claims Settlement Commission of the       45, V
     United States
Foreign Service Grievance Board                   22, IX
Foreign Service Impasse Disputes Panel            22, XIV
Foreign Service Labor Relations Board             22, XIV
Foreign-Trade Zones Board                         15, IV
Forest Service                                    36, II
General Services Administration                   5, LVII; 41, 105
  Contract Appeals, Board of                      48, 61

[[Page 265]]

  Federal Acquisition Regulation                  48, 5
  Federal Management Regulation                   41, 102
  Federal Property Management Regulations         41, 101
  Federal Travel Regulation System                41, Subtitle F
  General                                         41, 300
  Payment From a Non-Federal Source for Travel    41, 304
       Expenses
  Payment of Expenses Connected With the Death    41, 303
       of Certain Employees
  Relocation Allowances                           41, 302
  Temporary Duty (TDY) Travel Allowances          41, 301
Geological Survey                                 30, IV
Government Accountability Office                  4, I
Government Ethics, Office of                      5, XVI
Government National Mortgage Association          24, III
Grain Inspection, Packers and Stockyards          7, VIII; 9, II
     Administration
Great Lakes St. Lawrence Seaway Development       33, IV
     Corporation
Gulf Coast Ecosystem Restoration Council          2, LIX; 40, VIII
Harry S. Truman Scholarship Foundation            45, XVIII
Health and Human Services, Department of          2, III; 5, XLV; 45, 
                                                  Subtitle A
  Centers for Medicare & Medicaid Services        42, IV
  Child Support Services, Office of               45, III
  Children and Families, Administration for       45, II, IV, X, XIII
  Community Services, Office of                   45, X
  Families and Services, Administration of        45, III
  Family Assistance, Office of                    45, II
  Federal Acquisition Regulation                  48, 3
  Food and Drug Administration                    21, I
  Indian Health Service                           25, V
  Inspector General (Health Care), Office of      42, V
  Public Health Service                           42, I
  Refugee Resettlement, Office of                 45, IV
Homeland Security, Department of                  2, XXX; 5, XXXVI; 6, I; 8, 
                                                  I
  Coast Guard                                     33, I; 46, I; 49, IV
  Coast Guard (Great Lakes Pilotage)              46, III
  Customs and Border Protection                   19, I
  Federal Emergency Management Agency             44, I
  Human Resources Management and Labor Relations  5, XCVII
       Systems
  Immigration and Customs Enforcement Bureau      19, IV
  Transportation Security Administration          49, XII
HOPE for Homeowners Program, Board of Directors   24, XXIV
     of
Housing and Urban Development, Department of      2, XXIV; 5, LXV; 24, 
                                                  Subtitle B
  Community Planning and Development, Office of   24, V, VI
       Assistant Secretary for
  Equal Opportunity, Office of Assistant          24, I
       Secretary for
  Federal Acquisition Regulation                  48, 24
  Federal Housing Enterprise Oversight, Office    12, XVII
       of
  Government National Mortgage Association        24, III
  Housing--Federal Housing Commissioner, Office   24, II, VIII, X, XX
       of Assistant Secretary for
  Housing, Office of, and Multifamily Housing     24, IV
       Assistance Restructuring, Office of
  Inspector General, Office of                    24, XII
  Public and Indian Housing, Office of Assistant  24, IX
       Secretary for
  Secretary, Office of                            24, Subtitle A, VII
Housing--Federal Housing Commissioner, Office of  24, II, VIII, X, XX
     Assistant Secretary for
Housing, Office of, and Multifamily Housing       24, IV
     Assistance Restructuring, Office of
Immigration and Customs Enforcement Bureau        19, IV
Immigration Review, Executive Office for          8, V
Independent Counsel, Office of                    28, VII
Independent Counsel, Offices of                   28, VI
Indian Affairs, Bureau of                         25, I, V

[[Page 266]]

Indian Affairs, Office of the Assistant           25, VI
     Secretary
Indian Arts and Crafts Board                      25, II
Indian Health Service                             25, V
Industry and Security, Bureau of                  15, VII
Information Resources Management, Office of       7, XXVII
Information Security Oversight Office, National   32, XX
     Archives and Records Administration
Inspector General
  Agriculture Department                          7, XXVI
  Health and Human Services Department            42, V
  Housing and Urban Development Department        24, XII, XV
Institute of Peace, United States                 22, XVII
Intellectual Property Enforcement Coordinator,    5, CIV
     Office of
Inter-American Foundation                         5, LXIII; 22, X
Interior, Department of                           2, XIV
  American Indians, Office of the Special         25, VII
       Trustee
  Endangered Species Committee                    50, IV
  Federal Acquisition Regulation                  48, 14
  Federal Property Management Regulations System  41, 114
  Fish and Wildlife Service, United States        50, I, IV
  Geological Survey                               30, IV
  Indian Affairs, Bureau of                       25, I, V
  Indian Affairs, Office of the Assistant         25, VI
       Secretary
  Indian Arts and Crafts Board                    25, II
  Land Management, Bureau of                      43, II
  National Indian Gaming Commission               25, III
  National Park Service                           36, I
  Natural Resource Revenue, Office of             30, XII
  Ocean Energy Management, Bureau of              30, V
  Reclamation, Bureau of                          43, I
  Safety and Environmental Enforcement, Bureau    30, II
       of
  Secretary of the Interior, Office of            2, XIV; 43, Subtitle A
  Surface Mining Reclamation and Enforcement,     30, VII
       Office of
Internal Revenue Service                          26, I
International Boundary and Water Commission,      22, XI
     United States and Mexico, United States 
     Section
International Development, United States Agency   22, II
     for
  Federal Acquisition Regulation                  48, 7
International Development Cooperation Agency,     22, XII
     United States
International Development Finance Corporation,    5, XXXIII; 22, VII
     U.S.
International Joint Commission, United States     22, IV
     and Canada
International Organizations Employees Loyalty     5, V
     Board
International Trade Administration                15, III; 19, III
International Trade Commission, United States     19, II
Interstate Commerce Commission                    5, XL
Investment Security, Office of                    31, VIII
James Madison Memorial Fellowship Foundation      45, XXIV
Japan-United States Friendship Commission         22, XVI
Joint Board for the Enrollment of Actuaries       20, VIII
Justice, Department of                            2, XXVIII; 5, XXVIII; 28, 
                                                  I, XI; 40, IV
  Alcohol, Tobacco, Firearms, and Explosives,     27, II
       Bureau of
  Drug Enforcement Administration                 21, II
  Federal Acquisition Regulation                  48, 28
  Federal Claims Collection Standards             31, IX
  Federal Prison Industries, Inc.                 28, III
  Foreign Claims Settlement Commission of the     45, V
       United States
  Immigration Review, Executive Office for        8, V
  Independent Counsel, Offices of                 28, VI
  Prisons, Bureau of                              28, V
  Property Management Regulations                 41, 128
Labor, Department of                              2, XXIX; 5, XLII
  Benefits Review Board                           20, VII
  Employee Benefits Security Administration       29, XXV
  Employees' Compensation Appeals Board           20, IV

[[Page 267]]

  Employment and Training Administration          20, V
  Federal Acquisition Regulation                  48, 29
  Federal Contract Compliance Programs, Office    41, 60
       of
  Federal Procurement Regulations System          41, 50
  Labor-Management Standards, Office of           29, II, IV
  Mine Safety and Health Administration           30, I
  Occupational Safety and Health Administration   29, XVII
  Public Contracts                                41, 50
  Secretary of Labor, Office of                   29, Subtitle A
  Veterans' Employment and Training Service,      41, 61; 20, IX
       Office of the Assistant Secretary for
  Wage and Hour Division                          29, V
  Workers' Compensation Programs, Office of       20, I, VI
Labor-Management Standards, Office of             29, II, IV
Land Management, Bureau of                        43, II
Legal Services Corporation                        45, XVI
Libraries and Information Science, National       45, XVII
     Commission on
Library of Congress                               36, VII
  Copyright Royalty Board                         37, III
  U.S. Copyright Office                           37, II
Management and Budget, Office of                  5, III, LXXVII; 14, VI; 
                                                  48, 99
Marine Mammal Commission                          50, V
Maritime Administration                           46, II
Merit Systems Protection Board                    5, II, LXIV
Micronesian Status Negotiations, Office for       32, XXVII
Military Compensation and Retirement              5, XCIX
     Modernization Commission
Millennium Challenge Corporation                  22, XIII
Mine Safety and Health Administration             30, I
Minority Business Development Agency              15, XIV
Miscellaneous Agencies                            1, IV
Monetary Offices                                  31, I
Morris K. Udall Scholarship and Excellence in     36, XVI
     National Environmental Policy Foundation
Museum and Library Services, Institute of         2, XXXI
National Aeronautics and Space Administration     2, XVIII; 5, LIX; 14, V
  Federal Acquisition Regulation                  48, 18
National Agricultural Library                     7, XLI
National Agricultural Statistics Service          7, XXXVI
National and Community Service, Corporation for   2, XXII; 45, XII, XXV
National Archives and Records Administration      2, XXVI; 5, LXVI; 36, XII
  Information Security Oversight Office           32, XX
National Capital Planning Commission              1, IV, VI
National Counterintelligence Center               32, XVIII
National Credit Union Administration              5, LXXXVI; 12, VII
National Crime Prevention and Privacy Compact     28, IX
     Council
National Drug Control Policy, Office of           2, XXXVI; 21, III
National Endowment for the Arts                   2, XXXII
National Endowment for the Humanities             2, XXXIII
National Foundation on the Arts and the           45, XI
     Humanities
National Geospatial-Intelligence Agency           32, I
National Highway Traffic Safety Administration    23, II, III; 47, VI; 49, V
National Imagery and Mapping Agency               32, I
National Indian Gaming Commission                 25, III
National Institute of Food and Agriculture        7, XXXIV
National Institute of Standards and Technology    15, II; 37, IV
National Intelligence, Office of Director of      5, IV; 32, XVII
National Labor Relations Board                    5, LXI; 29, I
National Marine Fisheries Service                 50, II, IV
National Mediation Board                          5, CI; 29, X
National Oceanic and Atmospheric Administration   15, IX; 50, II, III, IV, 
                                                  VI
National Park Service                             36, I
National Railroad Adjustment Board                29, III
National Railroad Passenger Corporation (AMTRAK)  49, VII
National Science Foundation                       2, XXV; 5, XLIII; 45, VI

[[Page 268]]

  Federal Acquisition Regulation                  48, 25
National Security Council                         32, XXI; 47, II
National Technical Information Service            15, XI
National Telecommunications and Information       15, XXIII; 47, III, IV, V
     Administration
National Transportation Safety Board              49, VIII
Natural Resource Revenue, Office of               30, XII
Natural Resources Conservation Service            7, VI
Navajo and Hopi Indian Relocation, Office of      25, IV
Navy, Department of                               32, VI
  Federal Acquisition Regulation                  48, 52
Neighborhood Reinvestment Corporation             24, XXV
Northeast Interstate Low-Level Radioactive Waste  10, XVIII
     Commission
Nuclear Regulatory Commission                     2, XX; 5, XLVIII; 10, I
  Federal Acquisition Regulation                  48, 20
Occupational Safety and Health Administration     29, XVII
Occupational Safety and Health Review Commission  29, XX
Ocean Energy Management, Bureau of                30, V
Oklahoma City National Memorial Trust             36, XV
Operations Office                                 7, XXVIII
Patent and Trademark Office, United States        37, I
Payment From a Non-Federal Source for Travel      41, 304
     Expenses
Payment of Expenses Connected With the Death of   41, 303
     Certain Employees
Peace Corps                                       2, XXXVII; 22, III
Pennsylvania Avenue Development Corporation       36, IX
Pension Benefit Guaranty Corporation              29, XL
Personnel Management, Office of                   5, I, IV, XXXV; 45, VIII
  Federal Acquisition Regulation                  48, 17
  Federal Employees Group Life Insurance Federal  48, 21
       Acquisition Regulation
  Federal Employees Health Benefits Acquisition   48, 16
       Regulation
  Human Resources Management and Labor Relations  5, XCVII
       Systems, Department of Homeland Security
Pipeline and Hazardous Materials Safety           49, I
     Administration
Postal Regulatory Commission                      5, XLVI; 39, III
Postal Service, United States                     5, LX; 39, I
Postsecondary Education, Office of                34, VI
President's Commission on White House             1, IV
     Fellowships
Presidential Documents                            3
Presidio Trust                                    36, X
Prisons, Bureau of                                28, V
Privacy and Civil Liberties Oversight Board       6, X
Procurement and Property Management, Office of    7, XXXII
Public and Indian Housing, Office of Assistant    24, IX
     Secretary for
Public Contracts, Department of Labor             41, 50
Public Health Service                             42, I
Railroad Retirement Board                         20, II
Reclamation, Bureau of                            43, I
Refugee Resettlement, Office of                   45, IV
Relocation Allowances                             41, 302
Research and Innovative Technology                49, XI
     Administration
Rural Business-Cooperative Service                7, XVIII, XLII, L
Rural Housing Service                             7, XVIII, XXXV, L
Rural Utilities Service                           7, XVII, XVIII, XLII, L
Safety and Environmental Enforcement, Bureau of   30, II
Science and Technology Policy, Office of          32, XXIV; 47, II
Secret Service                                    31, IV
Securities and Exchange Commission                5, XXXIV; 17, II
Selective Service System                          32, XVI
Small Business Administration                     2, XXVII; 13, I
Smithsonian Institution                           36, V
Social Security Administration                    2, XXIII; 20, III; 48, 23
Soldiers' and Airmen's Home, United States        5, XI
Special Counsel, Office of                        5, VIII
Special Education and Rehabilitative Services,    34, III
   Office of
[[Page 269]]

State, Department of                              2, VI; 22, I; 28, XI
  Federal Acquisition Regulation                  48, 6
Surface Mining Reclamation and Enforcement,       30, VII
     Office of
Surface Transportation Board                      49, X
Susquehanna River Basin Commission                18, VIII
Tennessee Valley Authority                        5, LXIX; 18, XIII
Trade Representative, United States, Office of    15, XX
Transportation, Department of                     2, XII; 5, L
  Commercial Space Transportation                 14, III
  Emergency Management and Assistance             44, IV
  Federal Acquisition Regulation                  48, 12
  Federal Aviation Administration                 14, I
  Federal Highway Administration                  23, I, II
  Federal Motor Carrier Safety Administration     49, III
  Federal Railroad Administration                 49, II
  Federal Transit Administration                  49, VI
  Great Lakes St. Lawrence Seaway Development     33, IV
       Corporation
  Maritime Administration                         46, II
  National Highway Traffic Safety Administration  23, II, III; 47, IV; 49, V
  Pipeline and Hazardous Materials Safety         49, I
       Administration
  Secretary of Transportation, Office of          14, II; 49, Subtitle A
  Transportation Statistics Bureau                49, XI
Transportation, Office of                         7, XXXIII
Transportation Security Administration            49, XII
Transportation Statistics Bureau                  49, XI
Travel Allowances, Temporary Duty (TDY)           41, 301
Treasury, Department of the                       2, X; 5, XXI; 12, XV; 17, 
                                                  IV; 31, IX
  Alcohol and Tobacco Tax and Trade Bureau        27, I
  Community Development Financial Institutions    12, XVIII
       Fund
  Comptroller of the Currency                     12, I
  Customs and Border Protection                   19, I
  Engraving and Printing, Bureau of               31, VI
  Federal Acquisition Regulation                  48, 10
  Federal Claims Collection Standards             31, IX
  Federal Law Enforcement Training Center         31, VII
  Financial Crimes Enforcement Network            31, X
  Fiscal Service                                  31, II
  Foreign Assets Control, Office of               31, V
  Internal Revenue Service                        26, I
  Investment Security, Office of                  31, VIII
  Monetary Offices                                31, I
  Secret Service                                  31, IV
  Secretary of the Treasury, Office of            31, Subtitle A
Truman, Harry S. Scholarship Foundation           45, XVIII
United States Agency for Global Media             22, V
United States and Canada, International Joint     22, IV
     Commission
United States and Mexico, International Boundary  22, XI
     and Water Commission, United States Section
U.S. Copyright Office                             37, II
U.S. Office of Special Counsel                    5, CII
Utah Reclamation Mitigation and Conservation      43, III
     Commission
Veterans Affairs, Department of                   2, VIII; 38, I
  Federal Acquisition Regulation                  48, 8
Veterans' Employment and Training Service,        41, 61; 20, IX
     Office of the Assistant Secretary for
Vice President of the United States, Office of    32, XXVIII
Wage and Hour Division                            29, V
Water Resources Council                           18, VI
Workers' Compensation Programs, Office of         20, I, VI
World Agricultural Outlook Board                  7, XXXVIII

[[Page 271]]



List of CFR Sections Affected



All changes in this volume of the Code of Federal Regulations (CFR) that 
were made by documents published in the Federal Register since January 
1, 2019 are enumerated in the following list. Entries indicate the 
nature of the changes effected. Page numbers refer to Federal Register 
pages. The user should consult the entries for chapters, parts and 
subparts as well as sections for revisions.
For changes to this volume of the CFR prior to this listing, consult the 
annual edition of the monthly List of CFR Sections Affected (LSA). The 
LSA is available at www.govinfo.gov. For changes to this volume of the 
CFR prior to 2001, see the ``List of CFR Sections Affected, 1949-1963, 
1964-1972, 1973-1985, and 1986-2000'' published in 11 separate volumes. 
The ``List of CFR Sections Affected 1986-2000'' is available at 
www.govinfo.gov.

                                  2019

21 CFR
                                                                   84 FR
                                                                    Page
Chapter I
216 Notification............................................24027, 32268
216.23 Added........................................................4710

                                  2020

21 CFR
                                                                   85 FR
                                                                    Page
Chapter I
201.317 (c) revised................................................72907
251 Added..........................................................62126

                                  2021

21 CFR
                                                                   86 FR
                                                                    Page
Chapter I
201 Authority citation revised.....................................41401
201.128 Revised....................................................41401
207.1 Amended......................................................17061
207.3 Amended......................................................17061
207.13 (l)(1) amended..............................................17061
207.49 (a)(15)(i), (ii)(A), (B), (iii)(A) and (B) amended..........17061
207.53 (d)(1), (2)(i), (ii), (3)(i) and (ii) amended...............17061

                                  2022

21 CFR
                                                                   87 FR
                                                                    Page
Chapter I
216 Notification...................................................63947
251 Notification...................................................31954

                                  2023

21 CFR
                                                                   88 FR
                                                                    Page
Chapter I
201.63 (d) amended.................................................45065
202 Notification...................................................89303
202.1 Introductory text added; (e)(1) revised; eff. 5-20-24........80983

                                  2024

 (No regulations published from January 1, 2024, through April 1, 2024)


                                  [all]