[Title 21 CFR ]
[Code of Federal Regulations (annual edition) - April 1, 2023 Edition]
[From the U.S. Government Publishing Office]



[[Page i]]

          

          Title 21

Food and Drugs


________________________

Parts 600 to 799

                         Revised as of April 1, 2023

          Containing a codification of documents of general 
          applicability and future effect

          As of April 1, 2023
                    Published by the Office of the Federal Register 
                    National Archives and Records Administration as a 
                    Special Edition of the Federal Register

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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........................     169
      Alphabetical List of Agencies Appearing in the CFR......     189
      List of CFR Sections Affected...........................     199

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

                     Cite this Code: CFR
                     To cite the regulations in 
                       this volume use title, 
                       part and section number. 
                       Thus, 21 CFR 600.2 refers 
                       to title 21, part 600, 
                       section 2.

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

[[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 
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    To determine whether a Code volume has been amended since its 
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EFFECTIVE AND EXPIRATION DATES

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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 
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PAST PROVISIONS OF THE CODE

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``[RESERVED]'' TERMINOLOGY

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that volume.

[[Page vii]]

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    Oliver A. Potts,
    Director,
    Office of the Federal Register
    April 1, 2023







[[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-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, 2023.

    For this volume, Robert J. Sheehan, III 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 600 to 799)

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

chapter i--Food and Drug Administration, Department of 
  Health and Human Services (Continued).....................         600

[[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 F--BIOLOGICS
Part                                                                Page
600             Biological products: general................           5
601             Licensing...................................          23
606             Current good manufacturing practice for 
                    blood and blood components..............          45
607             Establishment registration and product 
                    listing for manufacturers of human blood 
                    and blood products and licensed devices.          59
610             General biological products standards.......          65
630             Requirements for blood and blood components 
                    intended for transfusion or for further 
                    manufacturing use.......................          83
640             Additional standards for human blood and 
                    blood products..........................          93
660             Additional standards for diagnostic 
                    substances for laboratory tests.........         116
680             Additional standards for miscellaneous 
                    products................................         133
                         SUBCHAPTER G--COSMETICS
700             General.....................................         136
701             Cosmetic labeling...........................         144
710             Voluntary registration of cosmetic product 
                    establishments..........................         157
720             Voluntary filing of cosmetic product 
                    ingredient composition statements.......         158
740             Cosmetic product warning statements.........         162
741-799

[Reserved]

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                         SUBCHAPTER F_BIOLOGICS





PART 600_BIOLOGICAL PRODUCTS: GENERAL--Table of Contents



                      Subpart A_General Provisions

Sec.
600.2 Mailing addresses.
600.3 Definitions.

                    Subpart B_Establishment Standards

600.10 Personnel.
600.11 Physical establishment, equipment, animals, and care.
600.12 Records.
600.13 Retention samples.
600.14 Reporting of biological product deviations by licenses 
          manufacturers.
600.15 Temperatures during shipment.

                   Subpart C_Establishment Inspection

600.20 Inspectors.
600.21 Time of inspection.
600.22 [Reserved]

               Subpart D_Reporting of Adverse Experiences

600.80 Postmarketing reporting of adverse experiences.
600.81 Distribution reports.
600.82 Notification of a permanent discontinuance or an interruption in 
          manufacturing.
600.90 Waivers.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 356c, 356e, 360, 360i, 
371, 374, 379k-l; 42 U.S.C. 216, 262, 263, 263a, 264.

    Cross References: For U.S. Customs Service regulations relating to 
viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal 
Service regulations relating to the admissibility to the United States 
mails see parts 124 and 125 of the Domestic Mail Manual, that is 
incorporated by reference in 39 CFR part 111.



                      Subpart A_General Provisions



Sec.  600.2  Mailing addresses.

    (a) Licensed biological products regulated by the Center for 
Biologics Evaluation and Research (CBER). Unless otherwise stated in 
paragraph (c) of this section, or as otherwise prescribed by FDA 
regulation, all submissions to CBER referenced in parts 600 through 680 
of this chapter, as applicable, must be sent to: 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. Examples of such submissions include: Biologics 
license applications (BLAs) and their amendments and supplements, 
biological product deviation reports, fatality reports, and other 
correspondence. Biological products samples must not be sent to this 
address but must be sent to the address in paragraph (c) of this 
section.
    (b) Licensed biological products regulated by the Center for Drug 
Evaluation and Research (CDER). Unless otherwise stated in paragraphs 
(b)(1), (b)(2), or (c) of this section, or as otherwise prescribed by 
FDA regulation, all submissions to CDER referenced in parts 600, 601, 
and 610 of this chapter, as applicable, must be sent to: CDER Central 
Document Room, Center for Drug Evaluation and Research, Food and Drug 
Administration, 5901B Ammendale Rd., Beltsville, MD 20705. Examples of 
such submissions include: BLAs and their amendments and supplements, and 
other correspondence.
    (1) Biological Product Deviation Reporting (CDER). All biological 
product deviation reports required under Sec.  600.14 must be sent to: 
Division of Compliance Risk Management and Surveillance, Office of 
Compliance, Center for Drug Evaluation and Research, Food and Drug 
Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002.
    (2) Advertising and Promotional Labeling (CDER). All advertising and 
promotional labeling supplements required under Sec.  601.12(f) of this 
chapter must be sent to: Division of Drug Marketing, Advertising and 
Communication, Center for Drug Evaluation and Research, Food and Drug 
Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266.
    (c) Samples and Protocols for licensed biological products regulated 
by CBER or CDER. (1) Biological product samples and/or protocols, other 
than radioactive biological product samples and protocols, required 
under Sec. Sec.  600.13, 600.22, 601.15, 610.2, 660.6, 660.36, or 660.46

[[Page 6]]

of this chapter must be sent by courier service to: Food and Drug 
Administration, Center for Biologics Evaluation and Research, ATTN: 
Sample Custodian, 10903 New Hampshire Ave., Bldg. 75, Rm. G707, Silver 
Spring, MD 20993-0002. The protocol(s) may be placed in the box used to 
ship the samples to CBER. A cover letter should not be included when 
submitting the protocol with the sample unless it contains pertinent 
information affecting the release of the lot.
    (2) Radioactive biological products required under Sec.  610.2 of 
this chapter must be sent by courier service to: Food and Drug 
Administration, Center for Biologics Evaluation and Research, ATTN: 
Sample Custodian, c/o White Oak Radiation Safety Program, 10903 New 
Hampshire Ave., Bldg. 52-72, Rm. G406A, Silver Spring, MD 20993-0002.
    (d) Address information for submissions to CBER and CDER other than 
those listed in parts 600 through 680 of this chapter are included 
directly in the applicable regulations.
    (e) Obtain updated mailing address information for biological 
products regulated by CBER at http://www.fda.gov/BiologicsBloodVaccines/
default.htm, or for biological products regulated by CDER at http://
www.fda.gov/Drugs/default.htm.

[70 FR 14981, Mar. 24, 2005, as amended at 74 FR 13114, Mar. 26, 2009; 
78 FR 19585, Apr. 2, 2013; 80 FR 18091, Apr. 3, 2015; 79 FR 33090, June 
10, 2014]



Sec.  600.3  Definitions.

    As used in this subchapter:
    (a) Act means the Public Health Service Act (58 Stat. 682), approved 
July 1, 1944.
    (b) Secretary means the Secretary of Health and Human Services and 
any other officer or employee of the Department of Health and Human 
Services to whom the authority involved has been delegated.
    (c) Commissioner of Food and Drugs means the Commissioner of the 
Food and Drug Administration.
    (d) Center for Biologics Evaluation and Research means Center for 
Biologics Evaluation and Research of the Food and Drug Administration.
    (e) State means a State or the District of Columbia, Puerto Rico, or 
the Virgin Islands.
    (f) Possession includes among other possessions, Puerto Rico and the 
Virgin Islands.
    (g) Products includes biological products and trivalent organic 
arsenicals.
    (h) Biological product means a virus, therapeutic serum, toxin, 
antitoxin, vaccine, blood, blood component or derivative, allergenic 
product, protein, or analogous product, or arsphenamine or derivative of 
arsphenamine (or any other trivalent organic arsenic compound), 
applicable to the prevention, treatment, or cure of a disease or 
condition of human beings.
    (1) A virus is interpreted to be a product containing the minute 
living cause of an infectious disease and includes but is not limited to 
filterable viruses, bacteria, rickettsia, fungi, and protozoa.
    (2) A therapeutic serum is a product obtained from blood by removing 
the clot or clot components and the blood cells.
    (3) A toxin is a product containing a soluble substance poisonous to 
laboratory animals or to man in doses of 1 milliliter or less (or 
equivalent in weight) of the product, and having the property, following 
the injection of non-fatal doses into an animal, of causing to be 
produced therein another soluble substance which specifically 
neutralizes the poisonous substance and which is demonstrable in the 
serum of the animal thus immunized.
    (4) An antitoxin is a product containing the soluble substance in 
serum or other body fluid of an immunized animal which specifically 
neutralizes the toxin against which the animal is immune.
    (5) A product is analogous:
    (i) To a virus if prepared from or with a virus or agent actually or 
potentially infectious, without regard to the degree of virulence or 
toxicogenicity of the specific strain used.
    (ii) To a therapeutic serum, if composed of whole blood or plasma or 
containing some organic constituent or product other than a hormone or 
an amino acid, derived from whole blood, plasma, or serum.

[[Page 7]]

    (iii) To a toxin or antitoxin, if intended, irrespective of its 
source of origin, to be applicable to the prevention, treatment, or cure 
of disease or injuries of man through a specific immune process.
    (6) A protein is any alpha amino acid polymer with a specific, 
defined sequence that is greater than 40 amino acids in size. When two 
or more amino acid chains in an amino acid polymer are associated with 
each other in a manner that occurs in nature, the size of the amino acid 
polymer for purposes of this paragraph (h)(6) will be based on the total 
number of amino acids in those chains, and will not be limited to the 
number of amino acids in a contiguous sequence.
    (i) Trivalent organic arsenicals means arsphenamine and its 
derivatives (or any other trivalent organic arsenic compound) applicable 
to the prevention, treatment, or cure of diseases or injuries of man.
    (j) A product is deemed applicable to the prevention, treatment, or 
cure of diseases or injuries of man irrespective of the mode of 
administration or application recommended, including use when intended 
through administration or application to a person as an aid in 
diagnosis, or in evaluating the degree of susceptibility or immunity 
possessed by a person, and including also any other use for purposes of 
diagnosis if the diagnostic substance so used is prepared from or with 
the aid of a biological product.
    (k) Proper name, as applied to a product, means the name designated 
in the license for use upon each package of the product.
    (l) Dating period means the period beyond which the product cannot 
be expected beyond reasonable doubt to yield its specific results.
    (m) Expiration date means the calendar month and year, and where 
applicable, the day and hour, that the dating period ends.
    (n) The word standards means specifications and procedures 
applicable to an establishment or to the manufacture or release of 
products, which are prescribed in this subchapter or established in the 
biologics license application designed to insure the continued safety, 
purity, and potency of such products.
    (o) The word continued as applied to the safety, purity and potency 
of products is interpreted to apply to the dating period.
    (p) The word safety means the relative freedom from harmful effect 
to persons affected, directly or indirectly, by a product when prudently 
administered, taking into consideration the character of the product in 
relation to the condition of the recipient at the time.
    (q) The word sterility is interpreted to mean freedom from viable 
contaminating microorganisms, as determined by the tests conducted under 
Sec.  610.12 of this chapter.
    (r) Purity means relative freedom from extraneous matter in the 
finished product, whether or not harmful to the recipient or deleterious 
to the product. Purity includes but is not limited to relative freedom 
from residual moisture or other volatile substances and pyrogenic 
substances.
    (s) The word potency is interpreted to mean the specific ability or 
capacity of the product, as indicated by appropriate laboratory tests or 
by adequately controlled clinical data obtained through the 
administration of the product in the manner intended, to effect a given 
result.
    (t) Manufacturer means any legal person or entity engaged in the 
manufacture of a product subject to license under the act; 
``Manufacturer'' also includes any legal person or entity who is an 
applicant for a license where the applicant assumes responsibility for 
compliance with the applicable product and establishment standards.
    (u) Manufacture means all steps in propagation or manufacture and 
preparation of products and includes but is not limited to filling, 
testing, labeling, packaging, and storage by the manufacturer.
    (v) Location includes all buildings, appurtenances, equipment and 
animals used, and personnel engaged by a manufacturer within a 
particular area designated by an address adequate for identification.
    (w) Establishment has the same meaning as ``facility'' in section 
351 of the

[[Page 8]]

Public Health Service Act and includes all locations.
    (x) Lot means that quantity of uniform material identified by the 
manufacturer as having been thoroughly mixed in a single vessel.
    (y) A filling refers to a group of final containers identical in all 
respects, which have been filled with the same product from the same 
bulk lot without any change that will affect the integrity of the 
filling assembly.
    (z) Process refers to a manufacturing step that is performed on the 
product itself which may affect its safety, purity or potency, in 
contrast to such manufacturing steps which do not affect intrinsically 
the safety, purity or potency of the product.
    (aa) Selling agent or distributor means any person engaged in the 
unrestricted distribution, other than by sale at retail, of products 
subject to license.
    (bb) Container (referred to also as ``final container'') is the 
immediate unit, bottle, vial, ampule, tube, or other receptacle 
containing the product as distributed for sale, barter, or exchange.
    (cc) Package means the immediate carton, receptacle, or wrapper, 
including all labeling matter therein and thereon, and the contents of 
the one or more enclosed containers. If no package, as defined in the 
preceding sentence, is used, the container shall be deemed to be the 
package.
    (dd) Label means any written, printed, or graphic matter on the 
container or package or any such matter clearly visible through the 
immediate carton, receptacle, or wrapper.
    (ee) Radioactive biological product means a biological product which 
is labeled with a radionuclide or intended solely to be labeled with a 
radionuclide.
    (ff) Amendment is the submission of information to a pending license 
application or supplement, to revise or modify the application as 
originally submitted.
    (gg) Supplement is a request to approve a change in an approved 
license application.
    (hh) Distributed means the biological product has left the control 
of the licensed manufacturer.
    (ii) Control means having responsibility for maintaining the 
continued safety, purity, and potency of the product and for compliance 
with applicable product and establishment standards, and for compliance 
with current good manufacturing practices.
    (jj) Assess the effects of the change, as used in Sec.  601.12 of 
this chapter, means to evaluate the effects of a manufacturing change on 
the identity, strength, quality, purity, and potency of a product as 
these factors may relate to the safety or effectiveness of the product.
    (kk) Specification, as used in Sec.  601.12 of this chapter, means 
the quality standard (i.e., tests, analytical procedures, and acceptance 
criteria) provided in an approved application to confirm the quality of 
products, intermediates, raw materials, reagents, components, in-process 
materials, container closure systems, and other materials used in the 
production of a product. For the purpose of this definition, acceptance 
criteria means numerical limits, ranges, or other criteria for the tests 
described.
    (ll) Complete response letter means a written communication to an 
applicant from FDA usually describing all of the deficiencies that the 
agency has identified in a biologics license application or supplement 
that must be satisfactorily addressed before it can be approved.
    (mm) Resubmission means a submission by the biologics license 
applicant or supplement applicant of all materials needed to fully 
address all deficiencies identified in the complete response letter. A 
biologics license application or supplement for which FDA issued a 
complete response letter, but which was withdrawn before approval and 
later submitted again, is not a resubmission.

[38 FR 32048, Nov. 20, 1973, as amended at 40 FR 31313, July 25, 1975; 
55 FR 11014, Mar. 26, 1990; 61 FR 24232, May 14, 1996; 62 FR 39901, July 
24, 1997; 64 FR 56449, Oct. 20, 1999; 65 FR 66634, Nov. 7, 2000; 69 FR 
18766, Apr. 8, 2004; 70 FR 14982, Mar. 24, 2005; 73 FR 39610, July 10, 
2008; 77 FR 26174, May 3, 2012; 85 FR 10063, Feb. 21, 2020]

[[Page 9]]



                    Subpart B_Establishment Standards



Sec.  600.10  Personnel.

    (a) [Reserved]
    (b) Personnel. Personnel shall have capabilities commensurate with 
their assigned functions, a thorough understanding of the manufacturing 
operations which they perform, the necessary training and experience 
relating to individual products, and adequate information concerning the 
application of the pertinent provisions of this subchapter to their 
respective functions. Personnel shall include such professionally 
trained persons as are necessary to insure the competent performance of 
all manufacturing processes.
    (c) Restrictions on personnel--(1) Specific duties. Persons whose 
presence can affect adversely the safety and purity of a product shall 
be excluded from the room where the manufacture of a product is in 
progress.
    (2) Sterile operations. Personnel performing sterile operations 
shall wear clean or sterilized protective clothing and devices to the 
extent necessary to protect the product from contamination.
    (3) Pathogenic viruses and spore-forming organisms. Persons working 
with viruses pathogenic for man or with spore-forming microorganisms, 
and persons engaged in the care of animals or animal quarters, shall be 
excluded from areas where other products are manufactured, or such 
persons shall change outer clothing, including shoes, or wear protective 
covering prior to entering such areas.
    (4) Live vaccine work areas. Persons may not enter a live vaccine 
processing area after having worked with other infectious agents in any 
other laboratory during the same working day. Only persons actually 
concerned with propagation of the culture, production of the vaccine, 
and unit maintenance, shall be allowed in live vaccine processing areas 
when active work is in progress. Casual visitors shall be excluded from 
such units at all times and all others having business in such areas 
shall be admitted only under supervision. Street clothing, including 
shoes, shall be replaced or covered by suitable laboratory clothing 
before entering a live vaccine processing unit. Persons caring for 
animals used in the manufacture of live vaccines shall be excluded from 
other animal quarters and from contact with other animals during the 
same working day.

[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55 
FR 11014, Mar. 26, 1990; 62 FR 53538, Oct. 15, 1997; 68 FR 75119, Dec. 
30, 2003]



Sec.  600.11  Physical establishment, equipment, animals, and care.

    (a) Work areas. All rooms and work areas where products are 
manufactured or stored shall be kept orderly, clean, and free of dirt, 
dust, vermin and objects not required for manufacturing. Precautions 
shall be taken to avoid clogging and back-siphonage of drainage systems. 
Precautions shall be taken to exclude extraneous infectious agents from 
manufacturing areas. Work rooms shall be well lighted and ventilated. 
The ventilation system shall be arranged so as to prevent the 
dissemination of microorganisms from one manufacturing area to another 
and to avoid other conditions unfavorable to the safety of the product. 
Filling rooms, and other rooms where open, sterile operations are 
conducted, shall be adequate to meet manufacturing needs and such rooms 
shall be constructed and equipped to permit thorough cleaning and to 
keep air-borne contaminants at a minimum. If such rooms are used for 
other purposes, they shall be cleaned and prepared prior to use for 
sterile operations. Refrigerators, incubators and warm rooms shall be 
maintained at temperatures within applicable ranges and shall be free of 
extraneous material which might affect the safety of the product.
    (b) Equipment. Apparatus for sterilizing equipment and the method of 
operation shall be such as to insure the destruction of contaminating 
microorganisms. The effectiveness of the sterilization procedure shall 
be no less than that achieved by an attained temperature of 121.5 [deg]C 
maintained for 20 minutes by saturated steam or by an attained 
temperature of 170 [deg]C maintained for 2 hours with dry heat. 
Processing and storage containers, filters, filling apparatus, and other 
pieces of

[[Page 10]]

apparatus and accessory equipment, including pipes and tubing, shall be 
designed and constructed to permit thorough cleaning and, where 
possible, inspection for cleanliness. All surfaces that come in contact 
with products shall be clean and free of surface solids, leachable 
contaminants, and other materials that will hasten the deterioration of 
the product or otherwise render it less suitable for the intended use. 
For products for which sterility is a factor, equipment shall be 
sterile, unless sterility of the product is assured by subsequent 
procedures.
    (c) Laboratory and bleeding rooms. Rooms used for the processing of 
products, including bleeding rooms, shall be effectively fly-proofed and 
kept free of flies and vermin. Such rooms shall be so constructed as to 
insure freedom from dust, smoke and other deleterious substances and to 
permit thorough cleaning and disinfection. Rooms for animal injection 
and bleeding, and rooms for smallpox vaccine animals, shall be 
disinfected and be provided with the necessary water, electrical and 
other services.
    (d) Animal quarters and stables. Animal quarters, stables and food 
storage areas shall be of appropriate construction, fly-proofed, 
adequately lighted and ventilated, and maintained in a clean, vermin-
free and sanitary condition. No manure or refuse shall be stored as to 
permit the breeding of flies on the premises, nor shall the 
establishment be located in close proximity to off-property manure or 
refuse storage capable of engendering fly breeding.
    (e) Restrictions on building and equipment use--(1) Work of a 
diagnostic nature. Laboratory procedures of a clinical diagnostic nature 
involving materials that may be contaminated, shall not be performed in 
space used for the manufacture of products except that manufacturing 
space which is used only occasionally may be used for diagnostic work 
provided spore-forming pathogenic microorganisms are not involved and 
provided the space is thoroughly cleaned and disinfected before the 
manufacture of products is resumed.
    (2) Spore-forming organisms for supplemental sterilization procedure 
control test. Spore-forming organisms used as an additional control in 
sterilization procedures may be introduced into areas used for the 
manufacture of products, only for the purposes of the test and only 
immediately before use for such purposes: Provided, That (i) the 
organism is not pathogenic for man or animals and does not produce 
pyrogens or toxins, (ii) the culture is demonstrated to be pure, (iii) 
transfer of test cultures to culture media shall be limited to the 
sterility test area or areas designated for work with spore-forming 
organisms, (iv) each culture be labeled with the name of the 
microorganism and the statement ``Caution: microbial spores. See 
directions for storage, use and disposition.'', and (v) the container of 
each culture is designed to withstand handling without breaking.
    (3) Work with spore-forming microorganisms. (i) Manufacturing 
processes using spore-forming microorganisms conducted in a multiproduct 
manufacturing site must be performed under appropriate controls to 
prevent contamination of other products and areas within the site. 
Prevention of spore contamination can be achieved by using a separate 
dedicated building or by using process containment if manufacturing is 
conducted in a multiproduct manufacturing building. All product and 
personnel movement between the area where the spore-forming 
microorganisms are manufactured and other manufacturing areas must be 
conducted under conditions that will prevent the introduction of spores 
into other areas of the facility.
    (ii) If process containment is employed in a multiproduct 
manufacturing area, procedures must be in place to demonstrate adequate 
removal of the spore-forming microorganism(s) from the manufacturing 
area for subsequent manufacture of other products. These procedures must 
provide for adequate removal or decontamination of the spore-forming 
microorganisms on and within manufacturing equipment, facilities, and 
ancillary room items as well as the removal of disposable or product 
dedicated items from the manufacturing area. Environmental monitoring 
specific for the spore-forming microorganism(s) must be conducted in 
adjacent areas during manufacturing

[[Page 11]]

operations and in the manufacturing area after completion of cleaning 
and decontamination.
    (4) Live vaccine processing. Live vaccine processing must be 
performed under appropriate controls to prevent cross contamination of 
other products and other manufacturing areas within the building. 
Appropriate controls must include, at a minimum:
    (i)(A) Using a dedicated manufacturing area that is either in a 
separate building, in a separate wing of a building, or in quarters at 
the blind end of a corridor and includes adequate space and equipment 
for all processing steps up to, but not including, filling into final 
containers; and
    (B) Not conducting test procedures that potentially involve the 
presence of microorganisms other than the vaccine strains or the use of 
tissue culture cell lines other than primary cultures in space used for 
processing live vaccine; or
    (ii) If manufacturing is conducted in a multiproduct manufacturing 
building or area, using procedural controls, and where necessary, 
process containment. Process containment is deemed to be necessary 
unless procedural controls are sufficient to prevent cross contamination 
of other products and other manufacturing areas within the building. 
Process containment is a system designed to mechanically isolate 
equipment or an area that involves manufacturing using live vaccine 
organisms. All product, equipment, and personnel movement between 
distinct live vaccine processing areas and between live vaccine 
processing areas and other manufacturing areas, up to, but not 
including, filling in final containers, must be conducted under 
conditions that will prevent cross contamination of other products and 
manufacturing areas within the building, including the introduction of 
live vaccine organisms into other areas. In addition, written procedures 
and effective processes must be in place to adequately remove or 
decontaminate live vaccine organisms from the manufacturing area and 
equipment for subsequent manufacture of other products. Written 
procedures must be in place for verification that processes to remove or 
decontaminate live vaccine organisms have been followed.
    (5) Equipment and supplies--contamination. Equipment and supplies 
used in work on or otherwise exposed to any pathogenic or potentially 
pathogenic agent shall be kept separated from equipment and supplies 
used in the manufacture of products to the extent necessary to prevent 
cross-contamination.
    (f) Animals used in manufacture--(1) Care of animals used in 
manufacturing. Caretakers and attendants for animals used for the 
manufacture of products shall be sufficient in number and have adequate 
experience to insure adequate care. Animal quarters and cages shall be 
kept in sanitary condition. Animals on production shall be inspected 
daily to observe response to production procedures. Animals that become 
ill for reasons not related to production shall be isolated from other 
animals and shall not be used for production until recovery is complete. 
Competent veterinary care shall be provided as needed.
    (2) Quarantine of animals--(i) General. No animal shall be used in 
processing unless kept under competent daily inspection and preliminary 
quarantine for a period of at least 7 days before use, or as otherwise 
provided in this subchapter. Only healthy animals free from detectable 
communicable diseases shall be used. Animals must remain in overt good 
health throughout the quarantine periods and particular care shall be 
taken during the quarantine periods to reject animals of the equine 
genus which may be infected with glanders and animals which may be 
infected with tuberculosis.
    (ii) Quarantine of monkeys. In addition to observing the pertinent 
general quarantine requirements, monkeys used as a source of tissue in 
the manufacture of vaccine shall be maintained in quarantine for at 
least 6 weeks prior to use, except when otherwise provided in this part. 
Only monkeys that have reacted negatively to tuberculin at the start of 
the quarantine period and again within 2 weeks prior to use shall be 
used in the manufacture of vaccine. Due precaution shall be taken to 
prevent cross-infection from any infected or potentially infected 
monkeys on the

[[Page 12]]

premises. Monkeys to be used in the manufacture of a live vaccine shall 
be maintained throughout the quarantine period in cages closed on all 
sides with solid materials except the front which shall be screened, 
with no more than two monkeys housed in one cage. Cage mates shall not 
be interchanged.
    (3) Immunization against tetanus. Horses and other animals 
susceptible to tetanus, that are used in the processing steps of the 
manufacture of biological products, shall be treated adequately to 
maintain immunity to tetanus.
    (4) Immunization and bleeding of animals used as a source of 
products. Toxins or other nonviable antigens administered in the 
immunization of animals used in the manufacture of products shall be 
sterile. Viable antigens, when so used, shall be free of contaminants, 
as determined by appropriate tests prior to use. Injections shall not be 
made into horses within 6 inches of bleeding site. Horses shall not be 
bled for manufacturing purposes while showing persistent general 
reaction or local reaction near the site of bleeding. Blood shall not be 
used if it was drawn within 5 days of injecting the animals with viable 
microorganisms. Animals shall not be bled for manufacturing purposes 
when they have an intercurrent disease. Blood intended for use as a 
source of a biological product shall be collected in clean, sterile 
vessels. When the product is intended for use by injection, such vessels 
shall also be pyrogen-free.
    (5) [Reserved]
    (6) Reporting of certain diseases. In cases of actual or suspected 
infection with foot and mouth disease, glanders, tetanus, anthrax, gas 
gangrene, equine infectious anemia; equine encephalomyelitis, or any of 
the pock diseases among animals intended for use or used in the 
manufacture of products, the manufacturer shall immediately notify the 
Director, Center for Biologics Evaluation and Research or the Director, 
Center for Drug Evaluation and Research (see mailing addresses in Sec.  
600.2(a) or (b)).
    (7) Monkeys used previously for experimental or test purposes. 
Monkeys that have been used previously for experimental or test purposes 
with live microbiological agents shall not be used as a source of kidney 
tissue for the manufacture of vaccine. Except as provided otherwise in 
this subchapter, monkeys that have been used previously for other 
experimental or test purposes may be used as a source of kidney tissue 
upon their return to a normal condition, provided all quarantine 
requirements have been met.
    (8) Necropsy examination of monkeys. Each monkey used in the 
manufacture of vaccine shall be examined at necropsy under the direction 
of a qualified pathologist, physician, or veterinarian having experience 
with diseases of monkeys, for evidence of ill health, particularly for 
(i) evidence of tuberculosis, (ii) presence of herpes-like lesions, 
including eruptions or plaques on or around the lips, in the buccal 
cavity or on the gums, and (iii) signs of conjunctivitis. If there are 
any such signs or other significant gross pathological lesions, the 
tissue shall not be used in the manufacture of vaccine.
    (g) Filling procedures. Filling procedures shall be such as will not 
affect adversely the safety, purity or potency of the product.
    (h) Containers and closures. All final containers and closures shall 
be made of material that will not hasten the deterioration of the 
product or otherwise render it less suitable for the intended use. All 
final containers and closures shall be clean and free of surface solids, 
leachable contaminants and other materials that will hasten the 
deterioration of the product or otherwise render it less suitable for 
the intended use. After filling, sealing shall be performed in a manner 
that will maintain the integrity of the product during the dating 
period. In addition, final containers and closures for products intended 
for use by injection shall be sterile and free from pyrogens. Except as 
otherwise provided in the regulations of this subchapter, final 
containers for products intended for use by injection shall be colorless 
and sufficiently transparent to permit visual examination of the 
contents under normal light. As soon as possible after filling final 
containers shall be labeled as prescribed in Sec.  610.60 et seq. of 
this chapter, except that final containers may be stored

[[Page 13]]

without such prescribed labeling provided they are stored in a sealed 
receptacle labeled both inside and outside with at least the name of the 
product, the lot number, and the filling identification.

[38 FR 32048, Nov. 20, 1973, as amended at 41 FR 10428, Mar. 11, 1976; 
49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 68 FR 75119, Dec. 
30, 2003; 70 FR 14982, Mar. 24, 2005; 72 FR 59003, Oct. 18, 2007; 80 FR 
18092, Apr. 3, 2015]



Sec.  600.12  Records.

    (a) Maintenance of records. Records shall be made, concurrently with 
the performance, of each step in the manufacture and distribution of 
products, in such a manner that at any time successive steps in the 
manufacture and distribution of any lot may be traced by an inspector. 
Such records shall be legible and indelible, shall identify the person 
immediately responsible, shall include dates of the various steps, and 
be as detailed as necessary for clear understanding of each step by one 
experienced in the manufacture of products.
    (b) Records retention--(1) General. Records shall be retained for 
such interval beyond the expiration date as is necessary for the 
individual product, to permit the return of any clinical report of 
unfavorable reactions. The retention period shall be no less than five 
years after the records of manufacture have been completed or six months 
after the latest expiration date for the individual product, whichever 
represents a later date.
    (2) Records of recall. Complete records shall be maintained 
pertaining to the recall from distribution of any product upon 
notification by the Director, Center for Biologics Evaluation and 
Research or the Director, Center for Drug Evaluation and Research, to 
recall for failure to conform with the standards prescribed in the 
regulations of this subchapter, because of deterioration of the product 
or for any other factor by reason of which the distribution of the 
product would constitute a danger to health.
    (3) Suspension of requirement for retention. The Director, Center 
for Biologics Evaluation and Research or the Director, Center for Drug 
Evaluation and Research, may authorize the suspension of the requirement 
to retain records of a specific manufacturing step upon a showing that 
such records no longer have significance for the purposes for which they 
were made: Provided, That a summary of such records shall be retained.
    (c) Records of sterilization of equipment and supplies. Records 
relating to the mode of sterilization, date, duration, temperature and 
other conditions relating to each sterilization of equipment and 
supplies used in the processing of products shall be made by means of 
automatic recording devices or by means of a system of recording which 
gives equivalent assurance of the accuracy and reliability of the 
record. Such records shall be maintained in a manner that permits an 
identification of the product with the particular manufacturing process 
to which the sterilization relates.
    (d) Animal necropsy records. A necropsy record shall be kept on each 
animal from which a biological product has been obtained and which dies 
or is sacrificed while being so used.
    (e) Records in case of divided manufacturing responsibility. If two 
or more establishments participate in the manufacture of a product, the 
records of each such establishment must show plainly the degree of its 
responsibility. In addition, each participating manufacturer shall 
furnish to the manufacturer who prepares the product in final form for 
sale, barter or exchange, a copy of all records relating to the 
manufacturing operations performed by such participating manufacturer 
insofar as they concern the safety, purity and potency of the lots of 
the product involved, and the manufacturer who prepares the product in 
final form shall retain a complete record of all the manufacturing 
operations relating to the product.

[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55 
FR 11013, Mar. 26, 1990; 70 FR 14982, Mar. 24, 2005]



Sec.  600.13  Retention samples.

    Manufacturers shall retain for a period of at least 6 months after 
the expiration date, unless a different time period is specified in 
additional standards, a quantity of representative material of each lot 
of each product, sufficient for examination and testing for

[[Page 14]]

safety and potency, except Whole Blood, Cryoprecipitated AHF, Platelets, 
Red Blood Cells, Plasma, and Source Plasma and Allergenic Products 
prepared to a physician's prescription. Samples so retained shall be 
selected at random from either final container material, or from bulk 
and final containers, provided they include at least one final container 
as a final package, or package-equivalent of such filling of each lot of 
the product as intended for distribution. Such sample material shall be 
stored at temperatures and under conditions which will maintain the 
identity and integrity of the product. Samples retained as required in 
this section shall be in addition to samples of specific products 
required to be submitted to the Center for Biologics Evaluation and 
Research or the Center for Drug Evaluation and Research (see mailing 
addresses in Sec.  600.2). Exceptions may be authorized by the Director, 
Center for Biologics Evaluation and Research or the Director, Center for 
Drug Evaluation and Research, when the lot yields relatively few final 
containers and when such lots are prepared by the same method in large 
number and in close succession.

[41 FR 10428, Mar. 11, 1976, as amended at 49 FR 23833, June 8, 1984; 50 
FR 4133, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 70 FR 14982, Mar. 
24, 2005]



Sec.  600.14  Reporting of biological product deviations by licensed
manufacturers.

    (a) Who must report under this section? (1) You, the manufacturer 
who holds the biological product license and who had control over the 
product when the deviation occurred, must report under this section. If 
you arrange for another person to perform a manufacturing, holding, or 
distribution step, while the product is in your control, that step is 
performed under your control. You must establish, maintain, and follow a 
procedure for receiving information from that person on all deviations, 
complaints, and adverse events concerning the affected product.
    (2) Exceptions:
    (i) Persons who manufacture only in vitro diagnostic products that 
are not subject to licensing under section 351 of the Public Health 
Service Act do not report biological product deviations for those 
products under this section but must report in accordance with part 803 
of this chapter;
    (ii) Persons who manufacture blood and blood components, including 
licensed manufacturers, unlicensed registered blood establishments, and 
transfusion services, do not report biological product deviations for 
those products under this section but must report under Sec.  606.171 of 
this chapter;
    (iii) Persons who manufacture Source Plasma or any other blood 
component and use that Source Plasma or any other blood component in the 
further manufacture of another licensed biological product must report:
    (A) Under Sec.  606.171 of this chapter, if a biological product 
deviation occurs during the manufacture of that Source Plasma or any 
other blood component; or
    (B) Under this section, if a biological product deviation occurs 
after the manufacture of that Source Plasma or any other blood 
component, and during manufacture of the licensed biological product.
    (b) What do I report under this section? You must report any event, 
and information relevant to the event, associated with the 
manufacturing, to include testing, processing, packing, labeling, or 
storage, or with the holding or distribution, of a licensed biological 
product, if that event meets all the following criteria:
    (1) Either:
    (i) Represents a deviation from current good manufacturing practice, 
applicable regulations, applicable standards, or established 
specifications that may affect the safety, purity, or potency of that 
product; or
    (ii) Represents an unexpected or unforeseeable event that may affect 
the safety, purity, or potency of that product; and
    (2) Occurs in your facility or another facility under contract with 
you; and
    (3) Involves a distributed biological product.
    (c) When do I report under this section? You should report a 
biological product deviation as soon as possible but you must report at 
a date not to exceed 45-calendar days from the date you, your agent, or 
another person who performs

[[Page 15]]

a manufacturing, holding, or distribution step under your control, 
acquire information reasonably suggesting that a reportable event has 
occurred.
    (d) How do I report under this section You must report on Form FDA-
3486.
    (e) Where do I report under this section? (1) For biological 
products regulated by the Center for Biologics Evaluation and Research 
(CBER), send the completed Form FDA 3486 to the CBER Document Control 
Center (see mailing address in Sec.  600.2(a)), or submit electronically 
using CBER's electronic Web-based application.
    (2) For biological products regulated by the Center for Drug 
Evaluation and Research (CDER), send the completed Form FDA-3486 to the 
Division of Compliance Risk Management and Surveillance (HFD-330) (see 
mailing addresses in Sec.  600.2). CDER does not currently accept 
electronic filings.
    (3) If you make a paper filing, you should identify on the envelope 
that a biological product deviation report (BPDR) is enclosed.
    (f) How does this regulation affect other FDA regulations? This part 
supplements and does not supersede other provisions of the regulations 
in this chapter. All biological product deviations, whether or not they 
are required to be reported under this section, should be investigated 
in accordance with the applicable provisions of parts 211 and 820 of 
this chapter.

[65 FR 66634, Nov. 7, 2000, as amended at 70 FR 14982, Mar. 24, 2005; 80 
FR 18092, Apr. 3, 2015]



Sec.  600.15  Temperatures during shipment.

    The following products shall be maintained during shipment at the 
specified temperatures:
    (a) Products.

------------------------------------------------------------------------
                Product                            Temperature
------------------------------------------------------------------------
Cryoprecipitated AHF...................  -18 [deg]C or colder.
Measles and Rubella Virus Vaccine Live.  10 [deg]C or colder.
Measles Live and Smallpox Vaccine......   Do.
Measles, Mumps, and Rubella Virus         Do.
 Vaccine Live.
Measles and Mumps Virus Vaccine Live...   Do.
Measles Virus Vaccine Live.............   Do.
Mumps Virus Vaccine Live...............   Do.
Fresh Frozen Plasma....................  -18 [deg]C or colder.
Liquid Plasma..........................  1 to 10 [deg]C.
Plasma.................................  -18 [deg]C or colder.
Platelet Rich Plasma...................  Between 1 and 10 [deg]C if the
                                          label indicates storage
                                          between 1 and 6 [deg]C, or all
                                          reasonable methods to maintain
                                          the temperature as close as
                                          possible to a range between 20
                                          and 24 [deg]C, if the label
                                          indicates storage between 20
                                          and 24 [deg]C.
Platelets..............................  Between 1 and 10 [deg]C if the
                                          label indicates storage
                                          between 1 and 6 [deg]C, or all
                                          reasonable methods to maintain
                                          the temperature as close as
                                          possible to a range between 20
                                          to 24 [deg]C, if the label
                                          indicates storage between 20
                                          and 24 [deg]C.
Poliovirus Vaccine Live Oral Trivalent.  0 [deg]C or colder.
Poliovirus Vaccine Live Oral Type I....   Do.
Poliovirus Vaccine Live Oral Type II...   Do.
Poliovirus Vaccine Live Oral Type III..   Do.
Red Blood Cells (liquid product).......  Between 1 and 10 [deg]C.
Red Blood Cells Frozen.................  -65 [deg]C or colder.
Rubella and Mumps Virus Vaccine Live...  10 [deg]C or colder.
Rubella Virus Vaccine Live.............   Do.
Smallpox Vaccine (Liquid Product)......  0 [deg]C or colder.
Source Plasma..........................  -5 [deg]C or colder.
Source Plasma Liquid...................  10 [deg]C or colder.
Whole Blood............................  Blood that is transported from
                                          the collecting facility to the
                                          processing facility shall be
                                          transported in an environment
                                          capable of continuously
                                          cooling the blood toward a
                                          temperature range of 1 to 10
                                          [deg]C, or at a temperature as
                                          close as possible to 20 to 24
                                          [deg]C for a period not to
                                          exceed 6 hours. Blood
                                          transported from the storage
                                          facility shall be placed in an
                                          appropriate environment to
                                          maintain a temperature range
                                          between 1 to 10 [deg]C during
                                          shipment.
Yellow Fever Vaccine...................  0 [deg]C or colder.
------------------------------------------------------------------------


[[Page 16]]

    (b) Exemptions. Exemptions or modifications shall be made only upon 
written approval, in the form of a supplement to the biologics license 
application, approved by the Director, Center for Biologics Evaluation 
and Research.

[39 FR 39872, Nov. 12, 1974, as amended at 49 FR 23833, June 8, 1984; 50 
FR 4133, Jan. 29, 1985; 50 FR 9000, Mar. 6, 1985; 55 FR 11013, Mar. 26, 
1990; 59 FR 49351, Sept. 28, 1994; 64 FR 56449, Oct. 20, 1999]



                   Subpart C_Establishment Inspection



Sec.  600.20  Inspectors.

    Inspections shall be made by an officer of the Food and Drug 
Administration having special knowledge of the methods used in the 
manufacture and control of products and designated for such purposes by 
the Commissioner of Food and Drugs, or by any officer, agent, or 
employee of the Department of Health and Human Services specifically 
designated for such purpose by the Secretary.

[38 FR 32048, Nov. 20, 1973]



Sec.  600.21  Time of inspection.

    The inspection of an establishment for which a biologics license 
application is pending need not be made until the establishment is in 
operation and is manufacturing the complete product for which a 
biologics license is desired.

[38 FR 32048, Nov. 20, 1973, as amended at 48 FR 26314, June 7, 1983; 64 
FR 56449, Oct. 20, 1999; 84 FR 12508, Apr. 2, 2019]



Sec.  600.22  [Reserved]



               Subpart D_Reporting of Adverse Experiences

    Source: 59 FR 54042, Oct. 27, 1994, unless otherwise noted.



Sec.  600.80  Postmarketing reporting of adverse experiences.

    (a) Definitions. The following definitions of terms apply to this 
section:
    Adverse experience. Any adverse event associated with the use of a 
biological product in humans, whether or not considered product related, 
including the following: An adverse event occurring in the course of the 
use of a biological product in professional practice; an adverse event 
occurring from overdose of the product whether accidental or 
intentional; an adverse event occurring from abuse of the product; an 
adverse event occurring from withdrawal of the product; and any failure 
of expected pharmacological action.
    Blood Component. As defined in Sec.  606.3(c) of this chapter.
    Disability. A substantial disruption of a person's ability to 
conduct normal life functions.
    Individual case safety report (ICSR). A description of an adverse 
experience related to an individual patient or subject.
    ICSR attachments. Documents related to the adverse experience 
described in an ICSR, such as medical records, hospital discharge 
summaries, or other documentation.
    Life-threatening adverse experience. Any adverse experience that 
places the patient, in the view of the initial reporter, at immediate 
risk of death from the adverse experience as it occurred, i.e., it does 
not include an adverse experience that, had it occurred in a more severe 
form, might have caused death.
    Serious adverse experience. Any adverse experience occurring at any 
dose that results in any of the following outcomes: Death, a life-
threatening adverse experience, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.
    Unexpected adverse experience: Any adverse experience that is not 
listed in the current labeling for the biological

[[Page 17]]

product. This includes events that may be symptomatically and 
pathophysiologically related to an event listed in the labeling, but 
differ from the event because of greater severity or specificity. For 
example, under this definition, hepatic necrosis would be unexpected (by 
virtue of greater severity) if the labeling only referred to elevated 
hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and 
cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the labeling only listed cerebral vascular accidents. 
``Unexpected,'' as used in this definition, refers to an adverse 
experience that has not been previously observed (i.e., included in the 
labeling) rather than from the perspective of such experience not being 
anticipated from the pharmacological properties of the pharmaceutical 
product.
    (b) Review of adverse experiences. Any person having a biologics 
license under Sec.  601.20 of this chapter must promptly review all 
adverse experience information pertaining to its product obtained or 
otherwise received by the applicant from any source, foreign or 
domestic, including information derived from commercial marketing 
experience, postmarketing clinical investigations, postmarketing 
epidemiological/surveillance studies, reports in the scientific 
literature, and unpublished scientific papers. Applicants are not 
required to resubmit to FDA adverse product experience reports forwarded 
to the applicant by FDA; applicants, however, must submit all followup 
information on such reports to FDA. Any person subject to the reporting 
requirements under paragraph (c) of this section must also develop 
written procedures for the surveillance, receipt, evaluation, and 
reporting of postmarketing adverse experiences to FDA.
    (c) Reporting requirements. The applicant must submit to FDA 
postmarketing 15-day Alert reports and periodic safety reports 
pertaining to its biological product as described in this section. These 
reports must be submitted to the Agency in electronic format as 
described in paragraph (h)(1) of this section, except as provided in 
paragraph (h)(2) of this section.
    (1)(i) Postmarketing 15-day ``Alert reports''. The applicant must 
report each adverse experience that is both serious and unexpected, 
whether foreign or domestic, as soon as possible but no later than 15 
calendar days from initial receipt of the information by the applicant.
    (ii) Postmarketing 15-day ``Alert reports''--followup. The applicant 
must promptly investigate all adverse experiences that are the subject 
of these postmarketing 15-day Alert reports and must submit followup 
reports within 15 calendar days of receipt of new information or as 
requested by FDA. If additional information is not obtainable, records 
should be maintained of the unsuccessful steps taken to seek additional 
information.
    (iii) Submission of reports. The requirements of paragraphs 
(c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of 
postmarketing 15-day Alert reports, also apply to any person whose name 
appears on the label of a licensed biological product as a manufacturer, 
packer, distributor, shared manufacturer, joint manufacturer, or any 
other participant involved in divided manufacturing. To avoid 
unnecessary duplication in the submission to FDA of reports required by 
paragraphs (c)(1)(i) and (c)(1)(ii) of this section, obligations of 
persons other than the applicant of the final biological product may be 
met by submission of all reports of serious adverse experiences to the 
applicant of the final product. If a person elects to submit adverse 
experience reports to the applicant rather than to FDA, the person must 
submit, by any appropriate means, each report to the applicant within 5 
calendar days of initial receipt of the information by the person, and 
the applicant must then comply with the requirements of this section. 
Under this circumstance, a person who elects to submit reports to the 
applicant of the final product shall maintain a record of this action 
which must include:
    (A) A copy of all adverse biological product experience reports 
submitted to the applicant of the final product;
    (B) The date the report was received by the person;

[[Page 18]]

    (C) The date the report was submitted to the applicant of the final 
product; and--
    (D) The name and address of the applicant of the final product.
    (2) Periodic adverse experience reports. (i) The applicant must 
report each adverse experience not reported under paragraph (c)(1)(i) of 
this section at quarterly intervals, for 3 years from the date of 
issuance of the biologics license, and then at annual intervals. The 
applicant must submit each quarterly report within 30 days of the close 
of the quarter (the first quarter beginning on the date of issuance of 
the biologics license) and each annual report within 60 days of the 
anniversary date of the issuance of the biologics license. Upon written 
notice, FDA may extend or reestablish the requirement that an applicant 
submit quarterly reports, or require that the applicant submit reports 
under this section at different times than those stated. Followup 
information to adverse experiences submitted in a periodic report may be 
submitted in the next periodic report.
    (ii) Each periodic report is required to contain:
    (A) Descriptive information. (1) A narrative summary and analysis of 
the information in the report;
    (2) An analysis of the 15-day Alert reports submitted during the 
reporting interval (all 15-day Alert reports being appropriately 
referenced by the applicant's patient identification code for nonvaccine 
biological product reports or by the unique case identification number 
for vaccine reports, adverse reaction term(s), and date of submission to 
FDA);
    (3) A history of actions taken since the last report because of 
adverse experiences (for example, labeling changes or studies 
initiated);
    (4) An index consisting of a line listing of the applicant's patient 
identification code for nonvaccine biological product reports or by the 
unique case identification number for vaccine reports and adverse 
reaction term(s) for ICSRs submitted under paragraph (c)(2)(ii)(B) of 
this section; and
    (B) ICSRs for serious, expected and, nonserious adverse experiences. 
An ICSR for each adverse experience not reported under paragraph 
(c)(1)(i) of this section (all serious, expected and nonserious adverse 
experiences). All such ICSRs must be submitted to FDA (either 
individually or in one or more batches) within the timeframe specified 
in paragraph (c)(2)(i) of this section. ICSRs must only be submitted to 
FDA once.
    (iii) Periodic reporting, except for information regarding 15-day 
Alert reports, does not apply to adverse experience information obtained 
from postmarketing studies (whether or not conducted under an 
investigational new drug application), from reports in the scientific 
literature, and from foreign marketing experience.
    (d) Scientific literature. A 15-day Alert report based on 
information in the scientific literature must be accompanied by a copy 
of the published article. The 15-day Alert reporting requirements in 
paragraph (c)(1)(i) of this section (i.e., serious, unexpected adverse 
experiences) apply only to reports found in scientific and medical 
journals either as case reports or as the result of a formal clinical 
trial.
    (e) Postmarketing studies. Applicants are not required to submit a 
15-day Alert report under paragraph (c) of this section for an adverse 
experience obtained from a postmarketing clinical study (whether or not 
conducted under a biological investigational new drug application) 
unless the applicant concludes that there is a reasonable possibility 
that the product caused the adverse experience.
    (f) Information reported on ICSRs for nonvaccine biological 
products. ICSRs for nonvaccine biological products include the following 
information:
    (1) Patient information.
    (i) Patient identification code;
    (ii) Patient age at the time of adverse experience, or date of 
birth;
    (iii) Patient gender; and
    (iv) Patient weight.
    (2) Adverse experience.
    (i) Outcome attributed to adverse experience;
    (ii) Date of adverse experience;
    (iii) Date of report;
    (iv) Description of adverse experience (including a concise medical 
narrative);
    (v) Adverse experience term(s);

[[Page 19]]

    (vi) Description of relevant tests, including dates and laboratory 
data; and
    (vii) Other relevant patient history, including preexisting medical 
conditions.
    (3) Suspect medical product(s).
    (i) Name;
    (ii) Dose, frequency, and route of administration used;
    (iii) Therapy dates;
    (iv) Diagnosis for use (indication);
    (v) Whether the product is a combination product as defined in Sec.  
3.2(e) of this chapter;
    (vi) Whether the product is a prescription or nonprescription 
product;
    (vii) Whether adverse experience abated after product use stopped or 
dose reduced;
    (viii) Whether adverse experience reappeared after reintroduction of 
the product;
    (ix) Lot number;
    (x) Expiration date;
    (xi) National Drug Code (NDC) number, or other unique identifier; 
and
    (xii) Concomitant medical products and therapy dates.
    (4) Initial reporter information.
    (i) Name, address, and telephone number;
    (ii) Whether the initial reporter is a health care professional; and
    (iii) Occupation, if a health care professional.
    (5) Applicant information.
    (i) Applicant name and contact office address;
    (ii) Telephone number;
    (iii) Report source, such as spontaneous, literature, or study;
    (iv) Date the report was received by applicant;
    (v) Application number and type;
    (vi) Whether the ICSR is a 15-day ``Alert report'';
    (vii) Whether the ICSR is an initial report or followup report; and
    (viii) Unique case identification number, which must be the same in 
the initial report and any subsequent followup report(s).
    (g) Information reported on ICSRs for vaccine products. ICSRs for 
vaccine products include the following information:
    (1) Patient information.
    (i) Patient name, address, telephone number;
    (ii) Patient age at the time of vaccination, or date of birth;
    (iii) Patient gender; and
    (iv) Patient birth weight for children under age 5.
    (2) Adverse experience.
    (i) Outcome attributed to adverse experience;
    (ii) Date and time of adverse experience;
    (iii) Date of report;
    (iv) Description of adverse experience (including a concise medical 
narrative);
    (v) Adverse experience term(s);
    (vi) Illness at the time of vaccination;
    (vii) Description of relevant tests, including dates and laboratory 
data; and
    (viii) Other relevant patient history, including preexisting medical 
conditions.
    (3) Suspect medical product(s), including vaccines administered on 
the same date.
    (i) Name;
    (ii) Dose, frequency, and route or site of administration used;
    (iii) Number of previous vaccine doses;
    (iv) Vaccination date(s) and time(s);
    (v) Diagnosis for use (indication);
    (vi) Whether the product is a combination product (as defined in 
Sec.  3.2(e) of this chapter);
    (vii) Whether the adverse experience abated after product use 
stopped or dose reduced;
    (viii) Whether the adverse experience reappeared after 
reintroduction of the product;
    (ix) Lot number;
    (x) Expiration date;
    (xi) National Drug Code (NDC) number, or other unique identifier; 
and
    (xii) Concomitant medical products and therapy dates.
    (4) Vaccine(s) administered in the 4 weeks prior to the vaccination 
date.
    (i) Name of vaccine;
    (ii) Manufacturer;
    (iii) Lot number;
    (iv) Route or site of administration;
    (v) Date given; and
    (vi) Number of previous doses.
    (5) Initial reporter information.
    (i) Name, address, and telephone number;
    (ii) Whether the initial reporter is a health care professional; and

[[Page 20]]

    (iii) Occupation, if a health care professional.
    (6) Facility and personnel where vaccine was administered.
    (i) Name of person who administered vaccine;
    (ii) Name of responsible physician at facility where vaccine was 
administered; and
    (iii) Name, address (including city, county, and state), and 
telephone number of facility where vaccine was administered.
    (7) Applicant information.
    (i) Applicant name and contact office address;
    (ii) Telephone number;
    (iii) Report source, such as spontaneous, literature, or study;
    (iv) Date received by applicant;
    (v) Application number and type;
    (vi) Whether the ICSR is a 15-day ``Alert report'';
    (vii) Whether the ICSR is an initial report or followup report; and
    (viii) Unique case identification number, which must be the same in 
the initial report and any subsequent followup report(s).
    (h) Electronic format for submissions. (1) Safety report 
submissions, including ICSRs, ICSR attachments, and the descriptive 
information in periodic reports, must be in an electronic format that 
FDA can process, review, and archive. FDA will issue guidance on how to 
provide the electronic submission (e.g., method of transmission, media, 
file formats, preparation and organization of files).
    (2) Persons subject to the requirements of paragraph (c) of this 
section may request, in writing, a temporary waiver of the requirements 
in paragraph (h)(1) of this section. These waivers will be granted on a 
limited basis for good cause shown. FDA will issue guidance on 
requesting a waiver of the requirements in paragraph (h)(1) of this 
section. Requests for waivers must be submitted in accordance with Sec.  
600.90.
    (i) Multiple reports. An applicant should not include in reports 
under this section any adverse experience that occurred in clinical 
trials if they were previously submitted as part of the biologics 
license application. If a report refers to more than one biological 
product marketed by an applicant, the applicant should submit the report 
to the biologics license application for the product listed first in the 
report.
    (j) Patient privacy. For nonvaccine biological products, an 
applicant should not include in reports under this section the names and 
addresses of individual patients; instead, the applicant should assign a 
unique code for identification of the patient. The applicant should 
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. The names of patients, health care professionals, 
hospitals, and geographical identifiers in adverse experience reports 
are not releasable to the public under FDA's public information 
regulations in part 20 of this chapter. For vaccine adverse experience 
reports, these data will become part of the CDC Privacy Act System 09-
20-0136, ``Epidemiologic Studies and Surveillance of Disease Problems.'' 
Information identifying the person who received the vaccine or that 
person's legal representative will not be made available to the public, 
but may be available to the vaccinee or legal representative.
    (k) Recordkeeping. The applicant must maintain for a period of 10 
years records of all adverse experiences known to the applicant, 
including raw data and any correspondence relating to the adverse 
experiences.
    (l) Revocation of biologics license. If an applicant fails to 
establish and maintain records and make reports required under this 
section with respect to a licensed biological product, FDA may revoke 
the biologics license for such a product in accordance with the 
procedures of Sec.  601.5 of this chapter.
    (m) Exemptions. Manufacturers of the following listed products are 
not required to submit adverse experience reports under this section:
    (1) Whole blood or components of whole blood.
    (2) In vitro diagnostic products, including assay systems for the 
detection of antibodies or antigens to retroviruses. These products are 
subject to the reporting requirements for devices.
    (n) Disclaimer. A report or information submitted by an applicant 
under

[[Page 21]]

this section (and any release by FDA of that report or information) does 
not necessarily reflect a conclusion by the applicant or FDA that the 
report or information constitutes an admission that the biological 
product caused or contributed to an adverse effect. An applicant need 
not admit, and may deny, that the report or information submitted under 
this section constitutes an admission that the biological product caused 
or contributed to an adverse effect. For purposes of this provision, 
this paragraph also includes any person reporting under paragraph 
(c)(1)(iii) of this section.

[59 FR 54042, Oct. 27, 1994, as amended at 62 FR 34168, June 25, 1997; 
62 FR 52252, Oct. 7, 1997; 63 FR 14612, Mar. 26, 1998; 64 FR 56449, Oct. 
20, 1999; 70 FR 14982, Mar. 24, 2005; 79 FR 33090, June 10, 2014]



Sec.  600.81  Distribution reports.

    (a) Reporting requirements. The applicant must submit to the Center 
for Biologics Evaluation and Research or the Center for Drug Evaluation 
and Research, information about the quantity of the product distributed 
under the biologics license, including the quantity distributed to 
distributors. The interval between distribution reports must be 6 
months. Upon written notice, FDA may require that the applicant submit 
distribution reports under this section at times other than every 6 
months. The distribution report must consist of the bulk lot number 
(from which the final container was filled), the fill lot numbers for 
the total number of dosage units of each strength or potency distributed 
(e.g., fifty thousand per 10-milliliter vials), the label lot number (if 
different from fill lot number), labeled date of expiration, number of 
doses in fill lot/label lot, date of release of fill lot/label lot for 
distribution at that time. If any significant amount of a fill lot/label 
lot is returned, include this information. Disclosure of financial or 
pricing data is not required. As needed, FDA may require submission of 
more detailed product distribution information. Upon written notice, FDA 
may require that the applicant submit reports under this section at 
times other than those stated. Requests by an applicant to submit 
reports at times other than those stated should be made as a request for 
a waiver under Sec.  600.90.
    (b)(1) Electronic format. Except as provided for in paragraph (b)(2) 
of this section, the distribution reports required under paragraph (a) 
of this section must be submitted to the Agency in an electronic format 
that FDA can process, review, and archive. FDA will issue guidance on 
how to provide the electronic submission (e.g., method of transmission, 
media, file formats, preparation and organization of files).
    (2) Waivers. An applicant may request, in writing, a temporary 
waiver of the requirements in paragraph (b)(1) of this section. These 
waivers will be granted on a limited basis for good cause shown. FDA 
will issue guidance on requesting a waiver of the requirements in 
paragraph (b)(1) of this section. Requests for waivers must be submitted 
in accordance with Sec.  600.90.

[59 FR 54042, Oct. 27, 1994, as amended at 64 FR 56449, Oct. 20, 1999; 
70 FR 14983, Mar. 24, 2005; 79 FR 33091, June 10, 2014]



Sec.  600.82  Notification of a permanent discontinuance or an interruption
in manufacturing.

    (a) Notification of a permanent discontinuance or an interruption in 
manufacturing. (1) An applicant of a biological product, other than 
blood or blood components for transfusion, which is licensed under 
section 351 of the Public Health Service Act, and which may be dispensed 
only under prescription under section 503(b)(1) of the Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 353(b)(1)), must notify FDA in writing 
of a permanent discontinuance of manufacture of the biological product 
or an interruption in manufacturing of the biological product that is 
likely to lead to a meaningful disruption in supply of that biological 
product in the United States if:
    (i) The biological product is life supporting, life sustaining, or 
intended for use in the prevention or treatment of a debilitating 
disease or condition, including any such biological product used in 
emergency medical care or during surgery; and
    (ii) The biological product is not a radiopharmaceutical biological 
product.

[[Page 22]]

    (2) An applicant of blood or blood components for transfusion, which 
is licensed under section 351 of the Public Health Service Act, and 
which may be dispensed only under prescription under section 503(b) of 
the Federal Food, Drug, and Cosmetic Act, must notify FDA in writing of 
a permanent discontinuance of manufacture of any product listed in its 
license or an interruption in manufacturing of any such product that is 
likely to lead to a significant disruption in supply of that product in 
the United States if:
    (i) The product is life supporting, life sustaining, or intended for 
use in the prevention or treatment of a debilitating disease or 
condition, including any such product used in emergency medical care or 
during surgery; and
    (ii) The applicant is a manufacturer of a significant percentage of 
the U.S. blood supply.
    (b) Submission and timing of notification. Notifications required by 
paragraph (a) of this section must be submitted to FDA electronically in 
a format that FDA can process, review, and archive:
    (1) At least 6 months prior to the date of the permanent 
discontinuance or interruption in manufacturing; or
    (2) If 6 months' advance notice is not possible because the 
permanent discontinuance or interruption in manufacturing was not 
reasonably anticipated 6 months in advance, as soon as practicable 
thereafter, but in no case later than 5 business days after such a 
permanent discontinuance or interruption in manufacturing occurs.
    (c) Information included in notification. Notifications required by 
paragraph (a) of this section must include the following information:
    (1) The name of the biological product subject to the notification, 
including the National Drug Code for such biological product, or an 
alternative standard for identification and labeling that has been 
recognized as acceptable by the Center Director;
    (2) The name of the applicant of the biological product;
    (3) Whether the notification relates to a permanent discontinuance 
of the biological product or an interruption in manufacturing of the 
biological product;
    (4) A description of the reason for the permanent discontinuance or 
interruption in manufacturing; and
    (5) The estimated duration of the interruption in manufacturing.
    (d)(1) Public list of biological product shortages. FDA will 
maintain a publicly available list of biological products that are 
determined by FDA to be in shortage. This biological product shortages 
list will include the following information:
    (i) The names and National Drug Codes for such biological products, 
or the alternative standards for identification and labeling that have 
been recognized as acceptable by the Center Director;
    (ii) The name of each applicant for such biological products;
    (iii) The reason for the shortage, as determined by FDA, selecting 
from the following categories: Requirements related to complying with 
good manufacturing practices; regulatory delay; shortage of an active 
ingredient; shortage of an inactive ingredient component; 
discontinuation of the manufacture of the biological product; delay in 
shipping of the biological product; demand increase for the biological 
product; or other reason; and
    (iv) The estimated duration of the shortage.
    (2) Confidentiality. FDA may choose not to make information 
collected to implement this paragraph available on the biological 
product shortages list or available under section 506C(c) of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 356c(c)) if FDA determines that 
disclosure of such information would adversely affect the public health 
(such as by increasing the possibility of hoarding or other disruption 
of the availability of the biological product to patients). FDA will 
also not provide information on the public shortages list or under 
section 506C(c) of the Federal Food, Drug, and Cosmetic Act that is 
protected by 18 U.S.C. 1905 or 5 U.S.C. 552(b)(4), including trade 
secrets and commercial or financial information that is considered 
confidential or privileged under Sec.  20.61 of this chapter.
    (e) Noncompliance letters. If an applicant fails to submit a 
notification as required under paragraph (a) of this

[[Page 23]]

section and in accordance with paragraph (b) of this section, FDA will 
issue a letter to the applicant informing it of such failure.
    (1) Not later than 30 calendar days after the issuance of such a 
letter, the applicant must submit to FDA a written response setting 
forth the basis for noncompliance and providing the required 
notification under paragraph (a) of this section and including the 
information required under paragraph (c) of this section; and
    (2) Not later than 45 calendar days after the issuance of a letter 
under this paragraph, FDA will make the letter and the applicant's 
response to the letter public, unless, after review of the applicant's 
response, FDA determines that the applicant had a reasonable basis for 
not notifying FDA as required under paragraph (a) of this section.
    (f) Definitions. The following definitions of terms apply to this 
section:
    Biological product shortage or shortage means a period of time when 
the demand or projected demand for the biological product within the 
United States exceeds the supply of the biological product.
    Intended for use in the prevention or treatment of a debilitating 
disease or condition means a biological product intended for use in the 
prevention or treatment of a disease or condition associated with 
mortality or morbidity that has a substantial impact on day-to-day 
functioning.
    Life supporting or life sustaining means a biological product that 
is essential to, or that yields information that is essential to, the 
restoration or continuation of a bodily function important to the 
continuation of human life.
    Meaningful disruption means a change in production that is 
reasonably likely to lead to a reduction in the supply of a biological 
product by a manufacturer that is more than negligible and affects the 
ability of the manufacturer to fill orders or meet expected demand for 
its product, and does not include interruptions in manufacturing due to 
matters such as routine maintenance or insignificant changes in 
manufacturing so long as the manufacturer expects to resume operations 
in a short period of time.
    Significant disruption means a change in production that is 
reasonably likely to lead to a reduction in the supply of blood or blood 
components by a manufacturer that substantially affects the ability of 
the manufacturer to fill orders or meet expected demand for its product, 
and does not include interruptions in manufacturing due to matters such 
as routine maintenance or insignificant changes in manufacturing so long 
as the manufacturer expects to resume operations in a short period of 
time.

[80 FR 38939, July 8, 2015]



Sec.  600.90  Waivers.

    (a) An applicant may ask the Food and Drug Administration to waive 
under this section any requirement that applies to the applicant under 
Sec. Sec.  600.80 and 600.81. A waiver request under this section is 
required to be submitted with supporting documentation. The waiver 
request is required to contain one of the following:
    (1) An explanation why the applicant's compliance with the 
requirement is unnecessary or cannot be achieved,
    (2) A description of an alternative submission that satisfies the 
purpose of the requirement, or
    (3) Other information justifying a waiver.
    (b) FDA may grant a waiver if it finds one of the following:
    (1) The applicant's compliance with the requirement is unnecessary 
or cannot be achieved,
    (2) The applicant's alternative submission satisfies the 
requirement, or
    (3) The applicant's submission otherwise justifies a waiver.

[59 FR 54042, Oct. 27, 1994, as amended at 79 FR 33092, June 10, 2014]



PART 601_LICENSING--Table of Contents



                      Subpart A_General Provisions

Sec.
601.2 Applications for biologics licenses; procedures for filing.
601.3 Complete response letter to the applicant.
601.4 Issuance and denial of license.
601.5 Revocation of license.
601.6 Suspension of license.
601.7 Procedure for hearings.

[[Page 24]]

601.8 Publication of revocation.
601.9 Licenses; reissuance.

Subpart B [Reserved]

                      Subpart C_Biologics Licensing

601.12 Changes to an approved application.
601.14 Regulatory submissions in electronic format.
601.15 Foreign establishments and products: Samples for each 
          importation.
601.20 Biologics licenses; issuance and conditions.
601.21 Products under development.
601.22 Products in short supply; initial manufacturing at other than 
          licensed location.
601.27 Pediatric studies.
601.28 Annual reports of postmarketing pediatric studies.
601.29 Guidance documents.

                Subpart D_Diagnostic Radiopharmaceuticals

601.30 Scope.
601.31 Definition.
601.32 General factors relevant to safety and effectiveness.
601.33 Indications.
601.34 Evaluation of effectiveness.
601.35 Evaluation of safety.

  Subpart E_Accelerated Approval of Biological Products for Serious or 
                       Life-Threatening Illnesses

601.40 Scope.
601.41 Approval based on a surrogate endpoint or on an effect on a 
          clinical endpoint other than survival or irreversible 
          morbidity.
601.42 Approval with restrictions to assure safe use.
601.43 Withdrawal procedures.
601.44 Postmarketing safety reporting.
601.45 Promotional materials.
601.46 Termination of requirements.

                Subpart F_Confidentiality of Information

601.50 Confidentiality of data and information in an investigational new 
          drug notice for a biological product.
601.51 Confidentiality of data and information in applications for 
          biologics licenses.

                     Subpart G_Postmarketing Studies

601.70 Annual progress reports of postmarketing studies.

 Subpart H_Approval of Biological Products When Human Efficacy Studies 
                       Are Not Ethical or Feasible

601.90 Scope.
601.91 Approval based on evidence of effectiveness from studies in 
          animals.
601.92 Withdrawal procedures.
601.93 Postmarketing safety reporting.
601.94 Promotional materials.
601.95 Termination of requirements.

    Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 355, 
356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216, 
241, 262, 263, 264; sec 122, Pub. L. 105-115, 111 Stat. 2322 (21 U.S.C. 
355 note).

    Source: 38 FR 32052, Nov. 20, 1973, unless otherwise noted.

    Cross References: For U.S. Customs Service regulations relating to 
viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal 
Service regulations relating to the admissibility to the United States 
mails see parts 124 and 125 of the Domestic Mail Manual, that is 
incorporated by reference in 39 CFR part 111.



                      Subpart A_General Provisions



Sec.  601.2  Applications for biologics licenses; procedures for filing.

    (a) General. To obtain a biologics license under section 351 of the 
Public Health Service Act for any biological product, the manufacturer 
shall submit an application to the Director, Center for Biologics 
Evaluation and Research or the Director, Center for Drug Evaluation and 
Research (see mailing addresses in Sec.  600.2(a) or (b) of this 
chapter), on forms prescribed for such purposes, and shall submit data 
derived from nonclinical laboratory and clinical studies which 
demonstrate that the manufactured product meets prescribed requirements 
of safety, purity, and potency; with respect to each nonclinical 
laboratory study, either a statement that the study was conducted in 
compliance with the requirements set forth in part 58 of this chapter, 
or, if the study was not conducted in compliance with such regulations, 
a brief statement of the reason for the noncompliance; statements 
regarding each clinical investigation involving

[[Page 25]]

human subjects contained in the application, that it either was 
conducted in compliance with the requirements for institutional review 
set forth in part 56 of this chapter; or was not subject to such 
requirements in accordance with Sec.  56.104 or Sec.  56.105, and was 
conducted in compliance with requirements for informed consent set forth 
in part 50 of this chapter. A full description of manufacturing methods; 
data establishing stability of the product through the dating period; 
sample(s) representative of the product for introduction or delivery for 
introduction into interstate commerce; summaries of results of tests 
performed on the lot(s) represented by the submitted sample(s); 
specimens of the labels, enclosures, and containers, and if applicable, 
any Medication Guide required under part 208 of this chapter proposed to 
be used for the product; and the address of each location involved in 
the manufacture of the biological product shall be listed in the 
biologics license application. The applicant shall also include a 
financial certification or disclosure statement(s) or both for clinical 
investigators as required by part 54 of this chapter. An application for 
a biologics license shall not be considered as filed until all pertinent 
information and data have been received by the Food and Drug 
Administration. The applicant shall also include either a claim for 
categorical exclusion under Sec.  25.30 or Sec.  25.31 of this chapter 
or an environmental assessment under Sec.  25.40 of this chapter. The 
applicant, or the applicant's attorney, agent, or other authorized 
official shall sign the application. An application for any of the 
following specified categories of biological products subject to 
licensure shall be handled as set forth in paragraph (c) of this 
section:
    (1) Therapeutic DNA plasmid products;
    (2) Therapeutic synthetic peptide products of 40 or fewer amino 
acids;
    (3) Monoclonal antibody products for in vivo use; and
    (4) Therapeutic recombinant DNA-derived products.
    (b) [Reserved]
    (c)(1) To obtain marketing approval for a biological product subject 
to licensure which is a therapeutic DNA plasmid product, therapeutic 
synthetic peptide product of 40 or fewer amino acids, monoclonal 
antibody product for in vivo use, or therapeutic recombinant DNA-derived 
product, an applicant shall submit a biologics license application in 
accordance with paragraph (a) of this section except that the following 
sections in parts 600 through 680 of this chapter shall not be 
applicable to such products: Sec. Sec.  600.10(b) and (c), 600.11, 
600.12, 600.13, 610.53, and 610.62 of this chapter.
    (2) To the extent that the requirements in this paragraph (c) 
conflict with other requirements in this subchapter, this paragraph (c) 
shall supersede other requirements.
    (d) Approval of a biologics license application or issuance of a 
biologics license shall constitute a determination that the 
establishment(s) and the product meet applicable requirements to ensure 
the continued safety, purity, and potency of such products. Applicable 
requirements for the maintenance of establishments for the manufacture 
of a product subject to this section shall include but not be limited to 
the good manufacturing practice requirements set forth in parts 210, 
211, 600, 606, and 820 of this chapter.
    (e) Any establishment and product license for a biological product 
issued under section 351 of the Public Health Service Act (42 U.S.C. 201 
et seq.) that has not been revoked or suspended as of December 20, 1999, 
shall constitute an approved biologics license application in effect 
under the same terms and conditions set forth in such product license 
and such portions of the establishment license relating to such product.
    (f) Withdrawal from sale of approved biological products. A holder 
of a biologics license application (BLA) must report to FDA, in 
accordance with the requirements of Sec. Sec.  207.61 and 207.65, the 
withdrawal from sale of an approved biological product. The information 
must be submitted to FDA within 30 working days of the biological 
product's withdrawal from sale. The following information must be 
submitted: The holder's name; product name; BLA number; the National 
Drug Code; and the date on which the product is expected to be no longer 
in commercial distribution. The reason for the withdrawal of the

[[Page 26]]

biological product is requested but not required to be submitted.

[64 FR 56450, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005; 
80 FR 18092, Apr. 3, 2015; 80 FR 37974, July 2, 2015; 81 FR 60221, Aug. 
31, 2016]



Sec.  601.3  Complete response letter to the applicant.

    (a) Complete response letter. The Food and Drug Administration will 
send the biologics license applicant or supplement applicant a complete 
response letter if the agency determines that it will not approve the 
biologics license application or supplement in its present form.
    (1) Description of specific deficiencies. A complete response letter 
will describe all of the deficiencies that the agency has identified in 
a biologics license application or supplement, except as stated in 
paragraph (a)(2) of this section.
    (2) Inadequate data. If FDA determines, after a biologics license 
application or supplement is filed, that the data submitted are 
inadequate to support approval, the agency might issue a complete 
response letter without first conducting required inspections, testing 
submitted product lots, and/or reviewing proposed product labeling.
    (3) Recommendation of actions for approval. When possible, a 
complete response letter will recommend actions that the applicant might 
take to place its biologics license application or supplement in 
condition for approval.
    (b) Applicant actions. After receiving a complete response letter, 
the biologics license applicant or supplement applicant must take either 
of the following actions:
    (1) Resubmission. Resubmit the application or supplement, addressing 
all deficiencies identified in the complete response letter.
    (2) Withdrawal. Withdraw the application or supplement. A decision 
to withdraw the application or supplement is without prejudice to a 
subsequent submission.
    (c) Failure to take action. (1) FDA may consider a biologics license 
applicant or supplement applicant's failure to either resubmit or 
withdraw the application or supplement within 1 year after issuance of a 
complete response letter to be a request by the applicant to withdraw 
the application or supplement, unless the applicant has requested an 
extension of time in which to resubmit the application or supplement. 
FDA will grant any reasonable request for such an extension. FDA may 
consider an applicant's failure to resubmit the application or 
supplement within the extended time period or request an additional 
extension to be a request by the applicant to withdraw the application.
    (2) If FDA considers an applicant's failure to take action in 
accordance with paragraph (c)(1) of this section to be a request to 
withdraw the application, the agency will notify the applicant in 
writing. The applicant will have 30 days from the date of the 
notification to explain why the application or supplement should not be 
withdrawn and to request an extension of time in which to resubmit the 
application or supplement. FDA will grant any reasonable request for an 
extension. If the applicant does not respond to the notification within 
30 days, the application or supplement will be deemed to be withdrawn.

[73 FR 39611, July 10, 2008]



Sec.  601.4  Issuance and denial of license.

    (a) A biologics license shall be issued upon a determination by the 
Director, Center for Biologics Evaluation and Research or the Director, 
Center for Drug Evaluation and Research that the establishment(s) and 
the product meet the applicable requirements established in this 
chapter. A biologics license shall be valid until suspended or revoked.
    (b) If the Commissioner determines that the establishment or product 
does not meet the requirements established in this chapter, the 
biologics license application shall be denied and the applicant shall be 
informed of the grounds for, and of an opportunity for a hearing on, the 
decision. If the applicant so requests, the Commissioner shall issue a 
notice of opportunity for hearing on the matter pursuant to Sec.  
12.21(b) of this chapter.

[42 FR 4718, Jan. 25, 1977, as amended at 42 FR 15676, Mar. 22, 1977; 42 
FR 19142, Apr. 12, 1977; 64 FR 56450, Oct. 20, 1999; 70 FR 14983, Mar. 
24, 2005]

[[Page 27]]



Sec.  601.5  Revocation of license.

    (a) A biologics license shall be revoked upon application of the 
manufacturer giving notice of intention to discontinue the manufacture 
of all products manufactured under such license or to discontinue the 
manufacture of a particular product for which a license is held and 
waiving an opportunity for a hearing on the matter.
    (b)(1) The Commissioner shall notify the licensed manufacturer of 
the intention to revoke the biologics license, setting forth the grounds 
for, and offering an opportunity for a hearing on the proposed 
revocation if the Commissioner finds any of the following:
    (i) Authorized Food and Drug Administration employees after 
reasonable efforts have been unable to gain access to an establishment 
or a location for the purpose of carrying out the inspection required 
under Sec.  600.21 of this chapter,
    (ii) Manufacturing of products or of a product has been discontinued 
to an extent that a meaningful inspection or evaluation cannot be made,
    (iii) The manufacturer has failed to report a change as required by 
Sec.  601.12 of this chapter,
    (iv) The establishment or any location thereof, or the product for 
which the license has been issued, fails to conform to the applicable 
standards established in the license and in this chapter designed to 
ensure the continued safety, purity, and potency of the manufactured 
product,
    (v) The establishment or the manufacturing methods have been so 
changed as to require a new showing that the establishment or product 
meets the requirements established in this chapter in order to protect 
the public health, or
    (vi) The licensed product is not safe and effective for all of its 
intended uses or is misbranded with respect to any such use.
    (2) Except as provided in Sec.  601.6 of this chapter, or in cases 
involving willfulness, the notification required in this paragraph shall 
provide a reasonable period for the licensed manufacturer to demonstrate 
or achieve compliance with the requirements of this chapter, before 
proceedings will be instituted for the revocation of the license. If 
compliance is not demonstrated or achieved and the licensed manufacturer 
does not waive the opportunity for a hearing, the Commissioner shall 
issue a notice of opportunity for hearing on the matter under Sec.  
12.21(b) of this chapter.

[64 FR 56451, Oct. 20, 1999]



Sec.  601.6  Suspension of license.

    (a) Whenever the Commissioner has reasonable grounds to believe that 
any of the grounds for revocation of a license exist and that by reason 
thereof there is a danger to health, the Commissioner may notify the 
licensed manufacturer that the biologics license is suspended and 
require that the licensed manufacturer do the following:
    (1) Notify the selling agents and distributors to whom such product 
or products have been delivered of such suspension, and
    (2) Furnish to the Center for Biologics Evaluation and Research or 
the Center for Drug Evaluation and Research, complete records of such 
deliveries and notice of suspension.
    (b) Upon suspension of a license, the Commissioner shall either:
    (1) Proceed under the provisions of Sec.  601.5(b) of this chapter 
to revoke the license, or
    (2) If the licensed manufacturer agrees, hold revocation in abeyance 
pending resolution of the matters involved.

[64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005]



Sec.  601.7  Procedure for hearings.

    (a) A notice of opportunity for hearing, notice of appearance and 
request for hearing, and grant or denial of hearing for a biological 
drug pursuant to this part, for which the exemption from the Federal 
Food, Drug, and Cosmetic Act in Sec.  310.4 of this chapter has been 
revoked, shall be subject to the provisions of Sec.  314.200 of this 
chapter except to the extent that the notice of opportunity for hearing 
on the matter issued pursuant to Sec.  12.21(b) of this chapter 
specifically provides otherwise.
    (b) Hearings pursuant to Sec. Sec.  601.4 through 601.6 shall be 
governed by part 12 of this chapter.

[[Page 28]]

    (c) When a license has been suspended pursuant to Sec.  601.6 and a 
hearing request has been granted, the hearing shall proceed on an 
expedited basis.

[42 FR 4718, Jan. 25, 1977, as amended at 42 FR 15676, Mar. 22, 1977; 42 
FR 19143, Apr. 12, 1977]



Sec.  601.8  Publication of revocation.

    The Commissioner, following revocation of a biologics license under 
21 CFR 601.5(b), will publish a notice in the Federal Register with a 
statement of the specific grounds for the revocation.

[74 FR 20585, May 5, 2009]



Sec.  601.9  Licenses; reissuance.

    (a) Compliance with requirements. A biologics license, previously 
suspended or revoked, may be reissued or reinstated upon a showing of 
compliance with requirements and upon such inspection and examination as 
may be considered necessary by the Director, Center for Biologics 
Evaluation and Research or the Director, Center for Drug Evaluation and 
Research.
    (b) Exclusion of noncomplying location. A biologics license, 
excluding a location or locations that fail to comply with the 
requirements in this chapter, may be issued without further application 
and concurrently with the suspension or revocation of the license for 
noncompliance at the excluded location or locations.
    (c) Exclusion of noncomplying product(s). In the case of multiple 
products included under a single biologics license application, a 
biologics license may be issued, excluding the noncompliant product(s), 
without further application and concurrently with the suspension or 
revocation of the biologics license for a noncompliant product(s).

[64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005]

Subpart B [Reserved]



                      Subpart C_Biologics Licensing



Sec.  601.12  Changes to an approved application.

    (a) General. (1) As provided by this section, an applicant must 
inform the Food and Drug Administration (FDA) (see mailing addresses in 
Sec.  600.2 of this chapter) about each change in the product, 
production process, quality controls, equipment, facilities, responsible 
personnel, or labeling established in the approved license 
application(s).
    (2) Before distributing a product made using a change, an applicant 
must assess the effects of the change and demonstrate through 
appropriate validation and/or other clinical and/or nonclinical 
laboratory studies the lack of adverse effect of the change on the 
identity, strength, quality, purity, or potency of the product as they 
may relate to the safety or effectiveness of the product.
    (3) Notwithstanding the requirements of paragraphs (b), (c), and (f) 
of this section, an applicant must make a change provided for in those 
paragraphs in accordance with a regulation or guidance that provides for 
a less burdensome notification of the change (for example, by submission 
of a supplement that does not require approval prior to distribution of 
the product or in an annual report).
    (4) The applicant must promptly revise all promotional labeling and 
advertising to make it consistent with any labeling change implemented 
in accordance with paragraphs (f)(1) and (f)(2) of this section.
    (5) A supplement or annual report must include a list of all changes 
contained in the supplement or annual report. For supplements, this list 
must be provided in the cover letter.
    (b) Changes requiring supplement submission and approval prior to 
distribution of the product made using the change (major changes). (1) A 
supplement shall be submitted for any change in the product, production 
process, quality controls, equipment, facilities, or responsible 
personnel that has a substantial potential to have an adverse effect on 
the identity, strength, quality, purity, or potency of the product as 
they may relate to the safety or effectiveness of the product.
    (2) These changes include, but are not limited to:
    (i) Except as provided in paragraphs (c) and (d) of this section, 
changes in the qualitative or quantitative formulation, including 
inactive ingredients,

[[Page 29]]

or in the specifications provided in the approved application;
    (ii) Changes requiring completion of an appropriate human study to 
demonstrate the equivalence of the identity, strength, quality, purity, 
or potency of the product as they may relate to the safety or 
effectiveness of the product;
    (iii) Changes in the virus or adventitious agent removal or 
inactivation method(s);
    (iv) Changes in the source material or cell line;
    (v) Establishment of a new master cell bank or seed; and
    (vi) Changes which may affect product sterility assurance, such as 
changes in product or component sterilization method(s), or an addition, 
deletion, or substitution of steps in an aseptic processing operation.
    (3) The applicant must obtain approval of the supplement from FDA 
prior to distribution of the product made using the change. Except for 
submissions under paragraph (e) of this section, the following shall be 
contained in the supplement:
    (i) A detailed description of the proposed change;
    (ii) The product(s) involved;
    (iii) The manufacturing site(s) or area(s) affected;
    (iv) A description of the methods used and studies performed to 
evaluate the effect of the change on the identity, strength, quality, 
purity, or potency of the product as they may relate to the safety or 
effectiveness of the product;
    (v) The data derived from such studies;
    (vi) Relevant validation protocols and data; and
    (vii) A reference list of relevant standard operating procedures 
(SOP's).
    (4) An applicant may ask FDA to expedite its review of a supplement 
for public health reasons or if a delay in making the change described 
in it would impose an extraordinary hardship on the applicant. Such a 
supplement and its mailing cover should be plainly marked: ``Prior 
Approval Supplement-Expedited Review Requested.
    (c) Changes requiring supplement submission at least 30 days prior 
to distribution of the product made using the change. (1) A supplement 
shall be submitted for any change in the product, production process, 
quality controls, equipment, facilities, or responsible personnel that 
has a moderate potential to have an adverse effect on the identity, 
strength, quality, purity, or potency of the product as they may relate 
to the safety or effectiveness of the product. The supplement shall be 
labeled ``Supplement--Changes Being Effected in 30 Days'' or, if 
applicable under paragraph (c)(5) of this section, ``Supplement--Changes 
Being Effected.''
    (2) These changes include, but are not limited to:
    (i) [Reserved]
    (ii) An increase or decrease in production scale during finishing 
steps that involves different equipment; and
    (iii) Replacement of equipment with that of similar, but not 
identical, design and operating principle that does not affect the 
process methodology or process operating parameters.
    (iv) Relaxation of an acceptance criterion or deletion of a test to 
comply with an official compendium that is consistent with FDA statutory 
and regulatory requirements.
    (3) Pending approval of the supplement by FDA, and except as 
provided in paragraph (c)(5) of this section, distribution of the 
product made using the change may begin not less than 30 days after 
receipt of the supplement by FDA. The information listed in paragraph 
(b)(3)(i) through (b)(3)(vii) of this section shall be contained in the 
supplement.
    (4) If within 30 days following FDA's receipt of the supplement, FDA 
informs the applicant that either:
    (i) The change requires approval prior to distribution of the 
product in accordance with paragraph (b) of this section; or
    (ii) Any of the information required under paragraph (c)(3) of this 
section is missing; the applicant shall not distribute the product made 
using the change until FDA determines that compliance with this section 
is achieved.
    (5) In certain circumstances, FDA may determine that, based on 
experience with a particular type of change,

[[Page 30]]

the supplement for such change is usually complete and provides the 
proper information, and on particular assurances that the proposed 
change has been appropriately submitted, the product made using the 
change may be distributed immediately upon receipt of the supplement by 
FDA. These circumstances may include substantial similarity with a type 
of change regularly involving a ``Supplement--Changes Being Effected'' 
supplement or a situation in which the applicant presents evidence that 
the proposed change has been validated in accordance with an approved 
protocol for such change under paragraph (e) of this section.
    (6) If the agency disapproves the supplemental application, it may 
order the manufacturer to cease distribution of the products made with 
the manufacturing change.
    (d) Changes to be described in an annual report (minor changes). (1) 
Changes in the product, production process, quality controls, equipment, 
facilities, or responsible personnel that have a minimal potential to 
have an adverse effect on the identity, strength, quality, purity, or 
potency of the product as they may relate to the safety or effectiveness 
of the product shall be documented by the applicant in an annual report 
submitted each year within 60 days of the anniversary date of approval 
of the application. The Director, Center for Biologics Evaluation and 
Research or the Director, Center for Drug Evaluation and Research, may 
approve a written request for an alternative date to combine annual 
reports for multiple approved applications into a single annual report 
submission.
    (2) These changes include, but are not limited to:
    (i) Any change made to comply with a change to an official 
compendium, except a change described in paragraph (c)(2)(iv) of this 
section, that is consistent with FDA statutory and regulatory 
requirements.
    (ii) The deletion or reduction of an ingredient intended only to 
affect the color of the product, except that a change intended only to 
affect Blood Grouping Reagents requires supplement submission and 
approval prior to distribution of the product made using the change in 
accordance with the requirements set forth in paragraph (b) of this 
section;
    (iii) An extension of an expiration dating period based upon full 
shelf life data on production batches obtained from a protocol approved 
in the application;
    (iv) A change within the container closure system for a nonsterile 
product, based upon a showing of equivalency to the approved system 
under a protocol approved in the application or published in an official 
compendium;
    (v) A change in the size and/or shape of a container containing the 
same number of dosage units for a nonsterile solid dosage form product, 
without a change from one container closure system to another;
    (vi) The addition by embossing, debossing, or engraving of a code 
imprint to a solid dosage form biological product other than a modified 
release dosage form, or a minor change in an existing code imprint; and
    (vii) The addition or revision of an alternative analytical 
procedure that provides the same or increased assurance of the identity, 
strength, quality, purity, or potency of the material being tested as 
the analytical procedure described in the approved application, or 
deletion of an alternative analytical procedure.
    (3) The following information for each change shall be contained in 
the annual report:
    (i) A list of all products involved; and
    (ii) A full description of the manufacturing and controls changes 
including: the manufacturing site(s) or area(s) involved; the date the 
change was made; a cross-reference to relevant validation protocols and/
or SOP's; and relevant data from studies and tests performed to evaluate 
the effect of the change on the identity, strength, quality, purity, or 
potency of the product as they may relate to the safety or effectiveness 
of the product.
    (iii) A statement by the holder of the approved application or 
license that the effects of the change have been assessed.
    (4) The applicant shall submit the report to the FDA office 
responsible for reviewing the application. The report

[[Page 31]]

shall include all the information required under this paragraph for each 
change made during the annual reporting interval which ends on the 
anniversary date in the order in which they were implemented.
    (e) An applicant may submit one or more protocols describing the 
specific tests and validation studies and acceptable limits to be 
achieved to demonstrate the lack of adverse effect for specified types 
of manufacturing changes on the identity, strength, quality, purity, or 
potency of the product as they may relate to the safety or effectiveness 
of the product. Any such protocols, or change to a protocol, shall be 
submitted as a supplement requiring approval from FDA prior to 
distribution of the product which, if approved, may justify a reduced 
reporting category for the particular change because the use of the 
protocol for that type of change reduces the potential risk of an 
adverse effect.
    (f) Labeling changes. (1) Labeling changes requiring supplement 
submission--FDA approval must be obtained before distribution of the 
product with the labeling change. Except as described in paragraphs 
(f)(2) and (f)(3) of this section, an applicant shall submit a 
supplement describing a proposed change in the package insert, package 
label, container label, or, if applicable, a Medication Guide required 
under part 208 of this chapter, and include the information necessary to 
support the proposed change. An applicant cannot use paragraph (f)(2) of 
this section to make any change to the information required in Sec.  
201.57(a) of this chapter. An applicant may report the minor changes to 
the information specified in paragraph (f)(3)(i)(D) of this section in 
an annual report. The supplement shall clearly highlight the proposed 
change in the labeling. The applicant shall obtain approval from FDA 
prior to distribution of the product with the labeling change.
    (2) Labeling changes requiring supplement submission--product with a 
labeling change that may be distributed before FDA approval. (i) An 
applicant shall submit, at the time such change is made, a supplement 
for any change in the package insert, package label, or container label 
to reflect newly acquired information, except for changes to the package 
insert required in Sec.  201.57(a) of this chapter (which must be made 
under paragraph (f)(1) of this section), to accomplish any of the 
following:
    (A) To add or strengthen a contraindication, warning, precaution, or 
adverse reaction for which the evidence of a causal association 
satisfies the standard for inclusion in the labeling under Sec.  
201.57(c) of this chapter;
    (B) To add or strengthen a statement about abuse, dependence, 
psychological effect, or overdosage;
    (C) To add or strengthen an instruction about dosage and 
administration that is intended to increase the safety of the use of the 
product; and
    (D) To delete false, misleading, or unsupported indications for use 
or claims for effectiveness.
    (E) Any labeling change normally requiring a supplement submission 
and approval prior to distribution of the product that FDA specifically 
requests be submitted under this provision.
    (ii) Pending approval of the supplement by FDA, the applicant may 
distribute a product with a package insert, package label, or container 
label bearing such change at the time the supplement is submitted. The 
supplement shall clearly identify the change being made and include 
necessary supporting data. The supplement and its mailing cover shall be 
plainly marked: ``Special Labeling Supplement--Changes Being Effected.''
    (3) Labeling changes requiring submission in an annual report. (i) 
An applicant shall submit any final printed package insert, package 
label, container label, or Medication Guide required under part 208 of 
this chapter incorporating the following changes in an annual report 
submitted to FDA each year as provided in paragraph (d)(1) of this 
section:
    (A) Editorial or similar minor changes;
    (B) A change in the information on how the product is supplied that 
does not involve a change in the dosage strength or dosage form;
    (C) A change in the information specified in Sec.  208.20(b)(8)(iii) 
and (b)(8)(iv) of this chapter for a Medication Guide; and

[[Page 32]]

    (D) A change to the information required in Sec.  201.57(a) of this 
chapter as follows:
    (1) Removal of a listed section(s) specified in Sec.  201.57(a)(5) 
of this chapter; and
    (2) Changes to the most recent revision date of the labeling as 
specified in Sec.  201.57(a)(15) of this chapter.
    (E) A change made pursuant to an exception or alternative granted 
under Sec.  201.26 or Sec.  610.68 of this chapter.
    (ii) The applicant may distribute a product with a package insert, 
package label, or container label bearing such change at the time the 
change is made.
    (4) Advertisements and promotional labeling. Advertisements and 
promotional labeling shall be submitted to the Center for Biologics 
Evaluation and Research or Center for Drug Evaluation and Research in 
accordance with the requirements set forth in Sec.  314.81(b)(3)(i) of 
this chapter.
    (5) The submission and grant of a written request for an exception 
or alternative under Sec.  201.26 or Sec.  610.68 of this chapter 
satisfies the requirements in paragraphs (f)(1) through (f)(2) of this 
section.
    (6) For purposes of paragraph (f)(2) of this section, information 
will be considered newly acquired if it consists of data, analyses, or 
other information not previously submitted to the agency, which may 
include (but are not limited to) data derived from new clinical studies, 
reports of adverse events, or new analyses of previously submitted data 
(e.g., meta-analyses) if the studies, events or analyses reveal risks of 
a different type or greater severity or frequency than previously 
included in submissions to FDA.
    (g) Failure to comply. In addition to other remedies available in 
law and regulations, in the event of repeated failure of the applicant 
to comply with this section, FDA may require that the applicant submit a 
supplement for any proposed change and obtain approval of the supplement 
by FDA prior to distribution of the product made using the change.
    (h) Administrative review. Under Sec.  10.75 of this chapter, an 
applicant may request internal FDA review of FDA employee decisions 
under this section.

[62 FR 39901, July 24, 1997, as amended at 63 FR 66399, Dec. 1, 1998. 
Redesignated at 65 FR 59718, Oct. 6, 2000, and amended at 69 FR 18766, 
Apr. 8, 2004; 70 FR 14983, Mar. 24, 2005; 71 FR 3997, Jan. 24, 2006; 72 
FR 73600, Dec. 28, 2007; 73 FR 49609, Aug. 22, 2008; 73 FR 68333, Nov. 
18, 2008; 80 FR 18092, Apr. 3, 2015]



Sec.  601.14  Regulatory submissions in electronic format.

    (a) General. Electronic format submissions must be in a form that 
FDA can process, review, and archive. FDA will periodically issue 
guidance on how to provide the electronic submission (e.g., method of 
transmission, media, file formats, preparation and organization of 
files.)
    (b) Labeling. The content of labeling required under Sec.  
201.100(d)(3) of this chapter (commonly referred to as the package 
insert or professional labeling), including all text, tables, and 
figures, must be submitted to the agency in electronic format as 
described in paragraph (a) of this section. This requirement is in 
addition to the provisions of Sec. Sec.  601.2(a) and 601.12(f) that 
require applicants to submit specimens of the labels, enclosures, and 
containers, or to submit other final printed labeling. Submissions under 
this paragraph must be made in accordance with part 11 of this chapter 
except for the requirements of Sec.  11.10(a), (c) through (h), and (k), 
and the corresponding requirements of Sec.  11.30.

[68 FR 69020, Dec. 11, 2003]



Sec.  601.15  Foreign establishments and products: samples for each
importation.

    Random samples of each importation, obtained by the District 
Director of Customs and forwarded to the Director, Center for Biologics 
Evaluation and Research or the Director, Center for Drug Evaluation and 
Research (see mailing addresses in Sec.  600.2(c) of this chapter) must 
be at least two final containers of each lot of product. A copy of the 
associated documents which describe and identify the shipment must 
accompany the shipment for forwarding with the samples to the Director, 
Center for Biologics Evaluation and Research or the Director, Center

[[Page 33]]

for Drug Evaluation and Research (see mailing addresses in Sec.  
600.2(c)). For shipments of 20 or less final containers, samples need 
not be forwarded, provided a copy of an official release from the Center 
for Biologics Evaluation and Research or Center for Drug Evaluation and 
Research accompanies each shipment.

[70 FR 14983, Mar. 24, 2005, as amended at 80 FR 18092, Apr. 3, 2015]



Sec.  601.20  Biologics licenses; issuance and conditions.

    (a) Examination--compliance with requirements. A biologics license 
application shall be approved only upon examination of the product and 
upon a determination that the product complies with the standards 
established in the biologics license application and the requirements 
prescribed in the regulations in this chapter including but not limited 
to the good manufacturing practice requirements set forth in parts 210, 
211, 600, 606, and 820 of this chapter.
    (b) Availability of product. No biologics license shall be issued 
unless:
    (1) The product intended for introduction into interstate commerce 
is available for examination, and
    (2) Such product is available for inspection during all phases of 
manufacture.
    (c) Manufacturing process--impairment of assurances. No product 
shall be licensed if any part of the process of or relating to the 
manufacture of such product, in the judgment of the Director, Center for 
Biologics Evaluation and Research or the Director, Center for Drug 
Evaluation and Research, would impair the assurances of continued 
safety, purity, and potency as provided by the regulations contained in 
this chapter.
    (d) Inspection--compliance with requirements. A biologics license 
shall be issued or a biologics license application approved only after 
inspection of the establishment(s) listed in the biologics license 
application and upon a determination that the establishment(s) complies 
with the standards established in the biologics license application and 
the requirements prescribed in applicable regulations.
    (e) One biologics license to cover all locations. One biologics 
license shall be issued to cover all locations meeting the establishment 
standards identified in the approved biologics license application and 
each location shall be subject to inspection by FDA officials.

[64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005]



Sec.  601.21  Products under development.

    A biological product undergoing development, but not yet ready for a 
biologics license, may be shipped or otherwise delivered from one State 
or possession into another State or possession provided such shipment or 
delivery is not for introduction or delivery for introduction into 
interstate commerce, except as provided in sections 505(i) and 520(g) of 
the Federal Food, Drug, and Cosmetic Act, as amended, and the 
regulations thereunder (21 CFR parts 312 and 812).

[64 FR 56451, Oct. 20, 1999]



Sec.  601.22  Products in short supply; initial manufacturing at other
than licensed location.

    A biologics license issued to a manufacturer and covering all 
locations of manufacture shall authorize persons other than such 
manufacturer to conduct at places other than such locations the initial, 
and partial manufacturing of a product for shipment solely to such 
manufacturer only to the extent that the names of such persons and 
places are registered with the Commissioner of Food and Drugs and it is 
found upon application of such manufacturer, that the product is in 
short supply due either to the peculiar growth requirements of the 
organism involved or to the scarcity of the animal required for 
manufacturing purposes, and such manufacturer has established with 
respect to such persons and places such procedures, inspections, tests 
or other arrangements as will ensure full compliance with the applicable 
regulations of this subchapter related to continued safety, purity, and 
potency. Such persons and places shall be subject to all regulations of 
this subchapter except Sec. Sec.  601.2 to 601.6, 601.9, 601.10, 601.20, 
601.21 to

[[Page 34]]

601.33, and 610.60 to 610.65 of this chapter. For persons and places 
authorized under this section to conduct the initial and partial 
manufacturing of a product for shipment solely to a manufacturer of a 
product subject to licensure under Sec.  601.2(c), the following 
additional regulations shall not be applicable: Sec. Sec.  600.10(b) and 
(c), 600.11, 600.12, 600.13, and 610.53 of this chapter. Failure of such 
manufacturer to maintain such procedures, inspections, tests, or other 
arrangements, or failure of any person conducting such partial 
manufacturing to comply with applicable regulations shall constitute a 
ground for suspension or revocation of the authority conferred pursuant 
to this section on the same basis as provided in Sec. Sec.  601.6 to 
601.8 with respect to the suspension and the revocation of licenses.

[42 FR 4718, Jan. 25, 1977, as amended at 61 FR 24233, May 14, 1996; 64 
FR 56452, Oct. 20, 1999; 80 FR 37974, July 2, 2015]



Sec.  601.27  Pediatric studies.

    (a) Required assessment. Except as provided in paragraphs (b), (c), 
and (d) of this section, each application for a new active ingredient, 
new indication, new dosage form, new dosing regimen, or new route of 
administration shall contain data that are adequate to assess the safety 
and effectiveness of the product for the claimed indications in all 
relevant pediatric subpopulations, and to support dosing and 
administration for each pediatric subpopulation for which the product is 
safe and effective. Where the course of the disease and the effects of 
the product are similar in adults and pediatric patients, FDA may 
conclude that pediatric effectiveness can be extrapolated from adequate 
and well-controlled effectiveness studies in adults, usually 
supplemented with other information in pediatric patients, such as 
pharmacokinetic studies. In addition, studies may not be needed in each 
pediatric age group, if data from one age group can be extrapolated to 
another. Assessments required under this section for a product that 
represents a meaningful therapeutic benefit over existing treatments 
must be carried out using appropriate formulations for the age group(s) 
for which the assessment is required.
    (b) Deferred submission. (1) FDA may, on its own initiative or at 
the request of an applicant, defer submission of some or all assessments 
of safety and effectiveness described in paragraph (a) of this section 
until after licensing of the product for use in adults. Deferral may be 
granted if, among other reasons, the product is ready for approval in 
adults before studies in pediatric patients are complete, pediatric 
studies should be delayed until additional safety or effectiveness data 
have been collected. If an applicant requests deferred submission, the 
request must provide an adequate justification for delaying pediatric 
studies, a description of the planned or ongoing studies, and evidence 
that the studies are being or will be conducted with due diligence and 
at the earliest possible time.
    (2) If FDA determines that there is an adequate justification for 
temporarily delaying the submission of assessments of pediatric safety 
and effectiveness, the product may be licensed for use in adults subject 
to the requirement that the applicant submit the required assessments 
within a specified time.
    (c) Waivers--(1) General. FDA may grant a full or partial waiver of 
the requirements of paragraph (a) of this section on its own initiative 
or at the request of an applicant. A request for a waiver must provide 
an adequate justification.
    (2) Full waiver. An applicant may request a waiver of the 
requirements of paragraph (a) of this section if the applicant certifies 
that:
    (i) The product does not represent a meaningful therapeutic benefit 
over existing therapies for pediatric patients and is not likely to be 
used in a substantial number of pediatric patients;
    (ii) Necessary studies are impossible or highly impractical because, 
e.g., the number of such patients is so small or geographically 
dispersed; or
    (iii) There is evidence strongly suggesting that the product would 
be ineffective or unsafe in all pediatric age groups.
    (3) Partial waiver. An applicant may request a waiver of the 
requirements of

[[Page 35]]

paragraph (a) of this section with respect to a specified pediatric age 
group, if the applicant certifies that:
    (i) The product does not represent a meaningful therapeutic benefit 
over existing therapies for pediatric patients in that age group, and is 
not likely to be used in a substantial number of patients in that age 
group;
    (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;
    (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.
    (4) FDA action on waiver. 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.
    (5) Definition of ``meaningful therapeutic benefit''. For purposes 
of this section, a product will be considered to offer a meaningful 
therapeutic benefit over existing therapies if FDA estimates that:
    (i) If approved, the product would represent a significant 
improvement in the treatment, diagnosis, or prevention of a disease, 
compared to marketed products adequately labeled for that use in the 
relevant pediatric population. Examples of how improvement might be 
demonstrated include, e.g., evidence of increased effectiveness in 
treatment, prevention, or diagnosis of disease; elimination or 
substantial reduction of a treatment-limiting drug reaction; documented 
enhancement of compliance; or evidence of safety and effectiveness in a 
new subpopulation; or
    (ii) The product is in a class of products or for an indication for 
which there is a need for additional therapeutic options.
    (d) Exemption for orphan drugs. This section does not apply to any 
product for an indication or indications for which orphan designation 
has been granted under part 316, subpart C, of this chapter.

[63 FR 66671, Dec. 2, 1998]



Sec.  601.28  Annual reports of postmarketing pediatric studies.

    Sponsors of licensed biological products shall submit the following 
information each year within 60 days of the anniversary date of approval 
of each product under the license to the Director, Center for Biologics 
Evaluation and Research or the Director, Center for Drug Evaluation and 
Research (see mailing addresses in Sec.  600.2(a) or (b) of this 
chapter):
    (a) Summary. A brief summary stating whether labeling supplements 
for pediatric use have been submitted and whether new studies in the 
pediatric population to support appropriate labeling for the pediatric 
population have been initiated. Where possible, an estimate of patient 
exposure to the drug product, with special reference to the pediatric 
population (neonates, infants, children, and adolescents) shall be 
provided, including dosage form.
    (b) Clinical data. Analysis of available safety and efficacy data in 
the pediatric population and changes proposed in the labeling based on 
this information. An assessment of data needed to ensure appropriate 
labeling for the pediatric population shall be included.
    (c) Status reports. A statement on the current status of any 
postmarketing studies in the pediatric population performed by, or on 
behalf of, the applicant. The statement shall include whether 
postmarketing clinical studies in pediatric populations were required or 
agreed to, and, if so, the status of these studies shall be reported to 
FDA in annual progress reports of postmarketing studies under Sec.  
601.70 rather than under this section.

[65 FR 59718, Oct. 6, 2000, as amended at 65 FR 64618, Oct. 30, 2000; 70 
FR 14984, Mar. 24, 2005; 80 FR 18092, Apr. 3, 2015]

[[Page 36]]



Sec.  601.29  Guidance documents.

    (a) FDA has made available guidance documents under Sec.  10.115 of 
this chapter to help you comply with certain requirements of this part.
    (b) The Center for Biologics Evaluation and Research (CBER) 
maintains a list of guidance documents that apply to the center's 
regulations. The lists are maintained on the Internet and are published 
annually in the Federal Register. You may request a copy of the CBER 
list from the Food and Drug Administration, Center for Biologics 
Evaluation and Research, Office of Communication, Outreach and 
Development, 10903 New Hampshire Ave., Bldg. 71, Rm. 3103, Silver 
Spring, MD 20993-0002.

[65 FR 56480, Sept. 19, 2000, as amended at 70 FR 14984, Mar. 24, 2005; 
80 FR 18092, Apr. 3, 2015]



                Subpart D_Diagnostic Radiopharmaceuticals

    Source: 64 FR 26668, May 17, 1999, unless otherwise noted.



Sec.  601.30  Scope.

    This subpart applies to radiopharmaceuticals intended for in vivo 
administration for diagnostic and monitoring use. It does not apply to 
radiopharmaceuticals intended for therapeutic purposes. In situations 
where a particular radiopharmaceutical is proposed for both diagnostic 
and therapeutic uses, the radiopharmaceutical must be evaluated taking 
into account each intended use.



Sec.  601.31  Definition.

    For purposes of this part,diagnostic radiopharmaceutical means:
    (a) An article that is intended for use in the diagnosis or 
monitoring of a disease or a manifestation of a disease in humans and 
that exhibits spontaneous disintegration of unstable nuclei with the 
emission of nuclear particles or photons; or
    (b) Any nonradioactive reagent kit or nuclide generator that is 
intended to be used in the preparation of such article as defined in 
paragraph (a) of this section.



Sec.  601.32  General factors relevant to safety and effectiveness.

    FDA's determination of the safety and effectiveness of a diagnostic 
radiopharmaceutical includes consideration of the following:
    (a) The proposed use of the diagnostic radiopharmaceutical in the 
practice of medicine;
    (b) The pharmacological and toxicological activity of the diagnostic 
radiopharmaceutical (including any carrier or ligand component of the 
diagnostic radiopharmaceutical); and
    (c) The estimated absorbed radiation dose of the diagnostic 
radiopharmaceutical.



Sec.  601.33  Indications.

    (a) For diagnostic radiopharmaceuticals, the categories of proposed 
indications for use include, but are not limited to, the following:
    (1) Structure delineation;
    (2) Functional, physiological, or biochemical assessment;
    (3) Disease or pathology detection or assessment; and
    (4) Diagnostic or therapeutic patient management.
    (b) Where a diagnostic radiopharmaceutical is not intended to 
provide disease-specific information, the proposed indications for use 
may refer to a biochemical, physiological, anatomical, or pathological 
process or to more than one disease or condition.



Sec.  601.34  Evaluation of effectiveness.

    (a) The effectiveness of a diagnostic radiopharmaceutical is 
assessed by evaluating its ability to provide useful clinical 
information related to its proposed indications for use. The method of 
this evaluation varies depending upon the proposed indication(s) and may 
use one or more of the following criteria:
    (1) The claim of structure delineation is established by 
demonstrating in a defined clinical setting the ability to locate 
anatomical structures and to characterize their anatomy.
    (2) The claim of functional, physiological, or biochemical 
assessment is established by demonstrating in a defined clinical setting 
reliable measurement of function(s) or physiological, biochemical, or 
molecular process(es).

[[Page 37]]

    (3) The claim of disease or pathology detection or assessment is 
established by demonstrating in a defined clinical setting that the 
diagnostic radiopharmaceutical has sufficient accuracy in identifying or 
characterizing the disease or pathology.
    (4) The claim of diagnostic or therapeutic patient management is 
established by demonstrating in a defined clinical setting that the test 
is useful in diagnostic or therapeutic patient management.
    (5) For a claim that does not fall within the indication categories 
identified in Sec.  601.33, the applicant or sponsor should consult FDA 
on how to establish the effectiveness of the diagnostic 
radiopharmaceutical for the claim.
    (b) The accuracy and usefulness of the diagnostic information is 
determined by comparison with a reliable assessment of actual clinical 
status. A reliable assessment of actual clinical status may be provided 
by a diagnostic standard or standards of demonstrated accuracy. In the 
absence of such diagnostic standard(s), the actual clinical status must 
be established in another manner, e.g., patient followup.



Sec.  601.35  Evaluation of safety.

    (a) Factors considered in the safety assessment of a diagnostic 
radiopharmaceutical include, among others, the following:
    (1) The radiation dose;
    (2) The pharmacology and toxicology of the radiopharmaceutical, 
including any radionuclide, carrier, or ligand;
    (3) The risks of an incorrect diagnostic determination;
    (4) The adverse reaction profile of the drug;
    (5) Results of human experience with the radiopharmaceutical for 
other uses; and
    (6) Results of any previous human experience with the carrier or 
ligand of the radiopharmaceutical when the same chemical entity as the 
carrier or ligand has been used in a previously studied product.
    (b) The assessment of the adverse reaction profile includes, but is 
not limited to, an evaluation of the potential of the diagnostic 
radiopharmaceutical, including the carrier or ligand, to elicit the 
following:
    (1) Allergic or hypersensitivity responses,
    (2) Immunologic responses,
    (3) Changes in the physiologic or biochemical function of the target 
and nontarget tissues, and
    (4) Clinically detectable signs or symptoms.
    (c)(1) To establish the safety of a diagnostic radiopharmaceutical, 
FDA may require, among other information, the following types of data:
    (A) Pharmacology data,
    (B) Toxicology data,
    (C) Clinical adverse event data, and
    (D) Radiation safety assessment.
    (2) The amount of new safety data required will depend on the 
characteristics of the product and available information regarding the 
safety of the diagnostic radiopharmaceutical, and its carrier or ligand, 
obtained from other studies and uses. Such information may include, but 
is not limited to, the dose, route of administration, frequency of use, 
half-life of the ligand or carrier, half-life of the radionuclide, and 
results of clinical and preclinical studies. FDA will establish 
categories of diagnostic radiopharmaceuticals based on defined 
characteristics relevant to risk and will specify the amount and type of 
safety data that are appropriate for each category (e.g., required 
safety data may be limited for diagnostic radiopharmaceuticals with a 
well established, low-risk profile). Upon reviewing the relevant product 
characteristics and safety information, FDA will place each diagnostic 
radiopharmaceutical into the appropriate safety risk category.
    (d) Radiation safety assessment. The radiation safety assessment 
must establish the radiation dose of a diagnostic radiopharmaceutical by 
radiation dosimetry evaluations in humans and appropriate animal models. 
The maximum tolerated dose need not be established.



  Subpart E_Accelerated Approval of Biological Products for Serious or 
                       Life-Threatening Illnesses

    Source: 57 FR 58959, Dec. 11, 1992, unless otherwise noted.

[[Page 38]]



Sec.  601.40  Scope.

    This subpart applies to certain biological products that have been 
studied for their safety and effectiveness in treating serious or life-
threatening illnesses and that provide meaningful therapeutic benefit to 
patients over existing treatments (e.g., ability to treat patients 
unresponsive to, or intolerant of, available therapy, or improved 
patient response over available therapy).



Sec.  601.41  Approval based on a surrogate endpoint or on an effect on
a clinical endpoint other than survival or irreversible morbidity.

    FDA may grant marketing approval for a biological product on the 
basis of adequate and well-controlled clinical trials establishing that 
the biological product has an effect on a surrogate endpoint that is 
reasonably likely, based on epidemiologic, therapeutic, 
pathophysiologic, or other evidence, to predict clinical benefit or on 
the basis of an effect on a clinical endpoint other than survival or 
irreversible morbidity. Approval under this section will be subject to 
the requirement that the applicant study the biological product further, 
to verify and describe its clinical benefit, where there is uncertainty 
as to the relation of the surrogate endpoint to clinical benefit, or of 
the observed clinical benefit to ultimate outcome. Postmarketing studies 
would usually be studies already underway. When required to be 
conducted, such studies must also be adequate and well-controlled. The 
applicant shall carry out any such studies with due diligence.



Sec.  601.42  Approval with restrictions to assure safe use.

    (a) If FDA concludes that a biological product shown to be effective 
can be safely used only if distribution or use is restricted, FDA will 
require such postmarketing restrictions as are needed to assure safe use 
of the biological product, such as:
    (1) Distribution restricted to certain facilities or physicians with 
special training or experience; or
    (2) Distribution conditioned on the performance of specified medical 
procedures.
    (b) The limitations imposed will be commensurate with the specific 
safety concerns presented by the biological product.



Sec.  601.43  Withdrawal procedures.

    (a) For biological products approved under Sec.  601.41 or Sec.  
601.42, FDA may withdraw approval, following a hearing as provided in 
part 15 of this chapter, as modified by this section, if:
    (1) A postmarketing clinical study fails to verify clinical benefit;
    (2) The applicant fails to perform the required postmarketing study 
with due diligence;
    (3) Use after marketing demonstrates that postmarketing restrictions 
are inadequate to ensure safe use of the biological product;
    (4) The applicant fails to adhere to the postmarketing restrictions 
agreed upon;
    (5) The promotional materials are false or misleading; or
    (6) Other evidence demonstrates that the biological product is not 
shown to be safe or effective under its conditions of use.
    (b) Notice of opportunity for a hearing. The Director of the Center 
for Biologics Evaluation and Research or the Director of the Center for 
Drug Evaluation and Research will give the applicant notice of an 
opportunity for a hearing on the Center's proposal to withdraw the 
approval of an application approved under Sec.  601.41 or Sec.  601.42. 
The notice, which will ordinarily be a letter, will state generally the 
reasons for the action and the proposed grounds for the order.
    (c) Submission of data and information. (1) If the applicant fails 
to file a written request for a hearing within 15 days of receipt of the 
notice, the applicant waives the opportunity for a hearing.
    (2) If the applicant files a timely request for a hearing, the 
agency will publish a notice of hearing in the Federal Register in 
accordance with Sec. Sec.  12.32(e) and 15.20 of this chapter.
    (3) An applicant who requests a hearing under this section must, 
within 30 days of receipt of the notice of opportunity for a hearing, 
submit the data and information upon which the applicant intends to rely 
at the hearing.

[[Page 39]]

    (d) Separation of functions. Separation of functions (as specified 
in Sec.  10.55 of this chapter) will not apply at any point in 
withdrawal proceedings under this section.
    (e) Procedures for hearings. Hearings held under this section will 
be conducted in accordance with the provisions of part 15 of this 
chapter, with the following modifications:
    (1) An advisory committee duly constituted under part 14 of this 
chapter will be present at the hearing. The committee will be asked to 
review the issues involved and to provide advice and recommendations to 
the Commissioner of Food and Drugs.
    (2) The presiding officer, the advisory committee members, up to 
three representatives of the applicant, and up to three representatives 
of the Center may question any person during or at the conclusion of the 
person's presentation. No other person attending the hearing may 
question a person making a presentation. The presiding officer may, as a 
matter of discretion, permit questions to be submitted to the presiding 
officer for response by a person making a presentation.
    (f) Judicial review. The Commissioner's decision constitutes final 
agency action from which the applicant may petition for judicial review. 
Before requesting an order from a court for a stay of action pending 
review, an applicant must first submit a petition for a stay of action 
under Sec.  10.35 of this chapter.

[57 FR 58959, Dec. 11, 1992, as amended at 68 FR 34797, June 11, 2003; 
70 FR 14984, Mar. 24, 2005]



Sec.  601.44  Postmarketing safety reporting.

    Biological products approved under this program are subject to the 
postmarketing recordkeeping and safety reporting applicable to all 
approved biological products.



Sec.  601.45  Promotional materials.

    For biological products being considered for approval under this 
subpart, unless otherwise informed by the agency, applicants must submit 
to the agency for consideration during the preapproval review period 
copies of all promotional materials, including promotional labeling as 
well as advertisements, intended for dissemination or publication within 
120 days following marketing approval. After 120 days following 
marketing approval, unless otherwise informed by the agency, the 
applicant must submit promotional materials at least 30 days prior to 
the intended time of initial dissemination of the labeling or initial 
publication of the advertisement.



Sec.  601.46  Termination of requirements.

    If FDA determines after approval that the requirements established 
in Sec.  601.42, Sec.  601.43, or Sec.  601.45 are no longer necessary 
for the safe and effective use of a biological product, it will so 
notify the applicant. Ordinarily, for biological products approved under 
Sec.  601.41, these requirements will no longer apply when FDA 
determines that the required postmarketing study verifies and describes 
the biological product's clinical benefit and the biological product 
would be appropriate for approval under traditional procedures. For 
biological products approved under Sec.  601.42, the restrictions would 
no longer apply when FDA determines that safe use of the biological 
product can be assured through appropriate labeling. FDA also retains 
the discretion to remove specific postapproval requirements upon review 
of a petition submitted by the sponsor in accordance with Sec.  10.30.



                Subpart F_Confidentiality of Information



Sec.  601.50  Confidentiality of data and information in an investigational
new drug notice for a biological product.

    (a) The existence of an IND notice for a biological product will not 
be disclosed by the Food and Drug Administration unless it has 
previously been publicly disclosed or acknowledged.
    (b) The availability for public disclosure of all data and 
information in an IND file for a biological product shall be handled in 
accordance with the provisions established in Sec.  601.51.
    (c) Notwithstanding the provisions of Sec.  601.51, the Food and 
Drug Administration shall disclose upon request to an individual on whom 
an investigational biological product has been used a copy

[[Page 40]]

of any adverse reaction report relating to such use.

[39 FR 44656, Dec. 24, 1974]



Sec.  601.51  Confidentiality of data and information in applications for
biologics licenses.

    (a) For purposes of this section the biological product file 
includes all data and information submitted with or incorporated by 
reference in any application for a biologics license, IND's incorporated 
into any such application, master files, and other related submissions. 
The availability for public disclosure of any record in the biological 
product file shall be handled in accordance with the provisions of this 
section.
    (b) The existence of a biological product file will not be disclosed 
by the Food and Drug Administration before a biologics license 
application has been approved unless it has previously been publicly 
disclosed or acknowledged. The Food and Drug Administration will 
maintain a list available for public disclosure of biological products 
for which a license application has been approved.
    (c) If the existence of a biological product file has not been 
publicly disclosed or acknowledged, no data or information in the 
biological product file is available for public disclosure.
    (d)(1) If the existence of a biological product file has been 
publicly disclosed or acknowledged before a license has been issued, no 
data or information contained in the file is available for public 
disclosure before such license is issued, but the Commissioner may, in 
his discretion, disclose a summary of such selected portions of the 
safety and effectiveness data as are appropriate for public 
consideration of a specific pending issue, e.g., at an open session of a 
Food and Drug Administration advisory committee or pursuant to an 
exchange of important regulatory information with a foreign government.
    (2) Notwithstanding paragraph (d)(1) of this section, FDA will make 
available to the public upon request the information in the IND that was 
required to be filed in Docket Number 95S-0158 in the Division of 
Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers 
Lane, rm. 1061, Rockville, MD 20852, for investigations involving an 
exception from informed consent under Sec.  50.24 of this chapter. 
Persons wishing to request this information shall submit a request under 
the Freedom of Information Act.
    (e) After a license has been issued, the following data and 
information in the biological product file are immediately available for 
public disclosure unless extraordinary circumstances are shown:
    (1) All safety and effectiveness data and information.
    (2) A protocol for a test or study, unless it is shown to fall 
within the exemption established for trade secrets and confidential 
commercial or financial information in Sec.  20.61 of this chapter.
    (3) Adverse reaction reports, product experience reports, consumer 
complaints, and other similar data and information, after deletion of:
    (i) Names and any information that would identify the person using 
the product.
    (ii) Names and any information that would identify any third party 
involved with the report, such as a physician or hospital or other 
institution.
    (4) A list of all active ingredients and any inactive ingredients 
previously disclosed to the public, as defined in Sec.  20.81 of this 
chapter.
    (5) An assay method or other analytical method, unless it serves no 
regulatory or compliance purpose and it is shown to fall within the 
exemption established in Sec.  20.61 of this chapter.
    (6) All correspondence and written summaries of oral discussions 
relating to the biological product file, in accordance with the 
provisions of part 20 of this chapter.
    (7) All records showing the manufacturer's testing of a particular 
lot, after deletion of data or information that would show the volume of 
the drug produced, manufacturing procedures and controls, yield from raw 
materials, costs, or other material falling within Sec.  20.61 of this 
chapter.
    (8) All records showing the testing of and action on a particular 
lot by the Food and Drug Administration.
    (f) The following data and information in a biological product file 
are not available for public disclosure unless

[[Page 41]]

they have been previously disclosed to the public as defined in Sec.  
20.81 of this chapter or they relate to a product or ingredient that has 
been abandoned and they no longer represent a trade secret or 
confidential commercial or financial information as defined in Sec.  
20.61 of this chapter:
    (1) Manufacturing methods or processes, including quality control 
procedures.
    (2) Production, sales, distribution, and similar data and 
information, except that any compilation of such data and information 
aggregated and prepared in a way that does not reveal data or 
information which is not available for public disclosure under this 
provision is available for public disclosure.
    (3) Quantitative or semiquantitative formulas.
    (g) For purposes of this regulation, safety and effectiveness data 
include all studies and tests of a biological product on animals and 
humans and all studies and tests on the drug for identity, stability, 
purity, potency, and bioavailability.

[39 FR 44656, Dec. 24, 1974, as amended at 42 FR 15676, Mar. 22, 1977; 
49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 61 FR 51530, Oct. 
2, 1996; 64 FR 56452, Oct. 20, 1999; 68 FR 24879, May 9, 2003; 69 FR 
13717, Mar. 24, 2004; 70 FR 14984, Mar. 24, 2005]



                     Subpart G_Postmarketing Studies

    Source: 65 FR 64618, Oct. 30, 2000, unless otherwise noted.



Sec.  601.70  Annual progress reports of postmarketing studies.

    (a) General requirements. This section applies to all required 
postmarketing studies (e.g., accelerated approval clinical benefit 
studies, pediatric studies) and postmarketing studies that an applicant 
has committed, in writing, to conduct either at the time of approval of 
an application or a supplement to an application, or after approval of 
an application or a supplement. Postmarketing studies within the meaning 
of this section are those that concern:
    (1) Clinical safety;
    (2) Clinical efficacy;
    (3) Clinical pharmacology; and
    (4) Nonclinical toxicology.
    (b) What to report. Each applicant of a licensed biological product 
shall submit a report to FDA on the status of postmarketing studies for 
each approved product application. The status of these postmarketing 
studies shall be reported annually until FDA notifies the applicant, in 
writing, that the agency concurs with the applicant's determination that 
the study commitment has been fulfilled, or that the study is either no 
longer feasible or would no longer provide useful information. Each 
annual progress report shall be accompanied by a completed transmittal 
Form FDA-2252, and shall include all the information required under this 
section that the applicant received or otherwise obtained during the 
annual reporting interval which ends on the U.S. anniversary date. The 
report must provide the following information for each postmarketing 
study:
    (1) Applicant's name.
    (2) Product name. Include the approved product's proper name and the 
proprietary name, if any.
    (3) Biologics license application (BLA) and supplement number.
    (4) Date of U.S. approval of BLA.
    (5) Date of postmarketing study commitment.
    (6) Description of postmarketing study commitment. The description 
must include sufficient information to uniquely describe the study. This 
information may include the purpose of the study, the type of study, the 
patient population addressed by the study and the indication(s) and 
dosage(s) that are to be studied.
    (7) Schedule for completion and reporting of the postmarketing study 
commitment. The schedule should include the actual or projected dates 
for submission of the study protocol to FDA, completion of patient 
accrual or initiation of an animal study, completion of the study, 
submission of the final study report to FDA, and any additional 
milestones or submissions for which projected dates were specified as 
part of the commitment. In addition, it should include a revised 
schedule, as appropriate. If the schedule has been previously revised, 
provide both the original schedule and the most recent, previously 
submitted revision.

[[Page 42]]

    (8) Current status of the postmarketing study commitment. The status 
of each postmarketing study should be categorized using one of the 
following terms that describes the study's status on the anniversary 
date of U.S. approval of the application or other agreed upon date:
    (i) Pending. The study has not been initiated, but does not meet the 
criterion for delayed.
    (ii) Ongoing. The study is proceeding according to or ahead of the 
original schedule described under paragraph (b)(7) of this section.
    (iii) Delayed. The study is behind the original schedule described 
under paragraph (b)(7) of this section.
    (iv) Terminated. The study was ended before completion but a final 
study report has not been submitted to FDA.
    (v) Submitted. The study has been completed or terminated and a 
final study report has been submitted to FDA.
    (9) Explanation of the study's status. Provide a brief description 
of the status of the study, including the patient accrual rate 
(expressed by providing the number of patients or subjects enrolled to 
date, and the total planned enrollment), and an explanation of the 
study's status identified under paragraph (b)(8) of this section. If the 
study has been completed, include the date the study was completed and 
the date the final study report was submitted to FDA, as applicable. 
Provide a revised schedule, as well as the reason(s) for the revision, 
if the schedule under paragraph (b)(7) of this section has changed since 
the previous report.
    (c) When to report. Annual progress reports for postmarketing study 
commitments entered into by applicants shall be reported to FDA within 
60 days of the anniversary date of the U.S. approval of the application 
for the product.
    (d) Where to report. Submit two copies of the annual progress report 
of postmarketing studies to the Center for Biologics Evaluation and 
Research or Center for Drug Evaluation and Research (see mailing 
addresses in Sec.  600.2(a) or (b) of this chapter).
    (e) Public disclosure of information. Except for the information 
described in this paragraph, FDA may publicly disclose any information 
concerning a postmarketing study, within the meaning of this section, if 
the agency determines that the information is necessary to identify an 
applicant or to establish the status of the study including the reasons, 
if any, for failure to conduct, complete, and report the study. Under 
this section, FDA will not publicly disclose trade secrets, as defined 
in Sec.  20.61 of this chapter, or information, described in Sec.  20.63 
of this chapter, the disclosure of which would constitute an unwarranted 
invasion of personal privacy.

[65 FR 64618, Oct. 30, 2000, as amended at 70 FR 14984, Mar. 24, 2005; 
80 FR 18092, Apr. 3, 2015]



 Subpart H_Approval of Biological Products When Human Efficacy Studies 
                       Are Not Ethical or Feasible

    Source: 67 FR 37996, May 31, 2002, unless otherwise noted.



Sec.  601.90  Scope.

    This subpart applies to certain biological products that have been 
studied for their safety and efficacy in ameliorating or preventing 
serious or life-threatening conditions caused by exposure to lethal or 
permanently disabling toxic biological, chemical, radiological, or 
nuclear substances. This subpart applies only to those biological 
products for which: Definitive human efficacy studies cannot be 
conducted because it would be unethical to deliberately expose healthy 
human volunteers to a lethal or permanently disabling toxic biological, 
chemical, radiological, or nuclear substance; and field trials to study 
the product's efficacy after an accidental or hostile exposure have not 
been feasible. This subpart does not apply to products that can be 
approved based on efficacy standards described elsewhere in FDA's 
regulations (e.g., accelerated approval based on surrogate markers or 
clinical endpoints other than survival or irreversible morbidity), nor 
does it address the safety evaluation for the products to which it does 
apply.

[[Page 43]]



Sec.  601.91  Approval based on evidence of effectiveness from studies
in animals.

    (a) FDA may grant marketing approval for a biological product for 
which safety has been established and for which the requirements of 
Sec.  601.90 are met based on adequate and well-controlled animal 
studies when the results of those animal studies establish that the 
biological product is reasonably likely to produce clinical benefit in 
humans. In assessing the sufficiency of animal data, the agency may take 
into account other data, including human data, available to the agency. 
FDA will rely on the evidence from studies in animals to provide 
substantial evidence of the effectiveness of these products only when:
    (1) There is a reasonably well-understood pathophysiological 
mechanism of the toxicity of the substance and its prevention or 
substantial reduction by the product;
    (2) The effect is demonstrated in more than one animal species 
expected to react with a response predictive for humans, unless the 
effect is demonstrated in a single animal species that represents a 
sufficiently well-characterized animal model for predicting the response 
in humans;
    (3) The animal study endpoint is clearly related to the desired 
benefit in humans, generally the enhancement of survival or prevention 
of major morbidity; and
    (4) The data or information on the kinetics and pharmacodynamics of 
the product or other relevant data or information, in animals and 
humans, allows selection of an effective dose in humans.
    (b) Approval under this subpart will be subject to three 
requirements:
    (1) Postmarketing studies. The applicant must conduct postmarketing 
studies, such as field studies, to verify and describe the biological 
product's clinical benefit and to assess its safety when used as 
indicated when such studies are feasible and ethical. Such postmarketing 
studies would not be feasible until an exigency arises. When such 
studies are feasible, the applicant must conduct such studies with due 
diligence. Applicants must include as part of their application a plan 
or approach to postmarketing study commitments in the event such studies 
become ethical and feasible.
    (2) Approval with restrictions to ensure safe use. If FDA concludes 
that a biological product shown to be effective under this subpart can 
be safely used only if distribution or use is restricted, FDA will 
require such postmarketing restrictions as are needed to ensure safe use 
of the biological product, commensurate with the specific safety 
concerns presented by the biological product, such as:
    (i) Distribution restricted to certain facilities or health care 
practitioners with special training or experience;
    (ii) Distribution conditioned on the performance of specified 
medical procedures, including medical followup; and
    (iii) Distribution conditioned on specified recordkeeping 
requirements.
    (3) Information to be provided to patient recipients. For biological 
products or specific indications approved under this subpart, applicants 
must prepare, as part of their proposed labeling, labeling to be 
provided to patient recipients. The patient labeling must explain that, 
for ethical or feasibility reasons, the biological product's approval 
was based on efficacy studies conducted in animals alone and must give 
the biological product's indication(s), directions for use (dosage and 
administration), contraindications, a description of any reasonably 
foreseeable risks, adverse reactions, anticipated benefits, drug 
interactions, and any other relevant information required by FDA at the 
time of approval. The patient labeling must be available with the 
product to be provided to patients prior to administration or dispensing 
of the biological product for the use approved under this subpart, if 
possible.



Sec.  601.92  Withdrawal procedures.

    (a) Reasons to withdraw approval. For biological products approved 
under this subpart, FDA may withdraw approval, following a hearing as 
provided in part 15 of this chapter, as modified by this section, if:
    (1) A postmarketing clinical study fails to verify clinical benefit;
    (2) The applicant fails to perform the postmarketing study with due 
diligence;

[[Page 44]]

    (3) Use after marketing demonstrates that postmarketing restrictions 
are inadequate to ensure safe use of the biological product;
    (4) The applicant fails to adhere to the postmarketing restrictions 
applied at the time of approval under this subpart;
    (5) The promotional materials are false or misleading; or
    (6) Other evidence demonstrates that the biological product is not 
shown to be safe or effective under its conditions of use.
    (b) Notice of opportunity for a hearing. The Director of the Center 
for Biologics Evaluation and Research or the Director of the Center for 
Drug Evaluation and Research will give the applicant notice of an 
opportunity for a hearing on the proposal to withdraw the approval of an 
application approved under this subpart. The notice, which will 
ordinarily be a letter, will state generally the reasons for the action 
and the proposed grounds for the order.
    (c) Submission of data and information. (1) If the applicant fails 
to file a written request for a hearing within 15 days of receipt of the 
notice, the applicant waives the opportunity for a hearing.
    (2) If the applicant files a timely request for a hearing, the 
agency will publish a notice of hearing in the Federal Register in 
accordance with Sec. Sec.  12.32(e) and 15.20 of this chapter.
    (3) An applicant who requests a hearing under this section must, 
within 30 days of receipt of the notice of opportunity for a hearing, 
submit the data and information upon which the applicant intends to rely 
at the hearing.
    (d) Separation of functions. Separation of functions (as specified 
in Sec.  10.55 of this chapter) will not apply at any point in 
withdrawal proceedings under this section.
    (e) Procedures for hearings. Hearings held under this section will 
be conducted in accordance with the provisions of part 15 of this 
chapter, with the following modifications:
    (1) An advisory committee duly constituted under part 14 of this 
chapter will be present at the hearing. The committee will be asked to 
review the issues involved and to provide advice and recommendations to 
the Commissioner of Food and Drugs.
    (2) The presiding officer, the advisory committee members, up to 
three representatives of the applicant, and up to three representatives 
of CBER may question any person during or at the conclusion of the 
person's presentation. No other person attending the hearing may 
question a person making a presentation. The presiding officer may, as a 
matter of discretion, permit questions to be submitted to the presiding 
officer for response by a person making a presentation.
    (f) Judicial review. The Commissioner of Food and Drugs' decision 
constitutes final agency action from which the applicant may petition 
for judicial review. Before requesting an order from a court for a stay 
of action pending review, an applicant must first submit a petition for 
a stay of action under Sec.  10.35 of this chapter.

[67 FR 37996, May 31, 2002, as amended at 70 FR 14984, Mar. 24, 2005]



Sec.  601.93  Postmarketing safety reporting.

    Biological products approved under this subpart are subject to the 
postmarketing recordkeeping and safety reporting applicable to all 
approved biological products.



Sec.  601.94  Promotional materials.

    For biological products being considered for approval under this 
subpart, unless otherwise informed by the agency, applicants must submit 
to the agency for consideration during the preapproval review period 
copies of all promotional materials, including promotional labeling as 
well as advertisements, intended for dissemination or publication within 
120 days following marketing approval. After 120 days following 
marketing approval, unless otherwise informed by the agency, the 
applicant must submit promotional materials at least 30 days prior to 
the intended time of initial dissemination of the labeling or initial 
publication of the advertisement.



Sec.  601.95  Termination of requirements.

    If FDA determines after approval under this subpart that the 
requirements established in Sec. Sec.  601.91(b)(2), 601.92, and 601.93 
are no longer necessary for the safe and effective use of

[[Page 45]]

a biological product, FDA will so notify the applicant. Ordinarily, for 
biological products approved under Sec.  601.91, these requirements will 
no longer apply when FDA determines that the postmarketing study 
verifies and describes the biological product's clinical benefit. For 
biological products approved under Sec.  601.91, the restrictions would 
no longer apply when FDA determines that safe use of the biological 
product can be ensured through appropriate labeling. FDA also retains 
the discretion to remove specific postapproval requirements upon review 
of a petition submitted by the sponsor in accordance with Sec.  10.30 of 
this chapter.



PART 606_CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND BLOOD COMPONENTS-
-Table of Contents



                      Subpart A_General Provisions

Sec.
606.3 Definitions.

                  Subpart B_Organization and Personnel

606.20 Personnel.

                     Subpart C_Plant and Facilities

606.40 Facilities.

                           Subpart D_Equipment

606.60 Equipment.
606.65 Supplies and reagents.

Subpart E [Reserved]

                Subpart F_Production and Process Controls

606.100 Standard operating procedures.
606.110 Plateletpheresis, leukapheresis, and plasmapheresis.

 Subpart G_Additional Labeling Standards for Blood and Blood Components

606.120 Labeling, general requirements.
606.121 Container label.
606.122 Circular of information.

                      Subpart H_Laboratory Controls

606.140 Laboratory controls.
606.145 Control of bacterial contamination of platelets.
606.151 Compatibility testing.

                      Subpart I_Records and Reports

606.160 Records.
606.165 Distribution and receipt; procedures and records.
606.170 Adverse reaction file.
606.171 Reporting of product deviations by licensed manufacturers, 
          unlicensed registered blood establishments, and transfusion 
          services.

    Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360j, 371, 374; 
42 U.S.C. 216, 262, 263a, 264.

    Source: 40 FR 53532, Nov. 18, 1975, unless otherwise noted.



                      Subpart A_General Provisions



Sec.  606.3  Definitions.

    As used in this part:
    (a) Blood means a product that is a fluid containing dissolved and 
suspended elements which was collected from the vascular system of a 
human.
    (b) Unit means the volume of blood or one of its components in a 
suitable volume of anticoagulant obtained from a single collection of 
blood from one donor.
    (c) Blood component means a product containing a part of human blood 
separated by physical or mechanical means.
    (d) Plasma for further manufacturing means that liquid portion of 
blood separated and used as material to prepare another product.
    (e) Plasmapheresis means the procedure in which blood is removed 
from the donor, the plasma is separated from the formed elements and at 
least the red blood cells are returned to the donor.
    (f) Plateletpheresis means the procedure in which blood is removed 
from a donor, a platelet concentrate is separated, and the remaining 
formed elements are returned to the donor along with a portion of the 
residual plasma.
    (g) Leukapheresis means the procedure in which blood is removed from 
the donor, a leukocyte concentrate is separated, and the remaining 
formed elements and residual plasma are returned to the donor.
    (h) Facilities means any area used for the collection, processing, 
compatibility testing, storage or distribution of blood and blood 
components.
    (i) Processing means any procedure employed after collection, and 
before or after compatibility testing of blood,

[[Page 46]]

and includes the identification of a unit of donor blood, the 
preparation of components from such unit of donor blood, serological 
testing, labeling and associated recordkeeping.
    (j) Compatibility testing means the procedures performed to 
establish the matching of a donor's blood or blood components with that 
of a potential recipient.
    (k) Distributed means:
    (1) The blood or blood components have left the control of the 
licensed manufacturer, unlicensed registered blood establishment, or 
transfusion service; or
    (2) The licensed manufacturer has provided Source Plasma or any 
other blood component for use in the manufacture of a licensed 
biological product.
    (l) Control means having responsibility for maintaining the 
continued safety, purity, and potency of the product and for compliance 
with applicable product and establishment standards, and for compliance 
with current good manufacturing practices.

[40 FR 53532, Nov. 18, 1975, as amended at 64 FR 45370, Aug. 19, 1999; 
65 FR 66635, Nov. 7, 2000; 66 FR 1835, Jan. 10, 2001; 66 FR 40889, Aug. 
6, 2001; 72 FR 45886, Aug. 16, 2007; 80 FR 29894, May 22, 2015]



                  Subpart B_Organization and Personnel



Sec.  606.20  Personnel.

    (a) [Reserved]
    (b) The personnel responsible for the collection, processing, 
compatibility testing, storage or distribution of blood or blood 
components shall be adequate in number, educational background, training 
and experience, including professional training as necessary, or 
combination thereof, to assure competent performance of their assigned 
functions, and to ensure that the final product has the safety, purity, 
potency, identity and effectiveness it purports or is represented to 
possess. All personnel shall have capabilities commensurate with their 
assigned functions, a thorough understanding of the procedures or 
control operations they perform, the necessary training or experience, 
and adequate information concerning the application of pertinent 
provisions of this part to their respective functions.
    (c) Persons whose presence can adversely affect the safety and 
purity of the products shall be excluded from areas where the 
collection, processing, compatibility testing, storage or distribution 
of blood or blood components is conducted.

[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55 
FR 11014, Mar. 26, 1990; 62 FR 53538, Oct. 15, 1997]



                     Subpart C_Plant and Facilities



Sec.  606.40  Facilities.

    Facilities shall be maintained in a clean and orderly manner, and 
shall be of suitable size, construction and location to facilitate 
adequate cleaning, maintenance and proper operations. The facilities 
shall:
    (a) Provide adequate space for the following when applicable:
    (1) Private and accurate examinations of individuals to determine 
their eligibility as blood donors.
    (2) The withdrawal of blood from donors with minimal risk of 
contamination, or exposure to activities and equipment unrelated to 
blood collection.
    (3) The storage of blood or blood components pending completion of 
tests.
    (4) The quarantine storage of blood or blood components in a 
designated location pending repetition of those tests that initially 
gave questionable serological results.
    (5) The storage of finished products prior to distribution.
    (6) The quarantine storage, handling and disposition of products and 
reagents not suitable for use.
    (7) The orderly collection, processing, compatibility testing, 
storage and distribution of blood and blood components to prevent 
contamination.
    (8) The adequate and proper performance of all steps in 
plasmapheresis, plateletpheresis and leukapheresis procedures.
    (9) The orderly conduction of all packaging, labeling and other 
finishing operations.
    (b) Provide adequate lighting, ventilation and screening of open 
windows and doors.

[[Page 47]]

    (c) Provide adequate, clean, and convenient handwashing facilities 
for personnel, and adequate, clean, and convenient toilet facilities for 
donors and personnel. Drains shall be of adequate size and, where 
connected directly to a sewer, shall be equipped with traps to prevent 
back-siphonage.
    (d) Provide for safe and sanitary disposal for the following:
    (1) Trash and items used during the collection, processing and 
compatibility testing of blood and blood components.
    (2) Blood and blood components not suitable for use or distribution.

[40 FR 53532, Nov. 18, 1975, as amended at 80 FR 29895, May 22, 2015]



                           Subpart D_Equipment



Sec.  606.60  Equipment.

    (a) Equipment used in the collection, processing, compatibility 
testing, storage and distribution of blood and blood components shall be 
maintained in a clean and orderly manner and located so as to facilitate 
cleaning and maintenance. The equipment shall be observed, standardized 
and calibrated on a regularly scheduled basis as prescribed in the 
Standard Operating Procedures Manual and shall perform in the manner for 
which it was designed so as to assure compliance with the official 
requirements prescribed in this chapter for blood and blood products.
    (b) Equipment that shall be observed, standardized and calibrated 
with at least the following frequency, include but are not limited to:

----------------------------------------------------------------------------------------------------------------
             Equipment                   Performance check            Frequency         Frequency of calibration
----------------------------------------------------------------------------------------------------------------
Temperature recorder..............  Compare against             Daily................  As necessary.
                                     thermometer.
Refrigerated centrifuge...........  Observe speed and           Each day of use......   Do.
                                     temperature.
Hematocrit centrifuge.............  ..........................  .....................  Standardize before
                                                                                        initial use, after
                                                                                        repairs or adjustments,
                                                                                        and annually. Timer
                                                                                        every 3 mo.
General lab centrifuge............  ..........................  .....................  Tachometer every 6 mo.
Automated blood-typing machine....  Observe controls for        Each day of use......
                                     correct results.
Hemoglobinometer..................  Standardize against         ......do.............
                                     cyanmethemoglobin
                                     standard.
Refractometer.....................  Standardize against         ......do.............
                                     distilled water.
Blood container scale.............  Standardize against         ......do.............  As necessary.
                                     container of known weight.
Water bath........................  Observe temperature.......  ......do.............   Do.
Rh view box.......................  ......do..................  ......do.............   Do.
Autoclave.........................  ......do..................  Each time of use.....   Do.
Serologic rotators................  Observe controls for        Each day of use......  Speed as necessary.
                                     correct results.
Laboratory thermometers...........  ..........................  .....................  Before initial use.
Electronic thermometers...........  ..........................  .....................  Monthly.
Vacuum blood agitator.............  Observe weight of the       Each day of use......  Standardize with
                                     first container of blood                           container of known mass
                                     filled for correct                                 or volume before initial
                                     results.                                           use, and after repairs
                                                                                        or adjustments.
----------------------------------------------------------------------------------------------------------------

    (c) Equipment employed in the sterilization of materials used in 
blood collection or for disposition of contaminated products shall be 
designed, maintained and utilized to ensure the destruction of 
contaminating microorganisms. The effectiveness of the sterilization 
procedure shall be no less than that achieved by an attained temperature 
of 121.5 [deg]C (251 [deg]F) maintained for 20 minutes by saturated 
steam or by an attained temperature of 170 [deg]C (338 [deg]F) 
maintained for 2 hours with dry heat.

[40 FR 53532, Nov. 18, 1975; 40 FR 55849, Dec. 2, 1975, as amended at 45 
FR 9261, Feb. 12, 1980; 57 FR 11263, Apr. 2, 1992; 57 FR 12862, Apr. 13, 
1992]



Sec.  606.65  Supplies and reagents.

    All supplies and reagents used in the collection, processing, 
compatibility testing, storage and distribution of blood and blood 
components shall be stored in a safe, sanitary and orderly manner.

[[Page 48]]

    (a) All surfaces coming in contact with blood and blood components 
intended for transfusion shall be sterile, pyrogen-free, and shall not 
interact with the product in such a manner as to have an adverse effect 
upon the safety, purity, potency or effectiveness of the product. All 
final containers and closures for blood and blood components not 
intended for transfusion shall be clean and free of surface solids and 
other contaminants.
    (b) Each blood collecting container and its satellite container(s), 
if any, shall be examined visually for damage or evidence of 
contamination prior to its use and immediately after filling. Such 
examination shall include inspection for breakage of seals, when 
indicated, and abnormal discoloration. Where any defect is observed, the 
container shall not be used, or, if detected after filling, shall be 
properly discarded.
    (c) Representative samples of each lot of the following reagents or 
solutions shall be tested on a regularly scheduled basis by methods 
described in the Standard Operating Procedures Manual to determine their 
capacity to perform as required:

------------------------------------------------------------------------
           Reagent or solution                  Frequency of testing
------------------------------------------------------------------------
Anti-human globulin......................  Each day of use.
Blood grouping reagents..................   Do.
Lectins..................................   Do.
Antibody screening and reverse grouping     Do.
 cells.
Hepatitis test reagents..................  Each run.
Syphilis serology reagents...............   Do.
Enzymes..................................  Each day of use.
------------------------------------------------------------------------

    (d) Supplies and reagents that do not bear an expiration date shall 
be stored in such a manner that the oldest is used first.
    (e) Supplies and reagents shall be used in a manner consistent with 
instructions provided by the manufacturer.
    (f) Items that are required to be sterile and come into contact with 
blood should be disposable whenever possible.

[40 FR 53532, Nov. 18, 1975, as amended at 59 FR 23636, May 6, 1994]

Subpart E [Reserved]



                Subpart F_Production and Process Controls



Sec.  606.100  Standard operating procedures.

    (a) In all instances, except clinical investigations, standard 
operating procedures shall comply with published additional standards in 
part 640 of this chapter for the products being processed; except that, 
references in part 640 relating to licenses, licensed establishments and 
submission of material or data to or approval by the Director, Center 
for Biologics Evaluation and Research, are not applicable to 
establishments not subject to licensure under section 351 of the Public 
Health Service Act.
    (b) Establishments must establish, maintain, and follow written 
standard operating procedures for all steps in the collection, 
processing, compatibility testing, storage, and distribution of blood 
and blood components for allogeneic transfusion, autologous transfusion, 
and further manufacturing purposes; for all steps in the investigation 
of product deviations related to Sec.  606.171; and for all steps in 
recordkeeping related to current good manufacturing practice and other 
applicable requirements and standards. Such procedures must be available 
to the personnel for use in the areas where the procedures are 
performed. The written standard operating procedures must include, but 
are not limited to, descriptions of the following, when applicable:
    (1) Criteria used to determine donor eligibility, including 
acceptable medical history criteria.
    (2) Methods of performing donor qualifying tests and measurements, 
including minimum and maximum values for a test or procedure when a 
factor in determining acceptability.
    (3) Solutions and methods used to prepare the site of phlebotomy to 
give maximum assurance of a sterile container of blood.
    (4) Method of accurately relating the product(s) to the donor.
    (5) Blood collection procedure, including in-process precautions 
taken to measure accurately the quantity of blood removed from the 
donor.

[[Page 49]]

    (6) Methods of component preparation, including any time 
restrictions for specific steps in processing.
    (7) All tests and repeat tests performed on blood and blood 
components during manufacturing.
    (8) Pretransfusion testing, where applicable, including precautions 
to be taken to identify accurately the recipient blood samples and 
crossmatched donor units.
    (9) Procedures for investigating adverse donor and recipient 
reactions.
    (10) Storage temperatures and methods of controlling storage 
temperatures for all blood products and reagents as prescribed in 
Sec. Sec.  600.15 and 610.53 of this chapter.
    (11) Length of expiration dates, if any, assigned for all final 
products as prescribed in Sec.  610.53 of this chapter.
    (12) Criteria for determining whether returned blood is suitable for 
reissue.
    (13) Procedures used for relating a unit of blood or blood component 
from the donor to its final disposition.
    (14) Quality control procedures for supplies and reagents employed 
in blood collection, processing and pretransfusion testing.
    (15) Schedules and procedures for equipment maintenance and 
calibration.
    (16) Labeling procedures, including safeguards to avoid labeling 
mixups.
    (17) Procedures of plasmapheresis, plateletpheresis, and 
leukapheresis, if performed, including precautions to be taken to ensure 
reinfusion of a donor's own cells.
    (18) Procedures for preparing recovered plasma, if performed, 
including details of separation, pooling, labeling, storage, and 
distribution.
    (19) Procedures under Sec. Sec.  610.46 and 610.47 of this chapter:
    (i) To identify previously donated blood and blood components from a 
donor who later tests reactive for evidence of human immunodeficiency 
virus (HIV) infection or hepatitis C virus (HCV) infection when tested 
under Sec.  610.40 of this chapter, or when a blood establishment is 
made aware of other reliable test results or information indicating 
evidence of HIV or HCV infection;
    (ii) To quarantine in-date blood and blood components previously 
donated by such a donor that are intended for use in another person or 
further manufacture into injectable products, except pooled components 
intended solely for further manufacturing into products that are 
manufactured using validated viral clearance procedures;
    (iii) To notify consignees to quarantine in-date blood and blood 
components previously donated by such a donor intended for use in 
another person or for further manufacture into injectable products, 
except pooled components intended solely for further manufacturing into 
products that are manufactured using validated viral clearance 
procedures;
    (iv) To determine the suitability for release, destruction, or 
relabeling of quarantined in-date blood and blood components;
    (v) To notify consignees of the results of the HIV or HCV testing 
performed on the donors of such blood and blood components;
    (vi) To notify the transfusion recipient, the recipient's physician 
of record, or the recipient's legal representative that the recipient 
received blood or blood components at increased risk of transmitting HIV 
or HCV, respectively.
    (20) Procedures for donor deferral as prescribed in Sec.  610.41 of 
this chapter.
    (21) Procedures for donor notification and notification of the 
referring physician of an autologous donor, including procedures for the 
appropriate followup if the initial attempt at notification fails, as 
prescribed in Sec.  630.40 of this chapter.
    (22) Procedures to control the risks of bacterial contamination of 
platelets, including all steps required under Sec.  606.145.
    (c) All records pertinent to the lot or unit maintained pursuant to 
these regulations shall be reviewed before the release or distribution 
of a lot or unit of final product. The review or portions of the review 
may be performed at appropriate periods during or after blood 
collecting, processing, compatibility testing and storing. A thorough 
investigation, including the conclusions and followup, of any 
unexplained discrepancy or the failure of a lot or unit to meet any of 
its specifications shall be made and recorded.

[[Page 50]]

    (d) In addition to the requirements of this subpart and in 
conformity with this section, any facility may utilize current standard 
operating procedures such as the manuals of the organizations, as long 
as such specific procedures are consistent with, and at least as 
stringent as, the requirements contained in this part.
    (1) American Association of Blood Banks.
    (2) American National Red Cross.
    (3) Other organizations or individual blood banks, subject to 
approval by the Director, Center for Biologics Evaluation and Research.

[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55 
FR 11013, Mar. 26, 1990; 61 FR 47422, Sept. 9, 1996; 64 FR 45370, Aug. 
19, 1999; 66 FR 31176, June 11, 2001; 72 FR 48798, Aug. 24, 2007; 80 FR 
80651, Dec. 28, 2015; 80 FR 29895, May 22, 2015]



Sec.  606.110  Plateletpheresis, leukapheresis, and plasmapheresis.

    (a) The use of plateletpheresis and leukapheresis procedures to 
obtain a product for a specific recipient may be at variance with the 
additional standards for specific products prescribed in this part 
provided that: (1) A physician has determined that the recipient must be 
transfused with the leukocytes or platelets from a specific donor, and 
(2) the procedure is performed under the supervision of a responsible 
physician who is aware of the health status of the donor, and the 
physician has determined and documented that the donor's health permits 
plateletpheresis or leukapheresis.
    (b) Plasmapheresis of donors who do not meet the donor requirements 
of Sec. Sec.  630.10, 630.15, 640.64 and 640.65 of this chapter for the 
collection of plasma containing rare antibodies shall be permitted only 
with the prior approval of the Director, Center for Biologics Evaluation 
and Research.

[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55 
FR 11013, Mar. 26, 1990; 80 FR 29895, May 22, 2015]



 Subpart G_Additional Labeling Standards for Blood and Blood Components



Sec.  606.120  Labeling, general requirements.

    (a) Labeling operations shall be separated physically or spatially 
from other operations in a manner adequate to prevent mixups.
    (b) The labeling operation shall include the following labeling 
controls:
    (1) Labels shall be held upon receipt, pending review and proofing 
against an approved final copy, to ensure accuracy regarding identity, 
content, and conformity with the approved copy.
    (2) Each type of label representing different products shall be 
stored and maintained in a manner to prevent mixups, and stocks of 
obsolete labels shall be destroyed.
    (3) All necessary checks in labeling procedures shall be utilized to 
prevent errors in translating test results to container labels.
    (c) All labeling shall be clear and legible.

[50 FR 35469, Aug. 30, 1985]



Sec.  606.121  Container label.

    (a) The container label requirements are designed to facilitate the 
use of a uniform container label for blood and blood components intended 
for use in transfusion or further manufacture by all blood 
establishments.
    (b) The label provided by the collecting facility and the initial 
processing facility must not be removed, altered, or obscured, except 
that the label may be altered to indicate the proper name of the 
product, with any appropriate modifiers and attributes, and other 
information required to identify accurately the contents of a container 
after blood components considered finished products have been prepared.
    (c) The container label must include the following information, as 
well as other specialized information as required in this section for 
specific products:
    (1) The proper name of the product in a prominent position, with any 
appropriate modifiers and attributes.

[[Page 51]]

    (2) The name, address, unique facility identifier, and, if a 
licensed product, the license number of each manufacturer; except the 
container label for blood and blood components for further manufacture 
is not required to include a unique facility identifier.
    (3) The donor or lot number relating the unit to the donor. If 
pooled, all donor numbers, all donation numbers, or a pool number that 
is traceable to each individual unit comprising the pool.
    (4)(i) The expiration date, including the day, month, and year, and, 
if the dating period for the product is 72 hours or less, including any 
product prepared in a system that might compromise sterility, the hour 
of expiration.
    (ii) If Source Plasma intended for manufacturing into noninjectable 
products is pooled, the expiration date for the pool is determined from 
the collection date of the oldest unit in the pool, and the pooling 
records must show the collection date for each unit in the pool.
    (5) For Whole Blood, Plasma, Platelets, and partial units of Red 
Blood Cells, the volume of the product, accurate to within 10 percent; or optionally for Platelets, the volume or 
volume range within reasonable limits.
    (6) Where applicable, the name and volume of source material.
    (7) The recommended storage temperature (in degrees Celsius).
    (8) If the product is intended for transfusion, the statements:
    (i) ``Rx only.''
    (ii) ``See circular of information for indications, 
contraindications, cautions, and methods of infusion.''
    (iii) ``Properly identify intended recipient.''
    (iv) ``This product may transmit infectious agents.''
    (v) The appropriate donor classification statement, i.e., ``paid 
donor'' or ``volunteer donor,'' in no less prominence than the proper 
name of the product.
    (A) A paid donor is a person who receives monetary payment for a 
blood donation.
    (B) A volunteer donor is a person who does not receive monetary 
payment for a blood donation.
    (C) Benefits, such as time off from work, membership in blood 
assurance programs, and cancellation of nonreplacement fees that are not 
readily convertible to cash, do not constitute monetary payment within 
the meaning of this paragraph.
    (9) If the product is intended for transfusion or as is otherwise 
appropriate, the ABO group and Rh type of the donor must be designated 
conspicuously. For Cryoprecipitated Antihemophiliac Factor (AHF), the Rh 
type may be omitted. The Rh type must be designated as follows:
    (i) If the test using Anti-D Blood Grouping Reagent is positive, the 
product must be labeled: ``Rh positive.''
    (ii) If the test using Anti-D Blood Grouping Reagent is negative, 
but the test for weak D (formerly Du) is positive, the 
product must be labeled: ``Rh positive.''
    (iii) If the test using Anti-D Blood Grouping Reagent is negative 
and the test for weak D (formerly Du) is negative, the 
product must be labeled: ``Rh negative.''
    (10) If the product is not intended for transfusion, a statement as 
applicable: ``Caution: For Manufacturing Use Only,'' or ``Caution: For 
Use in Manufacturing Noninjectable Products Only,'' or other cautionary 
statement as approved by the Director, Center for Biologics Evaluation 
and Research (CBER).
    (11) If the product is intended for further manufacturing use, a 
statement listing the results of all the tests for relevant transfusion-
transmitted infections required under Sec.  610.40 of this chapter for 
which the donation has been tested and found negative; except that the 
container label for Source Plasma is not required to list the negative 
results of serological syphilis testing under Sec.  640.65(b) of this 
chapter.
    (12) The blood and blood components must be labeled in accordance 
with Sec.  610.40 of this chapter, when the donation is tested and 
demonstrates evidence of infection due to a relevant transfusion-
transmitted infection(s).
    (13) The container label of blood or blood components intended for 
transfusion must bear encoded information in a format that is machine-
readable

[[Page 52]]

and approved for use by the Director, CBER.
    (i) Who is subject to this machine-readable requirement? All blood 
establishments that manufacture, process, repack, or relabel blood or 
blood components intended for transfusion and regulated under the 
Federal Food, Drug, and Cosmetic Act or the Public Health Service Act.
    (ii) What blood products are subject to this machine-readable 
requirement? All blood and blood components intended for transfusion are 
subject to the machine-readable information label requirement in this 
section.
    (iii) What information must be machine-readable? Each label must 
have machine-readable information that contains, at a minimum:
    (A) A unique facility identifier;
    (B) Lot number relating to the donor;
    (C) Product code; and
    (D) ABO and Rh of the donor, except as described in paragraphs 
(c)(9) and (i)(5) of this section.
    (iv) How must the machine-readable information appear? The machine-
readable information must:
    (A) Be unique to the blood or blood component;
    (B) Be surrounded by sufficient blank space so that the machine-
readable information can be scanned correctly; and
    (C) Remain intact under normal conditions of use.
    (v) Where does the machine-readable information go? The machine-
readable information must appear on the label of any blood or blood 
component which is or can be transfused to a patient or from which the 
blood or blood component can be taken and transfused to a patient.
    (d) Unless otherwise approved by the Director, CBER, the container 
label for blood and blood components intended for transfusion must be 
white and print must be solid black, with the following additional 
exceptions:
    (1) The ABO and Rh blood groups must be printed as follows:
    (i) Rh positive: Use black print on white background and use solid 
black or other solid color for ABO.
    (ii) Rh negative: Use white print on black background for Rh and use 
black outline on a white background for ABO.
    (2) The proper name of the product, with any appropriate modifiers 
and attributes, the donor classification statement, and the statement 
``properly identify intended recipient'' may be printed in solid red or 
in solid black.
    (3) The following color scheme may be used for differentiating ABO 
Blood groups:

------------------------------------------------------------------------
                 Blood group                        Color of label
------------------------------------------------------------------------
O...........................................  Blue
A...........................................  Yellow
B...........................................  Pink
AB..........................................  White
------------------------------------------------------------------------

    (4) Special labels, such as those described in paragraphs (h) and 
(i) of this section, may be color-coded.
    (e) Container label requirements for particular products or groups 
of products.
    (1) Whole Blood labels must include:
    (i) The name of the applicable anticoagulant approved for use by the 
Director, CBER.
    (ii) The volume of anticoagulant.
    (iii) If tests for unexpected antibodies are positive, blood 
intended for transfusion must be labeled: ``Contains (name of 
antibody).''
    (2) Except for frozen, deglycerolized, or washed Red Blood Cell 
products, Red Blood Cell labels must include:
    (i) The type of anticoagulant, and if applicable, the volume of 
Whole Blood and type of additive solution, with which the product was 
prepared.
    (ii) If tests for unexpected antibodies are positive and the product 
is intended for transfusion, the statement: ``Contains (name of 
antibody).''
    (3) If tests for unexpected antibodies are positive, Plasma intended 
for transfusion must be labeled: ``Contains (name of antibody).''
    (4) Recovered plasma labels must include:
    (i) In lieu of an expiration date, the date of collection of the 
oldest material in the container.
    (ii) For recovered plasma not meeting the requirements for 
manufacture into licensable products, the statement: ``Not for Use in 
Products Subject to License Under Section 351 of the Public Health 
Service Act.''

[[Page 53]]

    (iii) The type of anticoagulant with which the product was prepared.
    (5) Source Plasma labels must include the following information:
    (i) The cautionary statement, as specified in paragraph (c)(10) of 
this section, must follow the proper name with any appropriate modifiers 
and attributes and be of similar prominence as the proper name.
    (ii) The statement ``Store at -20 [deg]C or colder,'' provided, that 
where plasma is intended for manufacturing into noninjectable products, 
this statement may be replaced by a statement of the temperature 
appropriate for manufacture of the final product to be prepared from the 
plasma.
    (iii) The total volume or weight of plasma and total quantity and 
type of anticoagulant used.
    (iv) When plasma collected from a donor is reactive for a serologic 
test for syphilis, a statement that the plasma is reactive and must be 
used only for the manufacturing of positive control reagents for the 
serologic test for syphilis.
    (v) Source Plasma diverted for Source Plasma Salvaged must be 
relabeled ``Source Plasma Salvaged'' as prescribed in Sec.  640.76 of 
this chapter. Immediately following the proper name of the product, with 
any appropriate modifiers and attributes, the labeling must prominently 
state as applicable, ``STORAGE TEMPERATURE EXCEEDED -20 [deg]C'' or 
``SHIPPING TEMPERATURE EXCEEDED -5 [deg]C.''
    (vi) A statement as to whether the plasma was collected from normal 
donors, or from donors in specific collection programs approved by the 
Director, CBER. In the case of specific collection programs, the label 
must state the defining characteristics of the plasma. In the case of 
immunized donors, the label must state the immunizing antigen.
    (f) Blood and blood components determined to be unsuitable for 
transfusion must be prominently labeled ``NOT FOR TRANSFUSION,'' and the 
label must state the reason the unit is considered unsuitable. The 
provision does not apply to blood and blood components intended solely 
for further manufacture.
    (g) [Reserved]
    (h) The following additional information must appear on the label 
for blood and blood components shipped in an emergency prior to 
completion of required tests, in accordance with Sec.  610.40(g) of this 
chapter:
    (1) The statement: ``FOR EMERGENCY USE ONLY BY __ .''
    (2) Results of any tests prescribed under Sec. Sec.  610.40 and 
640.5(b) or (c) of this chapter completed before shipment.
    (3) Indication of any tests prescribed under Sec. Sec.  610.40 and 
640.5(b) or (c) of this chapter not completed before shipment.
    (i) The following additional information must appear on the label 
for blood and blood components intended for autologous transfusion:
    (1) Information adequately identifying the patient, e.g., name, date 
of birth, hospital, and identification number.
    (2) Date of donation.
    (3) The statement: ``AUTOLOGOUS DONOR.''
    (4) The ABO and Rh blood group and type, except as provided in 
paragraph (c)(9) of this section.
    (5) Each container of blood and blood component intended for 
autologous use and obtained from a donor who fails to meet any of the 
donor eligibility requirements under Sec.  630.10 of this chapter or who 
is reactive to or positive for one or more tests for evidence of 
infection due to relevant transfusion-transmitted infections under Sec.  
610.40 of this chapter must be prominently and permanently labeled ``FOR 
AUTOLOGOUS USE ONLY'' and as otherwise required under Sec.  610.40 of 
this chapter. Such units also may have the ABO and Rh blood group and 
type on the label.
    (6) Units of blood and blood components originally intended for 
autologous use, except those labeled as prescribed under paragraph 
(i)(5) of this section, may be issued for allogeneic transfusion 
provided the container label complies with all applicable provisions of 
paragraphs (b) through (e) of this section. In such case, the special 
label required under paragraphs (i)(1), (i)(2), and (i)(3) of this 
section must be removed or otherwise obscured.
    (j) A tie-tag attached to the container may be used for providing 
the information required by paragraphs

[[Page 54]]

(e)(1)(iii), (e)(2)(ii), and (e)(3), (h), or (i)(1), (i)(2), and (i)(3) 
of this section.

[77 FR 16, Jan. 3, 2012, as amended at 80 FR 29895, May 22, 2015]



Sec.  606.122  Circular of information.

    A circular of information must be available for distribution if the 
product is intended for transfusion. The circular of information must 
provide adequate directions for use, including the following 
information:
    (a) Instructions to mix the product before use.
    (b) Instructions to use a filter in the administration equipment.
    (c) The statement ``Do Not Add Medications'' or an explanation 
concerning allowable additives.
    (d) A description of the product, its source, and preparation, 
including the name and proportion of the anticoagulant used in 
collecting the Whole Blood from each product is prepared.
    (e) A statement that the product was prepared from blood that was 
found negative when tested for relevant transfusion-transmitted 
infections, as required under Sec.  610.40 of this chapter (include each 
test that was performed).
    (f) The statement: ``Warning: The risk of transmitting infectious 
agents is present. Careful donor selection and available laboratory 
tests do not eliminate the hazard.''
    (g) The names of cryoprotective agents and other additives that may 
still be present in the product.
    (h) The names and results of all tests performed when necessary for 
safe and effective use.
    (i) The use of the product, indications, contradications, side 
effects and hazards, dosage and administration recommendations.
    (j) [Reserved]
    (k) For Red Blood Cells, the circular of information must contain:
    (1) Instructions to administer a suitable plasma volume expander if 
Red Blood Cells are substituted when Whole Blood is the indicated 
product.
    (2) A warning not to add Lactated Ringer's Injection U.S.P. solution 
to Red Blood Cell products.
    (l) For Platelets, the circular of information must contain:
    (1) The approximate volume of plasma from which a sample unit of 
Platelets is prepared.
    (2) Instructions to begin administration as soon as possible, but 
not more than 4 hours after entering the container.
    (m) For Plasma, the circular of information must contain:
    (1) A warning against further processing of the frozen product if 
there is evidence of breakage or thawing.
    (2) Instructions to thaw the frozen product at a temperature 
appropriate for the product.
    (3) When applicable, instructions to begin administration of the 
product within a specified time after thawing.
    (4) Instructions to administer to ABO-group-compatible recipients.
    (5) A statement that this product has the same risk of transmitting 
infectious agents as Whole Blood; other plasma volume expanders without 
this risk are available for treating hypovolemia.
    (n) For Cryoprecipitated AHF, the circular of information must 
contain:
    (1) A statement that the average potency is 80 or more International 
Units of antihemophilic factor.
    (2) The statement: ``Usually contains at least 150 milligrams of 
fibrinogen''; or, alternatively, the average fibrinogen level determined 
by assay of representative units.
    (3) A warning against further processing of the product if there is 
evidence of breakage or thawing.
    (4) Instructions to thaw the product for no more than 15 minutes at 
a temperature of between 30 and 37 [deg]C.
    (5) Instructions to store at room temperature after thawing and to 
begin administration as soon as possible but no more than 4 hours after 
entering the container or after pooling and within 6 hours after 
thawing.
    (6) A statement that 0.9 percent Sodium Chloride Injection U.S.P. is 
the preferred diluent.
    (7) Adequate instructions for pooling to ensure complete removal of 
all concentrated material from each container.
    (8) The statement: ``Good patient management requires monitoring 
treatment responses to Cryoprecipitated AHF transfusions

[[Page 55]]

with periodic plasma factor VIII or fibrinogen assays in hemophilia A 
and hypofibrinogenemic recipients, respectively.''

[50 FR 35470, Aug. 30, 1985, as amended at 53 FR 116, Jan. 5, 1988; 64 
FR 45371, Aug. 19, 1999; 77 FR 18, Jan. 3, 2012; 80 FR 29895, May 22, 
2015]



                      Subpart H_Laboratory Controls



Sec.  606.140  Laboratory controls.

    Laboratory control procedures shall include:
    (a) The establishment of scientifically sound and appropriate 
specifications, standards and test procedures to assure that blood and 
blood components are safe, pure, potent and effective.
    (b) Adequate provisions for monitoring the reliability, accuracy, 
precision and performance of laboratory test procedures and instruments.
    (c) Adequate identification and handling of all test samples so that 
they are accurately related to the specific unit of product being 
tested, or to its donor, or to the specific recipient, where applicable.



Sec.  606.145  Control of bacterial contamination of platelets.

    (a) Blood collection establishments and transfusion services must 
assure that the risk of bacterial contamination of platelets is 
adequately controlled using FDA approved or cleared devices or other 
adequate and appropriate methods found acceptable for this purpose by 
FDA.
    (b) In the event that a blood collection establishment identifies 
platelets as bacterially contaminated, that establishment must not 
release for transfusion the product or any other component prepared from 
the same collection, and must take appropriate steps to identify the 
organism.
    (c) In the event that a transfusion service identifies platelets as 
bacterially contaminated, the transfusion service must not release the 
product and must notify the blood collection establishment that provided 
the platelets. The transfusion service must take appropriate steps to 
identify the organism; these steps may include contracting with the 
collection establishment or a laboratory to identify the organism. The 
transfusion service must further notify the blood collection 
establishment either by providing information about the species of the 
contaminating organism when the transfusion service has been able to 
identify it, or by advising the blood collection establishment when the 
transfusion service has determined that the species cannot be 
identified.
    (d) In the event that a contaminating organism is identified under 
paragraph (b) or (c) of this section, the collection establishment's 
responsible physician, as defined in Sec.  630.3(i) of this chapter, 
must determine whether the contaminating organism is likely to be 
associated with a bacterial infection that is endogenous to the 
bloodstream of the donor, in accordance with a standard operating 
procedure developed under Sec.  606.100(b)(22). This determination may 
not be further delegated.

[80 FR 29895, May 22, 2015]



Sec.  606.151  Compatibility testing.

    Standard operating procedures for compatibility testing shall 
include the following:
    (a) A method of collecting and identifying the blood samples of 
recipients to ensure positive identification.
    (b) The use of fresh recipient serum or plasma samples less than 3 
days old for all pretransfusion testing if the recipient has been 
pregnant or transfused within the previous 3 months.
    (c) Procedures to demonstrate incompatibility between the donor's 
cell type and the recipient's serum or plasma type.
    (d) A provision that, if the unit of donor's blood has not been 
screened by a method that will demonstrate agglutinating, coating and 
hemolytic antibodies, the recipient's cells shall be tested with the 
donor's serum (minor crossmatch) by a method that will so demonstrate.
    (e) Procedures to expedite transfusion in life-threatening 
emergencies. Records of all such incidents shall be maintained, 
including complete documentation justifying the emergency

[[Page 56]]

action, which shall be signed by a physician.

[40 FR 53532, Nov. 18, 1975, as amended at 64 FR 45371, Aug. 19, 1999; 
66 FR 1835, Jan. 10, 2001; 66 FR 40889, Aug. 6, 2001]



                      Subpart I_Records and Reports



Sec.  606.160  Records.

    (a)(1) Records shall be maintained concurrently with the performance 
of each significant step in the collection, processing, compatibility 
testing, storage and distribution of each unit of blood and blood 
components so that all steps can be clearly traced. All records shall be 
legible and indelible, and shall identify the person performing the 
work, include dates of the various entries, show test results as well as 
the interpretation of the results, show the expiration date assigned to 
specific products, and be as detailed as necessary to provide a complete 
history of the work performed.
    (2) Appropriate records shall be available from which to determine 
lot numbers of supplies and reagents used for specific lots or units of 
the final product.
    (b) Records shall be maintained that include, but are not limited 
to, the following when applicable:
    (1) Donor records:
    (i) Donor selection, including medical interview and examination and 
where applicable, informed consent.
    (ii) Permanent and temporary deferrals for health reasons including 
reason(s) for deferral.
    (iii) Donor adverse reaction complaints and reports, including 
results of all investigations and followup.
    (iv) Therapeutic bleedings, including signed requests from attending 
physicians, the donor's disease and disposition of units.
    (v) Immunization, including informed consent, identification of the 
antigen, dosage and route of administration.
    (vi) Blood collection, including identification of the phlebotomist.
    (vii) Records to relate the donor with the unit number of each 
previous donation from that donor.
    (viii) Records concerning the following activities performed under 
Sec. Sec.  610.46 and 610.47 of this chapter: Quarantine; consignee 
notification; testing; notification of a transfusion recipient, the 
recipient's physician of record, or the recipient's legal 
representative; and disposition.
    (ix) The donor's postal address provided at the time of donation 
where the donor may be contacted within 8 weeks after donation.
    (x) Records of notification of donors deferred or determined not to 
be eligible for donation, including appropriate followup if the initial 
attempt at notification fails, performed under Sec.  630.40 of this 
chapter.
    (xi) Records of notification of the referring physician of a 
deferred autologous donor, including appropriate followup if the initial 
attempt at notification fails, performed under Sec.  630.40 of this 
chapter.
    (2) Processing records:
    (i) Blood processing, including results and interpretation of all 
tests and retests.
    (ii) Component preparation, including all relevant dates and times.
    (iii) Separation and pooling of recovered plasma.
    (iv) Centrifugation and pooling of source plasma.
    (v) Labeling, including initials of the person(s) performing the 
procedure.
    (3) Storage and distribution records:
    (i) Distribution and disposition, as appropriate, of blood and blood 
products.
    (ii) Visual inspection of whole blood and red blood cells during 
storage and immediately before distribution.
    (iii) Storage temperature, including initialed temperature recorder 
charts.
    (iv) Reissue, including records of proper temperature maintenance.
    (v) Emergency release of blood, including signature of requesting 
physician obtained before or after release.
    (4) Compatibility test records:
    (i) Results of all compatibility tests, including crossmatching, 
testing of patient samples, antibody screening and identification.
    (ii) Results of confirmatory testing.
    (5) Quality control records:
    (i) Calibration and standardization of equipment.
    (ii) Performance checks of equipment and reagents.
    (iii) Periodic check on sterile technique.

[[Page 57]]

    (iv) Periodic tests of capacity of shipping containers to maintain 
proper temperature in transit.
    (v) Proficiency test results.
    (6) Transfusion reaction reports and complaints, including records 
of investigations and followup.
    (7) General records:
    (i) Sterilization of supplies and reagents prepared within the 
facility, including date, time interval, temperature and mode.
    (ii) Responsible personnel.
    (iii) Biological product deviations.
    (iv) Maintenance records for equipment and general physical plant.
    (v) Supplies and reagents, including name of manufacturer or 
supplier, lot numbers, expiration date and date of receipt.
    (vi) Disposition of rejected supplies and reagents used in the 
collection, processing and compatibility testing of blood and blood 
components.
    (c) A donor number shall be assigned to each accepted donor, which 
relates the unit of blood collected to that donor, to his medical 
record, to any component or blood product from that donor's unit of 
blood, and to all records describing the history and ultimate 
disposition of these products.
    (d) Records shall be retained for such interval beyond the 
expiration date for the blood or blood component as necessary to 
facilitate the reporting of any unfavorable clinical reactions. You must 
retain individual product records no less than 10 years after the 
records of processing are completed or 6 months after the latest 
expiration date for the individual product, whichever is the later date. 
When there is no expiration date, records shall be retained 
indefinitely.
    (e) Records of deferred donors. (1) Establishments must maintain at 
each location a record of all donors found to be ineligible or deferred 
at that location so that blood and blood components from an ineligible 
donor are not collected and/or released while the donor is ineligible or 
deferred; and
    (2) Establishments must maintain at all locations operating under 
the same license or under common management a cumulative record of 
donors deferred from donation under Sec.  610.41 of this chapter because 
their donation tested reactive under Sec.  610.40(a)(1) of this chapter 
for evidence of infection due to HIV, HBV, or HCV. In addition, 
establishments other than Source Plasma establishments must include in 
this cumulative record donors deferred from donation under Sec.  610.41 
of this chapter because their donation tested reactive under Sec.  
610.40(a)(2) of this chapter for evidence of infection due to HTLV or 
Chagas disease.
    (3) The cumulative record described in paragraph (e)(2) of this 
section must be updated at least monthly to add donors newly deferred 
under Sec.  610.41 of this chapter due to reactive tests for evidence of 
infection due to HIV, HBV, or HCV, and, if applicable, HTLV or Chagas 
disease.
    (4) Establishments must revise the cumulative record described in 
paragraph (e)(2) of this section to remove donors who have been 
requalified under Sec.  610.41(b) of this chapter.

[40 FR 53532, Nov. 18, 1975, as amended at 61 FR 47422, Sept. 9, 1996; 
64 FR 45371, Aug. 19, 1999; 65 FR 66635, Nov. 7, 2000; 66 FR 31176, June 
11, 2001; 72 FR 48798, Aug. 24, 2007; 80 FR 80651, Dec. 28, 2015; 80 FR 
29895, May 22, 2015]



Sec.  606.165  Distribution and receipt; procedures and records.

    (a) Distribution and receipt procedures shall include a system by 
which the distribution or receipt of each unit can be readily determined 
to facilitate its recall, if necessary.
    (b) Distribution records shall contain information to readily 
facilitate the identification of the name and address of the consignee, 
the date and quantity delivered, the lot number of the unit(s), the date 
of expiration or the date of collection, whichever is applicable, or for 
crossmatched blood and blood components, the name of the recipient.
    (c) Receipt records shall contain the name and address of the 
collecting facility, date received, donor or lot number assigned by the 
collecting facility and the date of expiration or the date of 
collection, whichever is applicable.



Sec.  606.170  Adverse reaction file.

    (a) Records shall be maintained of any reports of complaints of 
adverse reactions regarding each unit of blood or blood product arising 
as a result of

[[Page 58]]

blood collection or transfusion. A thorough investigation of each 
reported adverse reaction shall be made. A written report of the 
investigation of adverse reactions, including conclusions and followup, 
shall be prepared and maintained as part of the record for that lot or 
unit of final product by the collecting or transfusing facility. When it 
is determined that the product was at fault in causing a transfusion 
reaction, copies of all such written reports shall be forwarded to and 
maintained by the manufacturer or collecting facility.
    (b) When a complication of blood collection or transfusion is 
confirmed to be fatal, the Director, Office of Compliance and Biologics 
Quality, CBER, must be notified by telephone, facsimile, express mail, 
or electronically transmitted mail as soon as possible. A written report 
of the investigation must be submitted to the Director, Office of 
Compliance and Biologics Quality, CBER, by mail, facsimile, or 
electronically transmitted mail (for mailing address, see Sec.  600.2(a) 
of this chapter), within 7 days after the fatality by the collecting 
facility in the event of a donor reaction, or by the facility that 
performed the compatibility tests in the event of a transfusion 
reaction.

[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 50 
FR 35471, Aug. 30, 1985; 55 FR 11014, Mar. 26, 1990; 64 FR 45371, Aug. 
19, 1999; 67 FR 9586, Mar. 4, 2002; 77 FR 18, Jan. 3, 2012; 80 FR 18092, 
Apr. 3, 2015]



Sec.  606.171  Reporting of product deviations by licensed manufacturers,
unlicensed registered blood establishments, and transfusion services.

    (a) Who must report under this section? You, a licensed manufacturer 
of blood and blood components, including Source Plasma; an unlicensed 
registered blood establishment; or a transfusion service who had control 
over the product when the deviation occurred, must report under this 
section. If you arrange for another person to perform a manufacturing, 
holding, or distribution step, while the product is in your control, 
that step is performed under your control. You must establish, maintain, 
and follow a procedure for receiving information from that person on all 
deviations, complaints, and adverse events concerning the affected 
product.
    (b) What do I report under this section? You must report any event, 
and information relevant to the event, associated with the 
manufacturing, to include testing, processing, packing, labeling, or 
storage, or with the holding or distribution, of both licensed and 
unlicensed blood or blood components, including Source Plasma, if that 
event meets all the following criteria:
    (1) Either:
    (i) Represents a deviation from current good manufacturing practice, 
applicable regulations, applicable standards, or established 
specifications that may affect the safety, purity, or potency of that 
product; or
    (ii) Represents an unexpected or unforeseeable event that may affect 
the safety, purity, or potency of that product; and
    (2) Occurs in your facility or another facility under contract with 
you; and
    (3) Involves distributed blood or blood components.
    (c) When do I report under this section? You should report a 
biological product deviation as soon as possible but you must report at 
a date not to exceed 45-calendar days from the date you, your agent, or 
another person who performs a manufacturing, holding, or distribution 
step under your control, acquire information reasonably suggesting that 
a reportable event has occurred.
    (d) How do I report under this section? You must report on Form FDA-
3486.
    (e) Where do I report under this section? You must send the 
completed Form FDA 3486 to the Center for Biologics Evaluation and 
Research (CBER), either in paper or electronic format.
    (1) If you make a paper filing, send the completed form to the CBER 
Document Control Center (see mailing address in Sec.  600.2(a) of this 
chapter), and identify on the envelope that a BPDR (biological product 
deviation report) is enclosed; or
    (2) If you make an electronic filing, send the completed Form 
FDA3486 electronically using CBER's electronic Web-based application.
    (f) How does this regulation affect other FDA regulations? This part 
supplements and does not supersede other provisions of the regulations 
in this chapter. All

[[Page 59]]

biological product deviations, whether or not they are required to be 
reported under this section, should be investigated in accordance with 
the applicable provisions of parts 211, 606, and 820 of this chapter.

[65 FR 66635, Nov. 7, 2000, as amended at 70 FR 14984, Mar. 24, 2005; 80 
FR 18092, Apr. 3, 2015]



PART 607_ESTABLISHMENT REGISTRATION AND PRODUCT LISTING FOR MANUFACTURERS
OF HUMAN BLOOD AND BLOOD PRODUCTS AND LICENSED DEVICES--Table of Contents



                      Subpart A_General Provisions

Sec.
607.1 Scope.
607.3 Definitions.
607.7 Establishment registration and product listing of blood banks and 
          other firms manufacturing human blood and blood products.

     Subpart B_Procedures for Domestic Blood Product Establishments

607.20 Who must register and submit a blood product list.
607.21 Times for establishment registration and blood product listing.
607.22 How to register establishments and list blood products.
607.25 Information required for establishment registration and blood 
          product listing.
607.26 Amendments to establishment registration.
607.30 Updating blood product listing information.
607.31 Additional blood product listing information.
607.35 Blood product establishment registration number.
607.37 Public disclosure of establishment registration and blood product 
          listing information.
607.39 Misbranding by reference to establishment registration, 
          validation of registration, or to registration number.

      Subpart C_Procedures for Foreign Blood Product Establishments

607.40 Establishment registration and blood product listing requirements 
          for foreign blood product establishments.

                          Subpart D_Exemptions

607.65 Exemptions for blood product establishments.

  Subpart E_Establishment Registration and Product Listing Of Licensed 
                                 Devices

607.80 Applicability of part 607 to licensed devices.

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

    Source: 40 FR 52788, Nov. 12, 1975, unless otherwise noted.



                      Subpart A_General Provisions



Sec.  607.1  Scope.

    (a) This part establishes establishment registration and product 
listing requirements for manufacturers of human blood and blood 
products.
    (b) This part establishes establishment registration and product 
listing requirements for manufacturers of products that meet the 
definition of a device under the Federal Food, Drug, and Cosmetic Act 
and that are licensed under section 351 of the Public Health Service 
Act, as well as licensed biological products used in the manufacture of 
a licensed device.

[81 FR 60221, Aug. 31, 2016]



Sec.  607.3  Definitions.

    (a) The term act means the Federal Food, Drug, and Cosmetic Act 
approved June 25, 1938 (52 Stat. 1040 et seq., as amended, 21 U.S.C. 
301-392).
    (b) Blood and blood product means a drug which consists of human 
whole blood, plasma, or serum or any product derived from human whole 
blood, plasma, or serum, hereinafter referred to as ``blood product.'' 
For the purposes of this part only, blood and blood product also means 
those products that meet the definition of a device under the Federal 
Food, Drug, and Cosmetic Act and that are licensed under section 351 of 
the Public Health Service Act, as well as licensed biological products 
used in the manufacture of a licensed device.
    (c) Establishment means a place of business under one management at 
one general physical location. The term includes, among others, human 
blood and plasma donor centers, blood banks,

[[Page 60]]

transfusion services, other blood product manufacturers and independent 
laboratories that engage in quality control and testing for registered 
blood product establishments.
    (d) Manufacture means the collection, preparation, processing or 
compatibility testing by chemical, physical, biological, or other 
procedures of any blood product which meets the definition of a drug as 
defined in section 201(g) of the act, and including manipulation, 
sampling, testing, or control procedures applied to the final product or 
to any part of the process. The term includes packaging, labeling, 
repackaging or otherwise changing the container, wrapper, or labeling of 
any blood product package in furtherance of the distribution of the 
blood product from the original place of manufacture to the person who 
makes final delivery or sale to the ultimate consumer.
    (e) Commercial distribution means any distribution of a blood 
product except under the investigational use provisions of part 312 of 
this chapter, but does not include internal or interplant transfer of a 
bulk product substance between registered establishments within the same 
parent, subsidiary, and/or affiliate company. For foreign 
establishments, the term ``commercial distribution'' shall have the same 
meaning except that the term shall not include distribution of any blood 
or blood product that is neither imported nor offered for import into 
the United States.
    (f) Any material change includes but is not limited to any change in 
the name of the blood product, in the quantity or identity of the active 
ingredient(s) or in the quantity or identity of the inactive 
ingredient(s) where quantitative listing of all ingredients is required 
pursuant to Sec.  607.31(a)(2) and any significant change in the 
labeling of a blood product. Changes that are not significant include 
changes in arrangement or printing or changes of an editorial nature.
    (g) Bulk product substance means any substance that is represented 
for use in a blood product and when used in the manufacturing of a blood 
product becomes an active ingredient or a finished dosage form of such 
product.
    (h) Advertising and labeling include the promotional material 
described in Sec.  202.1(l) (1) and (2) of this chapter, respectively.
    (i) The definitions and interpretations contained in sections 201 
and 510 of the act shall be applicable to such terms when used in this 
part 607.
    (j) United States agent means a person residing or maintaining a 
place of business in the United States whom a foreign establishment 
designates as its agent. This definition excludes mailboxes, answering 
machines or services, or other places where an individual acting as the 
foreign establishment's agent is not physically present.
    (k) Importer means a person in the United States that is an owner, 
consignee, or recipient, at the time of entry, of a foreign 
establishment's blood product that is imported into the United States.
    (l) Foreign for the purpose of registration and listing under this 
part when used to modify the term ``establishment'' refers to an 
establishment that is located in a foreign country and is the site where 
a blood product that is imported or offered for import into the United 
States was manufactured.

[40 FR 52788, Nov. 12, 1975, as amended at 55 FR 11014, Mar. 26, 1990; 
66 FR 59158, Nov. 27, 2001; 81 FR 60222, Aug. 31, 2016]



Sec.  607.7  Establishment registration and product listing of blood 
banks and other firms manufacturing human blood and blood products.

    All owners or operators of establishments that engage in the 
manufacturing of blood products are required to register, pursuant to 
section 510 of the Federal Food, Drug, and Cosmetic Act. Registration 
and listing of blood products must comply with this part. Registration 
does not permit any blood bank or similar establishment to ship blood 
products in interstate commerce.

[81 FR 60222, Aug. 31, 2016]

[[Page 61]]



     Subpart B_Procedures for Domestic Blood Product Establishments



Sec.  607.20  Who must register and submit a blood product list.

    (a) Owners or operators of all establishments, not exempt under 
section 510(g) of the act or subpart D of this part, that engage in the 
manufacture of blood products shall register and submit a list of every 
blood product in commercial distribution (except that registration and 
listing information may be submitted by the parent, subsidiary, and/or 
affiliate company for all establishments when operations are conducted 
at more than one establishment and there exists joint ownership and 
control among all the establishments). Blood products manufactured, 
prepared, propagated, compounded, or processed in any State as defined 
in section 201(a)(1) of the act must be listed whether or not the output 
of such blood product establishment or any particular blood product so 
listed enters interstate commerce.
    (b) Preparatory to engaging in the manufacture of blood products, 
owners or operators of establishments who are submitting a biologics 
license application to manufacture blood products are required to 
register before the biologics license application is approved.
    (c) Except in the case of licensed device manufacturers, no 
registration fee is required. Establishment registration and blood 
product listing do not constitute an admission or agreement or 
determination that a blood product is a ``drug'' within the meaning of 
section 201(g) of the act.

[40 FR 52788, Nov. 12, 1975, as amended at 64 FR 56452, Oct. 20, 1999; 
66 FR 59158, Nov. 27, 2001; 81 FR 60222, Aug. 31, 2016]



Sec.  607.21  Times for establishment registration and blood product
listing.

    The owner or operator of an establishment entering into an operation 
defined in Sec.  607.3(d) shall register such establishment within 5 
days after the beginning of such operation and submit a list of every 
blood product in commercial distribution at the time. If the owner or 
operator of the establishment has not previously entered into such 
operation (defined in Sec.  607.3(d) of this chapter) for which a 
license is required, registration shall follow within 5 days after the 
submission of a biologics license application in order to manufacture 
blood products. Owners or operators of all establishments so engaged 
must register annually between October 1 and December 31 and must update 
their blood product listing every June and December.

[40 FR 52788, Nov. 12, 1975, as amended at 64 FR 56453, Oct. 20, 1999; 
81 FR 60222, Aug. 31, 2016]



Sec.  607.22  How to register establishments and list blood products.

    (a) Initial and subsequent registrations and product listings must 
be submitted electronically through the Blood Establishment Registration 
and Product Listing system, or any future superseding electronic system. 
This information must be submitted in accordance with part 11 of this 
chapter, except for the requirements in Sec.  11.10(b), (c), and (e), 
and the corresponding requirements in Sec.  11.30. All information 
submitted under this part must be transmitted to FDA electronically 
unless FDA has granted a request for waiver of this requirement prior to 
the date on which the 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 the Director of FDA's Center for Biologics Evaluation and 
Research through the Document Control Center (see addresses in Sec.  
600.2).
    (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,

[[Page 62]]

other information, and updates, as applicable.

[81 FR 60222, Aug. 31, 2016]



Sec.  607.25  Information required for establishment registration and
blood product listing.

    (a) The Blood Establishment Registration and Product Listing system 
requires furnishing or confirming registration information required by 
the Federal Food, Drug, and Cosmetic Act. This information includes the 
name and street address of the establishment, including post office 
code; a registration number if previously assigned by FDA and a Unique 
Facility Identifier in accordance with the system specified under 
section 510 of the Federal Food, Drug, and Cosmetic Act; all trade names 
used by the establishment; the kind of ownership or operation (that is, 
individually owned partnership, or corporation); and the name of the 
owner or operator of such establishment. The term ``name of the owner or 
operator'' must include, in the case of a partnership, the name of each 
partner and, in the case of a corporation, the name and title of each 
corporate officer and director and the name of the State of 
incorporation. The information required must be given separately for 
each establishment, as defined in Sec.  607.3(c).
    (b) The following information must also be provided:
    (1) A list of blood products by established name as defined in 
section 502(e) of the Federal Food, Drug, and Cosmetic Act and by 
proprietary name, if any, which are being manufactured for commercial 
distribution at the identified establishment and which have not been 
included in any list previously submitted to FDA through the Blood 
Establishment Registration and Product Listing system or any future 
superseding electronic system.
    (2) For each blood product so listed that is subject to section 351 
of the Public Health Service Act, the license number of the manufacturer 
issued by the Center for Biologics Evaluation and Research, Food and 
Drug Administration.
    (3) For each blood product listed, the registration number if 
previously assigned by FDA and the Unique Facility Identifier of the 
parent establishment. An establishment not owned, operated, or 
controlled by another firm or establishment is its own parent 
establishment.

[81 FR 60222, Aug. 31, 2016]



Sec.  607.26  Amendments to establishment registration.

    Changes in individual ownership, corporate or partnership structure, 
location, or blood product handling activity must be submitted 
electronically through the Blood Establishment Registration and Product 
Listing system, or any future superseding electronic system, as an 
amendment to registration within 5 calendar days of such changes. 
Changes in the names of officers and directors of the corporations do 
not require such amendment but must be shown at time of annual 
registration.

[40 FR 52788, Nov. 12, 1975, as amended at 66 FR 59158, Nov. 27, 2001; 
81 FR 60222, Aug. 31, 2016]



Sec.  607.30  Updating blood product listing information.

    (a) After submission of the initial blood product listing 
information, every person who is required to list blood products under 
Sec.  607.20 must submit electronically through the Blood Establishment 
Registration and Product Listing system, or any future superseding 
electronic system, at a minimum once in June and December of every year, 
the following information:
    (1) A list of each blood product introduced by the registrant for 
commercial distribution which has not been included in any list 
previously submitted. All of the information required by Sec.  607.25(b) 
shall be provided for each such blood product.
    (2) A list of each blood product formerly listed pursuant to Sec.  
607.25(b) for which commercial distribution has been discontinued, 
including for each blood product so listed the identity by established 
name and proprietary name, and date of discontinuance. It is requested 
but not required that the reason for discontinuance of distribution be 
included with this information.
    (3) A list of each blood product for which a notice of 
discontinuance was submitted pursuant to paragraph (a)(2)

[[Page 63]]

of this section and for which commercial distribution has been resumed, 
including for each blood product so listed the identity by established 
name as defined in section 502(e) of the act and by any proprietary 
name, the date of resumption, and any other information required by 
Sec.  607.25(b) not previously submitted.
    (4) Any material change in any information previously submitted.
    (b) When no changes have occurred since the previously submitted 
list, no listing information is required.

[40 FR 52788, Nov. 12, 1975, as amended at 81 FR 60222, Aug. 31, 2016]



Sec.  607.31  Additional blood product listing information.

    (a) In addition to the information routinely required by Sec. Sec.  
607.25 and 607.30, the Director of the Center for Biologics Evaluation 
and Research may require submission of the following information by 
letter or by Federal Register notice:
    (1) For a particular blood product so listed, upon request made by 
the Director of the Center for Biologics Evaluation and Research for 
good cause, a copy of all advertisements.
    (2) For a particular blood product so listed, upon a finding by the 
Director of the Center for Biologics Evaluation and Research that it is 
necessary to carry out the purposes of the act, a quantitative listing 
of all ingredients.
    (3) For each registrant, upon a finding by the Director of the 
Center for Biologics Evaluation and Research that it is necessary to 
carry out the purposes of the act, a list of each listed blood product 
containing a particular ingredient.
    (b) [Reserved]

[66 FR 59158, Nov. 27, 2001]



Sec.  607.35  Blood product establishment registration number.

    An establishment registration number will be assigned to each blood 
product establishment registered in accordance with this part.

[81 FR 60223, Aug. 31, 2016]



Sec.  607.37  Public disclosure of establishment registration and blood
product listing information.

    (a) Except as provided in paragraph (b) of this section, all 
registration and listing information obtained under Sec. Sec.  607.25, 
607.26, and 607.30 will be made available for public disclosure through 
the Center for Biologics Evaluation and Research (CBER) Blood 
Establishment Registration Database Web site by using the CBER 
electronic Web-based application or by going in person to the Food and 
Drug Administration, Division of Freedom of Information Public Reading 
Room (see addresses in Sec.  20.120(a) of this chapter).
    (b) FDA may find, in limited circumstances and on a case-by-case 
basis, that it would be consistent with the protection of the public 
health to exempt from public disclosure specific listing information 
obtained under Sec.  607.25 or Sec.  607.30.
    (c) Other requests for information regarding blood establishment 
registrations and blood product listings should be directed to the Food 
and Drug Administration, Center for Biologics Evaluation and Research 
Office of Communication, Outreach, and Development, 10903 New Hampshire 
Ave., Bldg. 71, Rm. 3103, Silver Spring, MD 20993-0002.

[81 FR 60223, Aug. 31, 2016]



Sec.  607.39  Misbranding by reference to establishment registration, 
validation of registration, or to registration number.

    Registration of an establishment, validation of registration, or 
assignment of a registration number does not in any way denote approval 
of the firm or its products nor does it mean that the products may be 
legally marketed. Any representation that creates an impression of 
official approval because of establishment registration, validation of 
registration, or possession of a registration number is misleading and 
constitutes misbranding.

[81 FR 60223, Aug. 31, 2016]

[[Page 64]]



      Subpart C_Procedures for Foreign Blood Product Establishments



Sec.  607.40  Establishment registration and blood product listing 
requirements for foreign blood product establishments.

    (a) Every foreign establishment shall comply with the establishment 
registration and blood product listing requirements contained in subpart 
B of this part, unless exempt under subpart D of this part or unless the 
blood product enters a foreign trade zone and is re-exported from that 
foreign trade zone without having entered U. S. commerce.
    (b) No blood product may be imported or offered for import into the 
United States unless it is the subject of a blood product listing as 
required under subpart B of this part and is manufactured, prepared, 
propagated, compounded, or processed at a registered foreign 
establishment; however, this restriction does not apply to a blood 
product imported or offered for import under the investigational use 
provisions of part 312 of this chapter or to a blood product imported 
under section 801(d)(4) of the act. The establishment registration and 
blood product listing information shall be in the English language.
    (c) Each foreign establishment required to register under paragraph 
(a) of this section shall, as part of the establishment registration and 
blood product listing, submit the name and address of the establishment 
and the name of the individual responsible for submitting establishment 
registration and blood product listing information. Any changes in this 
information shall be reported to the Food and Drug Administration at the 
intervals specified for updating establishment registration information 
in Sec.  607.26 and blood product listing information in Sec.  
607.30(a).
    (d) Each foreign establishment required to register under paragraph 
(a) of this section must submit the name, address, telephone number, and 
email address of its United States agent as part of its initial and 
updated registration information in accordance with subpart B of this 
part. Each foreign establishment must designate only one United States 
agent.
    (1) The United States agent shall reside or maintain a place of 
business in the United States.
    (2) Upon request from FDA, the United States agent shall assist FDA 
in communications with the foreign establishment, respond to questions 
concerning the foreign establishment's products that are imported or 
offered for import into the United States, and assist FDA in scheduling 
inspections of the foreign establishment. If the agency is unable to 
contact the foreign establishment directly or expeditiously, FDA may 
provide information or documents to the United States agent, and such an 
action shall be considered to be equivalent to providing the same 
information or documents to the foreign establishment.
    (3) The foreign establishment or the United States agent must report 
changes in the United States agent's name, address, telephone number, or 
email address to FDA within 30 calendar days of the change.
    (e) Each foreign establishment required to register under paragraph 
(a) of this section must register and list blood products using the 
Blood Establishment Registration and Product Listing system, or any 
superseding electronic system, unless FDA waives the electronic 
submission requirement in accordance with Sec.  607.22.

[66 FR 59159, Nov. 27, 2001, as amended at 81 FR 60223, Aug. 31, 2016]



                          Subpart D_Exemptions



Sec.  607.65  Exemptions for blood product establishments.

    The following classes of persons are exempt from registration and 
blood product listing in accordance with this part 607 under the 
provisions of section 510(g)(1), (g)(2), and (g)(3) of the act, or 
because the Commissioner of Food and Drugs has found, under section 
510(g)(5), that such registration is not necessary for the protection of 
the public health. The exemptions in paragraphs (a), (b), (f), and (g) 
of this section are limited to those classes of persons located in any 
State as defined in section 201(a)(1) of the act.

[[Page 65]]

    (a) Pharmacies that are operating under applicable local laws 
regulating dispensing of prescription drugs and that are not 
manufacturing blood products for sale other than in the regular course 
of the practice of the profession of pharmacy including the business of 
dispensing and selling blood products at retail. The supplying by such 
pharmacies of blood products to a practitioner licensed to administer 
such blood products for his use in the course of his professional 
practice or to other pharmacies to meet temporary inventory shortages 
are not acts which require such pharmacies to register.
    (b) Practitioners who are licensed by law to prescribe or administer 
drugs and who manufacture blood products solely for use in the course of 
their professional practice.
    (c) Persons who manufacture blood products which are not for sale, 
rather, are solely for use in research, teaching, or analysis, including 
laboratory samples.
    (d) Carriers, by reason of their receipt, carriage, holding, or 
delivery of blood products in the usual course of business as carriers.
    (e) Persons who engage solely in the manufacture of in vitro 
diagnostic blood products and reagents not subject to licensing under 
section 351 of the Public Health Service Act (42 U.S.C. 262). This 
paragraph does not exempt such persons from registration and listing for 
medical devices required under part 807 of this chapter.
    (f) Transfusion services which are a part of a facility that is 
certified under the Clinical Laboratory Improvement Amendments of 1988 
(42 U.S.C. 263a) and 42 CFR part 493 or has met equivalent requirements 
as determined by the Centers for Medicare and Medicaid Services and 
which are engaged in the compatibility testing and transfusion of blood 
and blood components, but which neither routinely collect nor process 
blood and blood components. The collection and processing of blood and 
blood components in an emergency situation as determined by a 
responsible person and documented in writing, therapeutic collection of 
blood or plasma, the preparation of recovered human plasma for further 
manufacturing use, or preparation of red blood cells for transfusion are 
not acts requiring such transfusion services to register.
    (g) Persons who engage solely in the production of any plasma 
derivative, including, but not limited to, albumin, Immune Globulin, 
Factor VIII and Factor IX, bulk product substances such as fractionation 
intermediates or pastes, or recombinant versions of plasma derivatives 
or animal derived plasma derivatives. These persons must register and 
list under part 207 of this chapter.

[40 FR 52788, Nov. 12, 1975, as amended at 43 FR 37997, Aug. 25, 1978; 
45 FR 85729, Dec. 30, 1980; 49 FR 34449, Aug. 31, 1984; 66 FR 31162, 
June 11, 2001; 66 FR 59159, Nov. 27, 2001; 72 FR 45886, Aug. 16, 2007; 
81 FR 60223, Aug. 31, 2016]



  Subpart E_Establishment Registration and Product Listing Of Licensed 
                                 Devices



Sec.  607.80  Applicability of part 607 to licensed devices.

    Manufacturers of products that meet the definition of a device under 
the Federal Food, Drug, and Cosmetic Act and that are licensed under 
section 351 of the Public Health Service Act, as well as licensed 
biological products used in the manufacture of a licensed device, must 
register and list following the procedures under this part, with respect 
to their manufacture of those products, unless otherwise noted in this 
section.

[81 FR 60223, Aug. 31, 2016]



PART 610_GENERAL BIOLOGICAL PRODUCTS STANDARDS--Table of Contents



                     Subpart A_Release Requirements

Sec.
610.1 Tests prior to release required for each lot.
610.2 Requests for samples and protocols; official release.

                      Subpart B_General Provisions

610.9 Equivalent methods and processes.
610.10 Potency.
610.11-610.11a [Reserved]
610.12 Sterility.
610.13 Purity.
610.14 Identity.
610.15 Constituent materials.
610.16 Total solids in serums.
610.17 Permissible combinations.

[[Page 66]]

610.18 Cultures.

Subparts C--D [Reserved]

  Subpart E_Testing Requirements for Relevant Transfusion-Transmitted 
                               Infections

610.39 Definitions.
610.40 Test requirements.
610.41 Donor deferral.
610.42 Restrictions on use for further manufacture of medical devices.
610.44 Use of reference panels by manufacturers of test kits.
610.46 Human immunodeficiency virus (HIV) ``lookback'' requirements.
610.47 Hepatitis C virus (HCV) ``lookback'' requirements.
610.48 [Reserved]

                   Subpart F_Dating Period Limitations

610.50 Date of manufacture for biological products.
610.53 Dating periods for Whole Blood and blood components.

                      Subpart G_Labeling Standards

610.60 Container label.
610.61 Package label.
610.62 Proper name; package label; legible type.
610.63 Divided manufacturing responsibility to be shown.
610.64 Name and address of distributor.
610.65 Products for export.
610.67 Bar code label requirements.
610.68 Exceptions or alternatives to labeling requirements for 
          biological products held by the Strategic National Stockpile.

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 360d, 
360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a, 264.

    Source: 38 FR 32056, Nov. 20, 1973, unless otherwise noted.

    Cross References: For U.S. Customs Service regulations relating to 
viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal 
Service regulations relating to the admissibility to the United States 
mails see parts 124 and 125 of the Domestic Mail Manual, that is 
incorporated by reference in 39 CFR part 111.



                     Subpart A_Release Requirements



Sec.  610.1  Tests prior to release required for each lot.

    No lot of any licensed product shall be released by the manufacturer 
prior to the completion of tests for conformity with standards 
applicable to such product. Each applicable test shall be made on each 
lot after completion of all processes of manufacture which may affect 
compliance with the standard to which the test applies. The results of 
all tests performed shall be considered in determining whether or not 
the test results meet the test objective, except that a test result may 
be disregarded when it is established that the test is invalid due to 
causes unrelated to the product.



Sec.  610.2  Requests for samples and protocols; official release.

    (a) Licensed biological products regulated by CBER. Samples of any 
lot of any licensed product together with the protocols showing results 
of applicable tests, may at any time be required to be sent to the 
Director, Center for Biologics Evaluation and Research (see mailing 
addresses in Sec.  600.2(c) of this chapter). Upon notification by the 
Director, Center for Biologics Evaluation and Research, a manufacturer 
shall not distribute a lot of a product until the lot is released by the 
Director, Center for Biologics Evaluation and Research: Provided, That 
the Director, Center for Biologics Evaluation and Research, shall not 
issue such notification except when deemed necessary for the safety, 
purity, or potency of the product.
    (b) Licensed biological products regulated by CDER. Samples of any 
lot of any licensed product together with the protocols showing results 
of applicable tests, may at any time be required to be sent to the 
Director, Center for Drug Evaluation and Research (see mailing addresses 
in Sec.  600.2(c) of this chapter) for official release. Upon 
notification by the Director, Center for Drug Evaluation and Research, a 
manufacturer shall not distribute a lot of a biological product until 
the lot is released by the Director, Center for Drug Evaluation and 
Research: Provided, That the Director, Center for Drug Evaluation and 
Research shall not issue such notification except when deemed necessary 
for the safety, purity, or potency of the product.

[40 FR 31313, July 25, 1975, as amended at 49 FR 23834, June 8, 1984; 50 
FR 10941, Mar. 19, 1985; 55 FR 11013, 11014, Mar. 26, 1990; 67 FR 9587, 
Mar. 4, 2002; 70 FR 14984, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015]

[[Page 67]]



                      Subpart B_General Provisions



Sec.  610.9  Equivalent methods and processes.

    Modification of any particular test method or manufacturing process 
or the conditions under which it is conducted as required in this part 
or in the additional standards for specific biological products in parts 
620 through 680 of this chapter shall be permitted only under the 
following conditions:
    (a) The applicant presents evidence, in the form of a license 
application, or a supplement to the application submitted in accordance 
with Sec.  601.12(b) or (c), demonstrating that the modification will 
provide assurances of the safety, purity, potency, and effectiveness of 
the biological product equal to or greater than the assurances provided 
by the method or process specified in the general standards or 
additional standards for the biological product; and
    (b) Approval of the modification is received in writing from the 
Director, Center for Biologics Evaluation and Research or the Director, 
Center for Drug Evaluation and Research.

[62 FR 39903, July 24, 1997, as amended at 70 FR 14984, Mar. 24, 2005]



Sec.  610.10  Potency.

    Tests for potency shall consist of either in vitro or in vivo tests, 
or both, which have been specifically designed for each product so as to 
indicate its potency in a manner adequate to satisfy the interpretation 
of potency given by the definition in Sec.  600.3(s) of this chapter.



Sec.  610.11-610.11a  [Reserved]



Sec.  610.12  Sterility.

    (a) The test. Except as provided in paragraph (h) of this section, 
manufacturers of biological products must perform sterility testing of 
each lot of each biological product's final container material or other 
material, as appropriate and as approved in the biologics license 
application or supplement for that product.
    (b) Test requirements. (1) The sterility test must be appropriate to 
the material being tested such that the material does not interfere with 
or otherwise hinder the test.
    (2) The sterility test must be validated to demonstrate that the 
test is capable of reliably and consistently detecting the presence of 
viable contaminating microorganisms.
    (3) The sterility test and test components must be verified to 
demonstrate that the test method can consistently detect the presence of 
viable contaminating microorganisms.
    (c) Written procedures. Manufacturers must establish, implement, and 
follow written procedures for sterility testing that describe, at a 
minimum, the following:
    (1) The sterility test method to be used;
    (i) If culture-based test methods are used, include, at a minimum:
    (A) Composition of the culture media;
    (B) Growth-promotion test requirements; and
    (C) Incubation conditions (time and temperature).
    (ii) If non-culture-based test methods are used, include, at a 
minimum:
    (A) Composition of test components;
    (B) Test parameters, including acceptance criteria; and
    (C) Controls used to verify the method's ability to detect the 
presence of viable contaminating microorganisms.
    (2) The method of sampling, including the number, volume, and size 
of articles to be tested;
    (3) Written specifications for the acceptance or rejection of each 
lot; and
    (4) A statement of any other function critical to the particular 
sterility test method to ensure consistent and accurate results.
    (d) The sample. The sample must be appropriate to the material being 
tested, considering, at a minimum:
    (1) The size and volume of the final product lot;
    (2) The duration of manufacturing of the drug product;
    (3) The final container configuration and size;
    (4) The quantity or concentration of inhibitors, neutralizers, and 
preservatives, if present, in the tested material;

[[Page 68]]

    (5) For a culture-based test method, the volume of test material 
that results in a dilution of the product that is not bacteriostatic or 
fungistatic; and
    (6) For a non-culture-based test method, the volume of test material 
that results in a dilution of the product that does not inhibit or 
otherwise hinder the detection of viable contaminating microorganisms.
    (e) Verification. (1) For culture-based test methods, studies must 
be conducted to demonstrate that the performance of the test organisms 
and culture media are suitable to consistently detect the presence of 
viable contaminating microorganisms, including tests for each lot of 
culture media to verify its growth-promoting properties over the shelf-
life of the media.
    (2) For non-culture-based test methods, within the test itself, 
appropriate controls must be used to demonstrate the ability of the test 
method to continue to consistently detect the presence of viable 
contaminating microorganisms.
    (f) Repeat test procedures. (1) If the initial test indicates the 
presence of microorganisms, the product does not comply with the 
sterility test requirements unless a thorough investigation by the 
quality control unit can ascribe definitively the microbial presence to 
a laboratory error or faulty materials used in conducting the sterility 
testing.
    (2) If the investigation described in paragraph (f)(1) of this 
section finds that the initial test indicated the presence of 
microorganisms due to laboratory error or the use of faulty materials, a 
sterility test may be repeated one time. If no evidence of 
microorganisms is found in the repeat test, the product examined 
complies with the sterility test requirements. If evidence of 
microorganisms is found in the repeat test, the product examined does 
not comply with the sterility test requirements.
    (3) If a repeat test is conducted, the same test method must be used 
for both the initial and repeat tests, and the repeat test must be 
conducted with comparable product that is reflective of the initial 
sample in terms of sample location and the stage in the manufacturing 
process from which it was obtained.
    (g) Records. The records related to the test requirements of this 
section must be prepared and maintained as required by Sec. Sec.  
211.167 and 211.194 of this chapter.
    (h) Exceptions. Sterility testing must be performed on final 
container material or other appropriate material as defined in the 
approved biologics license application or supplement and as described in 
this section, except as follows:
    (1) This section does not require sterility testing for Whole Blood, 
Cryoprecipitated Antihemophilic Factor, Platelets, Red Blood Cells, 
Plasma, Source Plasma, Smallpox Vaccine, Reagent Red Blood Cells, Anti-
Human Globulin, and Blood Grouping Reagents.
    (2) A manufacturer is not required to comply with the sterility test 
requirements if the Director of the Center for Biologics Evaluation and 
Research or the Director of the Center for Drug Evaluation and Research, 
as appropriate, determines that data submitted in the biologics license 
application or supplement adequately establish that the route of 
administration, the method of preparation, or any other aspect of the 
product precludes or does not necessitate a sterility test to assure the 
safety, purity, and potency of the product.

[77 FR 26174, May 3, 2012]



Sec.  610.13  Purity.

    Products shall be free of extraneous material except that which is 
unavoidable in the manufacturing process described in the approved 
biologics license application. In addition, products shall be tested as 
provided in paragraphs (a) and (b) of this section.
    (a)(1) Test for residual moisture. Each lot of dried product shall 
be tested for residual moisture and shall meet and not exceed 
established limits as specified by an approved method on file in the 
biologics license application. The test for residual moisture may be 
exempted by the Director, Center for Biologics Evaluation and Research 
or the Director, Center for Drug Evaluation

[[Page 69]]

and Research, when deemed not necessary for the continued safety, 
purity, and potency of the product.
    (2) Records. Appropriate records for residual moisture under 
paragraph (a)(1) of this section shall be prepared and maintained as 
required by the applicable provisions of Sec. Sec.  211.188 and 211.194 
of this chapter.
    (b) Test for pyrogenic substances. Each lot of final containers of 
any product intended for use by injection shall be tested for pyrogenic 
substances by intravenous injection into rabbits as provided in 
paragraphs (b) (1) and (2) of this section: Provided, That 
notwithstanding any other provision of Subchapter F of this chapter, the 
test for pyrogenic substances is not required for the following 
products: Products containing formed blood elements; Cryoprecipitate; 
Plasma; Source Plasma; Normal Horse Serum; bacterial, viral, and 
rickettsial vaccines and antigens; toxoids; toxins; allergenic extracts; 
venoms; diagnostic substances and trivalent organic arsenicals.
    (1) Test dose. The test dose for each rabbit shall be at least 3 
milliliters per kilogram of body weight of the rabbit and also shall be 
at least equivalent proportionately, on a body weight basis, to the 
maximum single human dose recommended, but need not exceed 10 
milliliters per kilogram of body weight of the rabbit, except that: (i) 
Regardless of the human dose recommended, the test dose per kilogram of 
body weight of each rabbit shall be at least 1 milliliter for immune 
globulins derived from human blood; (ii) for Streptokinase, the test 
dose shall be at least equivalent proportionately, on a body weight 
basis, to the maximum single human dose recommended.
    (2) Test procedure, results, and interpretation; standards to be 
met. The test for pyrogenic substances shall be performed according to 
the requirements specified in United States Pharmacopeia XX.
    (3) Retest. If the lot fails to meet the test requirements 
prescribed in paragraph (b)(2) of this section, the test may be repeated 
once using five other rabbits. The temperature rises recorded for all 
eight rabbits used in testing shall be included in determining whether 
the requirements are met. The lot meets the requirements for absence of 
pyrogens if not more than three of the eight rabbits show individual 
rises in temperature of 0.6 [deg]C or more, and if the sum of the eight 
individual maximum temperature rises does not exceed 3.7 [deg]C.

[38 FR 32056, Nov. 20, 1973, as amended at 40 FR 29710, July 15, 1975; 
41 FR 10429, Mar. 11, 1976; 41 FR 41424, Sept. 22, 1976; 44 FR 40289, 
July 10, 1979; 46 FR 62845, Dec. 29, 1981; 49 FR 15187, Apr. 18, 1984; 
50 FR 4134, Jan. 29, 1985; 55 FR 28381, July 11, 1990; 64 FR 56453, Oct. 
20, 1999; 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005]



Sec.  610.14  Identity.

    The contents of a final container of each filling of each lot shall 
be tested for identity after all labeling operations shall have been 
completed. The identity test shall be specific for each product in a 
manner that will adequately identify it as the product designated on 
final container and package labels and circulars, and distinguish it 
from any other product being processed in the same laboratory. Identity 
may be established either through the physical or chemical 
characteristics of the product, inspection by macroscopic or microscopic 
methods, specific cultural tests, or in vitro or in vivo immunological 
tests.



Sec.  610.15  Constituent materials.

    (a) Ingredients, preservatives, diluents, adjuvants. All ingredients 
used in a licensed product, and any diluent provided as an aid in the 
administration of the product, shall meet generally accepted standards 
of purity and quality. Any preservative used shall be sufficiently 
nontoxic so that the amount present in the recommended dose of the 
product will not be toxic to the recipient, and in the combination used 
it shall not denature the specific substances in the product to result 
in a decrease below the minimum acceptable potency within the dating 
period when stored at the recommended temperature. Products in multiple-
dose containers shall contain a preservative, except that a preservative 
need not be added to Yellow Fever Vaccine; Poliovirus Vaccine Live Oral; 
viral vaccines labeled for use with the jet injector;

[[Page 70]]

dried vaccines when the accompanying diluent contains a preservative; or 
to an Allergenic Product in 50 percent or more volume in volume (v/v) 
glycerin. An adjuvant shall not be introduced into a product unless 
there is satisfactory evidence that it does not affect adversely the 
safety or potency of the product. The amount of aluminum in the 
recommended individual dose of a biological product shall not exceed:
    (1) 0.85 milligrams if determined by assay;
    (2) 1.14 milligrams if determined by calculation on the basis of the 
amount of aluminum compound added; or
    (3) 1.25 milligrams determined by assay provided that data 
demonstrating that the amount of aluminum used is safe and necessary to 
produce the intended effect are submitted to and approved by the 
Director, Center for Biologics Evaluation and Research or the Director, 
Center for Drug Evaluation and Research (see mailing addresses in Sec.  
600.2(a) or (b) of this chapter).
    (b) Extraneous protein; cell culture produced vaccines. Extraneous 
protein known to be capable of producing allergenic effects in human 
subjects shall not be added to a final virus medium of cell culture 
produced vaccines intended for injection. If serum is used at any stage, 
its calculated concentration in the final medium shall not exceed 
1:1,000,000.
    (c) Antibiotics. A minimum concentration of antibiotics, other than 
penicillin, may be added to the production substrate of viral vaccines.
    (d) The Director of the Center for Biologics Evaluation and Research 
or the Director of the Center for Drug Evaluation and Research may 
approve an exception or alternative to any requirement in this section. 
Requests for such exceptions or alternatives must be in writing.

[38 FR 32056, Nov. 20, 1973, as amended at 46 FR 51903, Oct. 23, 1981; 
48 FR 13025, Mar. 29, 1983; 48 FR 37023, Aug. 16, 1983; 49 FR 23834, 
June 8, 1984; 50 FR 4134, Jan. 29, 1985; 51 FR 15607, Apr. 25, 1986; 55 
FR 11013, Mar. 26, 1990; 70 FR 14985, Mar. 24, 2005; 76 FR 20518, Apr. 
13, 2011; 80 FR 18093, Apr. 3, 2015]



Sec.  610.16  Total solids in serums.

    Except as otherwise provided by regulation, no liquid serum or 
antitoxin shall contain more than 20 percent total solids.



Sec.  610.17  Permissible combinations.

    Licensed products may not be combined with other licensed products 
either therapeutic, prophylactic or diagnostic, except as a license is 
obtained for the combined product. Licensed products may not be combined 
with nonlicensable therapeutic, prophylactic, or diagnostic substances 
except as a license is obtained for such combination.



Sec.  610.18  Cultures.

    (a) Storage and maintenance. Cultures used in the manufacture of 
products shall be stored in a secure and orderly manner, at a 
temperature and by a method that will retain the initial characteristics 
of the organisms and insure freedom from contamination and 
deterioration.
    (b) Identity and verification. Each culture shall be clearly 
identified as to source strain. A complete identification of the strain 
shall be made for each new stock culture preparation. Primary and 
subsequent seed lots shall be identified by lot number and date of 
preparation. Periodic tests shall be performed as often as necessary to 
verify the integrity of the strain characteristics and freedom from 
extraneous organisms. Results of all periodic tests for verification of 
cultures and determination of freedom from extraneous organisms shall be 
recorded and retained.
    (c) Cell lines used for manufacturing biological products--(1) 
General requirements. Cell lines used for manufacturing biological 
products shall be:
    (i) Identified by history;
    (ii) Described with respect to cytogenetic characteristics and 
tumorigenicity;
    (iii) Characterized with respect to in vitro growth characteristics 
and life potential; and
    (iv) Tested for the presence of detectable microbial agents.
    (2) Tests. Tests that are necessary to assure the safety, purity, 
and potency of a product may be required by the Director, Center for 
Biologics Evaluation

[[Page 71]]

and Research or the Director, Center for Drug Evaluation and Research.
    (3) Applicability. This paragraph applies to diploid and nondiploid 
cell lines. Primary cell cultures that are not subcultivated and primary 
cell cultures that are subsequently subcultivated for only a very 
limited number of population doublings are not subject to the provisions 
of this paragraph (c).
    (d) Records. The records appropriate for cultures under this section 
shall be prepared and maintained as required by the applicable 
provisions of Sec. Sec.  211.188 and 211.194 of this chapter.

[38 FR 32056, Nov. 20, 1973, as amended at 51 FR 44453, Dec. 10, 1986; 
55 FR 11013, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 
24, 2005]

Subparts C--D [Reserved]



  Subpart E_Testing Requirements for Relevant Transfusion-Transmitted 
                               Infections



Sec.  610.39  Definitions.

    The definitions set out in Sec.  630.3 of this chapter apply to this 
subpart.

[80 FR 29896, May 22, 2015]



Sec.  610.40  Test requirements.

    (a) Human blood and blood components. Except as specified in 
paragraphs (c) and (d) of this section, you, an establishment that 
collects blood and blood components for transfusion or for use in 
manufacturing a product, including donations intended as a component of, 
or used to manufacture, a medical device, must comply with the following 
requirements:
    (1) Test each donation for evidence of infection due to the relevant 
transfusion-transmitted infections described in Sec.  630.3(h)(1)(i) 
through (iii) of this chapter (HIV, HBV, and HCV).
    (2) Test each donation for evidence of infection due to the relevant 
transfusion-transmitted infections described in Sec.  630.3(h)(1)(iv) 
through (vii) of this chapter (HTLV, syphilis, West Nile virus, and 
Chagas disease). The following exceptions apply:
    (i) To identify evidence of infection with syphilis in donors of 
Source Plasma, you must test donors for evidence of such infection in 
accordance with Sec.  640.65(b) of this chapter, and not under this 
section.
    (ii) You are not required to test donations of Source Plasma for 
evidence of infection due to the relevant transfusion-transmitted 
infections described in Sec.  630.3(h)(1)(iv), (vi), and (vii) of this 
chapter (HTLV, West Nile virus, and Chagas disease).
    (iii) For each of the relevant transfusion-transmitted infections 
described in Sec.  630.3(h)(1)(iv) through (vii) of this chapter (HTLV, 
syphilis, West Nile virus, and Chagas disease):
    (A) If, based on evidence related to the risk of transmission of 
that relevant transfusion-transmitted infection, testing each donation 
is not necessary to reduce adequately and appropriately the risk of 
transmission of such infection by blood or a blood component, you may 
adopt an adequate and appropriate alternative testing procedure that has 
been found acceptable for this purpose by FDA.
    (B) If, based on evidence related to the risk of transmission of 
that relevant transfusion-transmitted infection, testing previously 
required for that infection is no longer necessary to reduce adequately 
and appropriately the risk of transmission of such infection by blood or 
a blood component, you may stop such testing in accordance with 
procedures found acceptable for this purpose by FDA.
    (3) For each of the relevant transfusion-transmitted infections 
described in Sec.  630.3(h)(1)(viii) through (x) of this chapter (CJD, 
vCJD, malaria) and Sec.  630.3(h)(2) of this chapter (other transfusion-
transmitted infections):
    (i) You must test for evidence of infection when the following 
conditions are met:
    (A) A test(s) for the relevant transfusion-transmitted infection is 
licensed, approved or cleared by FDA for use as a donor screening test 
and is available for such use; and
    (B) Testing for the relevant transfusion-transmitted infection is 
necessary to reduce adequately and appropriately the risk of 
transmission of the relevant transfusion-transmitted infection by blood, 
or blood component, or blood derivative product manufactured from the 
collected blood or blood component.

[[Page 72]]

    (ii) You must perform this testing on each donation, unless one of 
the following exceptions applies:
    (A) Testing of each donation is not necessary to reduce adequately 
and appropriately the risk of transmission of such infection by blood, 
blood component, or blood derivative product manufactured from the 
collected blood or blood component. When evidence related to the risk of 
transmission of such infection supports this determination, you may 
adopt an adequate and appropriate alternative testing procedure that has 
been found acceptable for this purpose by FDA.
    (B) Testing of each donation is not necessary to reduce adequately 
and appropriately the risk of transmission of such infection by blood, 
blood component, or blood derivative product manufactured from the 
collected blood or blood component. When evidence related to the risk of 
transmission of such infection supports this determination, you may stop 
such testing in accordance with procedures found acceptable for this 
purpose by FDA.
    (4) Evidence related to the risk of transmission of a relevant 
transfusion-transmitted infection that would support a determination 
that testing is not necessary, or that testing of each donation is not 
necessary, to reduce adequately and appropriately the risk of 
transmission of such infection by blood or blood component, as described 
in paragraphs (a)(2)(iii)(A) and (B) of this section, or by blood, blood 
component, or blood derivative, as described in paragraphs (a)(3)(ii)(A) 
and (B) of this section, includes epidemiological or other scientific 
evidence. It may include evidence related to the seasonality or 
geographic limitation of risk of transmission of such infection by blood 
or blood component, or other information related to when and how a 
donation is at risk of transmitting a relevant transfusion-transmitted 
infection. It may also include evidence related to the effectiveness of 
manufacturing steps (for example, the use of pathogen reduction 
technology) that reduce the risk of transmission of the relevant 
transfusion-transmitted infection by blood, blood components, or blood 
derivatives, as applicable.
    (b) Testing using one or more licensed, approved, or cleared 
screening tests. To perform testing for evidence of infection due to 
relevant transfusion-transmitted infections as required in paragraph (a) 
of this section, you must use screening tests that FDA has licensed, 
approved, or cleared for such use, in accordance with the manufacturer's 
instructions. You must perform one or more such tests as necessary to 
reduce adequately and appropriately the risk of transmission of relevant 
transfusion-transmitted infections.
    (c) Exceptions to testing for dedicated donations, medical devices, 
and samples.--(1) Dedicated donations. (i) You must test donations of 
human blood and blood components from a donor whose donations are 
dedicated to and used solely by a single identified recipient under 
paragraphs (a), (b), and (e) of this section; except that, if the donor 
makes multiple donations for a single identified recipient, you may 
perform such testing only on the first donation in each 30-day period. 
If an untested dedicated donation is made available for any use other 
than transfusion to the single, identified recipient, then this 
exemption from the testing required under this section no longer 
applies.
    (ii) Each donation must be labeled as required under Sec.  606.121 
of this chapter and with a label entitled ``INTENDED RECIPIENT 
INFORMATION LABEL'' containing the name and identifying information of 
the recipient. Each donation must also have the following label, as 
appropriate:

------------------------------------------------------------------------
      Donor Testing Status                         Label
------------------------------------------------------------------------
Tests negative                    Label as required under Sec.   606.121
Tested negative within the last   ``DONOR TESTED WITHIN THE LAST 30
 30 days                           DAYS''
------------------------------------------------------------------------

    (2) Medical device. (i) You are not required to test donations of 
human blood or blood components intended solely as a component of, or 
used to prepare, a medical device for evidence of infection due to the 
relevant transfusion-transmitted infections listed in Sec.  630.3(h)(iv) 
of this chapter unless the final device contains viable leukocytes.
    (ii) Donations of human blood and blood components intended solely 
as a component of, or used to prepare, a

[[Page 73]]

medical device must be labeled ``Caution: For Further Manufacturing Use 
as a Component of, or to Prepare, a Medical Device.''
    (3) Samples. You are not required to test samples of blood, blood 
components, plasma, or sera if used or distributed for clinical 
laboratory testing or research purposes and not intended for 
administration to humans or in the manufacture of a product.
    (d) Autologous donations. You, an establishment that collects human 
blood or blood components from autologous donors, or you, an 
establishment that is a consignee of a collecting establishment, are not 
required to test donations of human blood or blood components from 
autologous donors for evidence of infection due to relevant transfusion-
transmitted infections listed in paragraph (a) of this section, except:
    (1) If you allow any autologous donation to be used for allogeneic 
transfusion, you must assure that all autologous donations are tested 
under this section.
    (2) If you ship autologous donations to another establishment that 
allows autologous donations to be used for allogeneic transfusion, you 
must assure that all autologous donations shipped to that establishment 
are tested under this section.
    (3) If you ship autologous donations to another establishment that 
does not allow autologous donations to be used for allogeneic 
transfusion, you must assure that, at a minimum, the first donation in 
each 30-day period is tested under this section.
    (4) Each autologous donation must be labeled as required under Sec.  
606.121 of this chapter and with the following label, as appropriate:

------------------------------------------------------------------------
      Donor Testing Status                         Label
------------------------------------------------------------------------
Untested                          ``DONOR UNTESTED''
Tests negative                    Label as required under Sec.   606.121
Reactive on current collection/   ``BIOHAZARD'' legend in Sec.
 reactive in the last 30 days      610.40(h)(2)(ii)(B)
Tested negative within the last   ``DONOR TESTED WITHIN THE LAST 30
 30 days                           DAYS''
------------------------------------------------------------------------

    (e) Further testing. You must further test each donation, including 
autologous donations, found to be reactive by a donor screening test 
performed under paragraphs (a) and (b) of this section using a licensed, 
approved, or cleared supplemental test, when available. If no such 
supplemental test is available, you must perform one or more licensed, 
approved, or cleared tests as adequate and appropriate to provide 
additional information concerning the reactive donor's infection status. 
Except:
    (1) For autologous donations:
    (i) You must further test under this section, at a minimum, the 
first reactive donation in each 30 calendar day period; or
    (ii) If you have a record for that donor of a positive result on 
further testing performed under this section, you do not have to further 
test an autologous donation.
    (2) You are not required to perform further testing of a donation 
found to be reactive by a treponemal donor screening test for syphilis.
    (f) Testing responsibility. Required testing under this section, 
must be performed by a laboratory registered in accordance with part 607 
of this chapter and either certified to perform such testing on human 
specimens under the Clinical Laboratory Improvement Amendments of 1988 
(42 U.S.C. 263a) under 42 CFR part 493 or has met equivalent 
requirements as determined by the Centers for Medicare and Medicaid 
Services in accordance with those provisions.
    (g) Release or shipment prior to testing. Human blood or blood 
components that are required to be tested for evidence of infection due 
to relevant transfusion-transmitted infections designated in paragraph 
(a) of this section may be released or shipped prior to completion of 
testing in the following circumstances provided that you label the blood 
or blood components under Sec.  606.121(h) of this chapter, you complete 
the tests for evidence of infection due to relevant transfusion-
transmitted infections as soon as possible after release or shipment, 
and that you provide the results promptly to the consignee:
    (1) Only in appropriately documented medical emergency situations; 
or
    (2) For further manufacturing use as approved in writing by FDA.
    (h) Restrictions on shipment or use--(1) Reactive screening test. 
You must not

[[Page 74]]

ship or use human blood or blood components that have a reactive 
screening test for evidence of infection due to relevant transfusion-
transmitted infection(s) designated in paragraph (a) of this section or 
that are collected from a donor with a previous record of a reactive 
screening test for evidence of infection due to relevant transfusion-
transmitted infection(s) designated in paragraph (a) of this section, 
except as provided in paragraphs (h)(2)(i) through (h)(2)(vii) of this 
section.
    (2) Exceptions. (i) You may ship or use blood or blood components 
intended for autologous use, including reactive donations, as described 
in paragraph (d) of this section.
    (ii) You must not ship or use human blood or blood components that 
have a reactive screening test for evidence of infection due to a 
relevant transfusion-transmitted infection(s) designated in paragraph 
(a) of this section or that are collected from a donor deferred under 
Sec.  610.41(a) unless you meet the following conditions:
    (A) Except for autologous donations, you must obtain from FDA 
written approval for the shipment or use;
    (B) You must appropriately label such blood or blood components as 
required under Sec.  606.121 of this chapter, and with the ``BIOHAZARD'' 
legend;
    (C) Except for autologous donations, you must label such human blood 
and blood components as reactive for the appropriate screening test for 
evidence of infection due to the identified relevant transfusion-
transmitted infection(s);
    (D) If the blood or blood components are intended for further 
manufacturing use into injectable products, you must include a statement 
on the container label indicating the exempted use specifically approved 
by FDA.
    (E) Each blood or blood component with a reactive screening test and 
intended solely as a component of, or used to prepare a medical device, 
must be labeled with the following label, as appropriate:

------------------------------------------------------------------------
     Type of Medical Device                        Label
------------------------------------------------------------------------
A medical device other than an    ``Caution: For Further Manufacturing
 in vitro diagnostic reagent       Use as a Component of a Medical
                                   Device For Which There Are No
                                   Alternative Sources''
An in vitro diagnostic reagent    ``Caution: For Further Manufacturing
                                   Into In Vitro Diagnostic Reagents For
                                   Which There Are No Alternative
                                   Sources''
------------------------------------------------------------------------

    (iii) The restrictions on shipment or use do not apply to samples of 
blood, blood components, plasma, or sera if used or distributed for 
clinical laboratory testing or research purposes, and not intended for 
administration in humans or in the manufacture of a product.
    (iv) You may use human blood or blood components from a donor with a 
previous record of a reactive screening test(s) for evidence of 
infection due to a relevant transfusion-transmitted infection(s) 
designated in paragraph (a) of this section, if:
    (A) At the time of donation, the donor is shown or was previously 
shown to be eligible by a requalification method or process found 
acceptable for such purposes by FDA under Sec.  610.41(b); and
    (B) tests performed under paragraphs (a) and (b) of this section are 
nonreactive.
    (v) Anti-HBc reactive donations, otherwise nonreactive when tested 
as required under this section, may be used for further manufacturing 
into plasma derivatives without prior FDA approval or a ``BIOHAZARD'' 
legend as required under paragraphs (h)(2)(ii)(A) and (h)(2)(ii)(B) of 
this section.
    (vi) You may use human blood or blood components, excluding Source 
Plasma, that test reactive by a screening test for syphilis as required 
under paragraph (a) of this section if, the donation is further tested 
by an adequate and appropriate test which demonstrates that the reactive 
screening test is a biological false positive. You must label the blood 
or blood components with both test results.
    (vii) You may use Source Plasma from a donor who tests reactive by a 
screening test for syphilis as required under Sec.  640.65(b)(1)(i) of 
this chapter, if the donor meets the requirements of Sec.  
640.65(b)(2)(ii) through (iv) of this chapter.

[66 FR 31162, June 11, 2001, as amended at 77 FR 18, Jan. 3, 2012; 80 FR 
29896, May 22, 2015; 86 FR 49922, July 9, 2021]

[[Page 75]]



Sec.  610.41  Donor deferral.

    (a) You, an establishment that collects human blood or blood 
components, must defer donors testing reactive by a screening test for 
evidence of infection due to a relevant transfusion-transmitted 
infection(s) under Sec.  610.40(a), from future donations of human blood 
and blood components, except:
    (1) You are not required to defer a donor who tests reactive for 
anti-HBc or anti-HTLV, types I and II, on only one occasion. However, 
you must defer the donor if further testing for HBV or HTLV has been 
performed under Sec.  610.40(e) and the donor is found to be positive, 
or if a second, licensed, cleared, or approved screening test for HBV or 
HTLV has been performed on the same donation under Sec.  610.40(a) and 
is reactive, or if the donor tests reactive for anti-HBc or anti-HTLV, 
types I and II, on more than one occasion;
    (2) A deferred donor who tests reactive for evidence of infection 
due to a relevant transfusion-transmitted infection(s) under Sec.  
610.40(a) may serve as a donor for blood or blood components shipped or 
used under Sec.  610.40(h)(2)(ii);
    (3) A deferred donor who showed evidence of infection due to 
hepatitis B surface antigen (HBsAg) when previously tested under Sec.  
610.40(a), (b), and (e) subsequently may donate Source Plasma for use in 
the preparation of Hepatitis B Immune Globulin (Human) provided the 
current donation tests nonreactive for HBsAg and the donor is otherwise 
determined to be eligible;
    (4) A deferred donor, who otherwise is determined to be eligible for 
donation and tests reactive for anti-HBc or for evidence of infection 
due to HTLV, types I and II, may serve as a donor of Source Plasma;
    (5) A deferred donor who tests reactive for a relevant transfusion-
transmitted infections(s) under Sec.  610.40(a), may serve as an 
autologous donor under Sec.  610.40(d).
    (b) A deferred donor subsequently may be found to be eligible as a 
donor of blood or blood components by a requalification method or 
process found acceptable for such purposes by FDA. Such a donor is 
considered no longer deferred.
    (c) You must comply with the requirements under Sec. Sec.  610.46 
and 610.47 when a donor tests reactive by a screening test for HIV or 
HCV required under Sec.  610.40(a) and (b), or when you are aware of 
other reliable test results or information indicating evidence of HIV or 
HCV infection.

[66 FR 31164, June 11, 2001, as amended at 72 FR 48798, Aug. 24, 2007; 
80 FR 29897, May 22, 2015]



Sec.  610.42  Restrictions on use for further manufacture of medical
devices.

    (a) In addition to labeling requirements in subchapter H of this 
chapter, when a medical device contains human blood or a blood component 
as a component of the final device, and the human blood or blood 
component was found to be reactive by a screening test performed under 
Sec.  610.40(a) and (b), then you must include in the device labeling a 
statement of warning indicating that the product was manufactured from a 
donation found to be reactive by a screening test for evidence of 
infection due to the identified relevant transfusion-transmitted 
infection(s).
    (b) FDA may approve an exception or alternative to the statement of 
warning required in paragraph (a) of this section based on evidence that 
the reactivity of the human blood or blood component in the medical 
device presents no significant health risk through use of the medical 
device.

[66 FR 31164, June 11, 2001, as amended at 80 FR 29897, May 22, 2015]



Sec.  610.44  Use of reference panels by manufacturers of test kits.

    (a) When available and appropriate to verify acceptable sensitivity 
and specificity, you, a manufacturer of test kits, must use a reference 
panel you obtain from FDA or from an FDA designated source to test lots 
of the following products. You must test each lot of the following 
products, unless FDA informs you that less frequent testing is 
appropriate, based on your consistent prior production of products of 
acceptable sensitivity and specificity:
    (1) A test kit approved for use in testing donations of human blood 
and blood components for evidence of infection due to relevant 
transfusion-transmitted infections under Sec.  610.40(a); and

[[Page 76]]

    (2) Human immunodeficiency virus (HIV) test kit approved for use in 
the diagnosis, prognosis, or monitoring of this relevant transfusion-
transmitted infection.
    (b) You must not distribute a lot that is found to be not acceptable 
for sensitivity and specificity under Sec.  610.44(a). FDA may approve 
an exception or alternative to this requirement. Applicants must submit 
such requests in writing. However, in limited circumstances, such 
requests may be made orally and permission may be given orally by FDA. 
Oral requests and approvals must be promptly followed by written 
requests and written approvals.

[66 FR 31164, June 11, 2001, as amended at 80 FR 29897, May 22, 2015]



Sec.  610.46  Human immunodeficiency virus (HIV) ``lookback'' 
requirements.

    (a) If you are an establishment that collects Whole Blood or blood 
components, including Source Plasma and Source Leukocytes, you must 
establish, maintain, and follow an appropriate system for the following 
actions:
    (1) Within 3 calendar days after a donor tests reactive for evidence 
of human immunodeficiency virus (HIV) infection when tested under Sec.  
610.40(a) and (b) or when you are made aware of other reliable test 
results or information indicating evidence of HIV infection, you must 
review all records required under Sec.  606.160(d) of this chapter, to 
identify blood and blood components previously donated by such a donor. 
For those identified blood and blood components collected:
    (i) Twelve months and less before the donor's most recent 
nonreactive screening tests, or
    (ii) Twelve months and less before the donor's reactive direct viral 
detection test, e.g., nucleic acid test or HIV p24 antigen test, and 
nonreactive antibody screening test, whichever is the lesser period, you 
must:
    (A) Quarantine all previously collected in-date blood and blood 
components identified under paragraph (a)(1) of this section if intended 
for use in another person or for further manufacture into injectable 
products, except pooled blood components intended solely for further 
manufacturing into products that are manufactured using validated viral 
clearance procedures; and
    (B) Notify consignees to quarantine all previously collected in-date 
blood and blood components identified under paragraph (a)(1) of this 
section if intended for use in another person or for further manufacture 
into injectable products, except pooled blood components intended solely 
for further manufacturing into products that are manufactured using 
validated viral clearance procedures;
    (2) You must perform further testing for HIV as required under Sec.  
610.40(e) of this chapter on the reactive donation.
    (3) You must notify consignees of the results of further testing for 
HIV, or the results of the reactive screening test if further testing 
under paragraph (a)(2) of this section is not available, or if under an 
investigational new drug application (IND) or investigational device 
exemption (IDE), is exempted for such use by FDA, within 45 calendar 
days after the donor tests reactive for evidence of HIV infection under 
Sec.  610.40(a) and (b) of this chapter. Notification of consignees must 
include the test results for blood and blood components identified under 
paragraph (a)(1) of this section that were previously collected from 
donors who later test reactive for evidence of HIV infection.
    (4) You must release from quarantine, destroy, or relabel 
quarantined in-date blood and blood components, consistent with the 
results of the further testing performed under paragraph (a)(2) of this 
section or the results of the reactive screening test if further testing 
is not available, or if under an IND or IDE, exempted for such use by 
FDA.
    (b) If you are a consignee of Whole Blood or blood components, 
including Source Plasma and Source Leukocytes, you must establish, 
maintain, and follow an appropriate system for the following actions:
    (1) You must quarantine all previously collected in-date blood and 
blood components identified under paragraph (a)(1) of this section, 
except pooled blood components intended solely for further manufacturing 
into products that are manufactured using validated viral clearance 
procedures, when

[[Page 77]]

notified by the collecting establishment.
    (2) You must release from quarantine, destroy, or relabel 
quarantined in-date blood and blood components consistent with the 
results of the further testing performed under paragraph (a)(2) of this 
section, or the results of the reactive screening test if further 
testing is not available, or if under an IND or IDE, is exempted for 
such use by FDA.
    (3) When further testing for HIV is positive or when the screening 
test is reactive and further testing is not available, or if under an 
IND or IDE is exempted for such use by FDA, you must notify transfusion 
recipients of previous collections of blood and blood components at 
increased risk of transmitting HIV infection, or the recipient's 
physician of record, of the need for recipient HIV testing and 
counseling. You must notify the recipient's physician of record or a 
legal representative or relative if the recipient is a minor, deceased, 
adjudged incompetent by a State court, or, if the recipient is competent 
but State law permits a legal representative or relative to receive 
information on behalf of the recipient. You must make reasonable 
attempts to perform the notification within 12 weeks after receiving the 
results of further testing for evidence of HIV infection from the 
collecting establishment, or after receiving the donor's reactive 
screening test result for HIV if further testing is not available, or if 
under an IND or IDE is exempted for such use by FDA.
    (c) Actions under this section do not constitute a recall as defined 
in Sec.  7.3 of this chapter.

[72 FR 48799, Aug. 24, 2007, as amended at 80 FR 29897, May 22, 2015]



Sec.  610.47  Hepatitis C virus (HCV) ``lookback'' requirements.

    (a) If you are an establishment that collects Whole Blood or blood 
components, including Source Plasma and Source Leukocytes, you must 
establish, maintain, and follow an appropriate system for the following 
actions:
    (1) Within 3 calendar days after a donor tests reactive for evidence 
of hepatitis C virus (HCV) infection when tested under Sec.  610.40(a) 
and (b) of this chapter or when you are made aware of other reliable 
test results or information indicating evidence of HCV infection, you 
must review all records required under Sec.  606.160(d) of this chapter, 
to identify blood and blood components previously donated by such a 
donor. For those identified blood and blood components collected:
    (i) Twelve months and less before the donor's most recent 
nonreactive screening tests, or
    (ii) Twelve months and less before the donor's reactive direct viral 
detection test, e.g., nucleic acid test and nonreactive antibody 
screening test, whichever is the lesser period, you must:
    (A) Quarantine all previously collected in-date blood and blood 
components identified under paragraph (a)(1) of this section if intended 
for use in another person or for further manufacture into injectable 
products, except pooled blood components intended solely for further 
manufacturing into products that are manufactured using validated viral 
clearance procedures; and
    (B) Notify consignees to quarantine all previously collected in-date 
blood and blood components identified under paragraph (a)(1) of this 
section if intended for use in another person or for further manufacture 
into injectable products, except pooled blood components intended solely 
for further manufacturing into products that are manufactured using 
validated viral clearance procedures;
    (2) You must perform further testing for HCV as required under Sec.  
610.40(e) on the reactive donation.
    (3) You must notify consignees of the results of further testing for 
HCV, or the results of the reactive screening test if further testing is 
not available, or if under an investigational new drug application (IND) 
or investigational device exemption (IDE), is exempted for such use by 
FDA, within 45 calendar days after the donor tests reactive for evidence 
of HCV infection under Sec.  610.40(a) and (b). Notification of 
consignees must include the test results for blood and blood components 
identified under paragraph (a)(1) of this section that were previously 
collected from donors who later test reactive for evidence of HCV 
infection.

[[Page 78]]

    (4) You must release from quarantine, destroy, or relabel 
quarantined in-date blood and blood components consistent with the 
results of the further testing performed under paragraph (a)(2) of this 
section, or the results of the reactive screening test if further 
testing is not available, or if under an IND or IDE, exempted for such 
use by FDA.
    (b) If you are a consignee of Whole Blood or blood components, 
including Source Plasma or Source Leukocytes, you must establish, 
maintain, and follow an appropriate system for the following actions:
    (1) You must quarantine all previously collected in-date blood and 
blood components identified under paragraph (a)(1) of this section, 
except pooled blood components intended solely for further manufacturing 
into products that are manufactured using validated viral clearance 
procedures, when notified by the collecting establishment.
    (2) You must release from quarantine, destroy, or relabel 
quarantined in-date blood and blood components, consistent with the 
results of the further testing performed under paragraph (a)(2) of this 
section, or the results of the reactive screening test if further 
testing is not available, or if under an IND or IDE, is exempted for 
such use by FDA.
    (3) When the further testing for HCV is positive or when the 
screening test is reactive and further testing is not available, or if 
under an IND or IDE, is exempted for such use by FDA, you must notify 
transfusion recipients of previous collections of blood and blood 
components at increased risk of transmitting HCV infection, or the 
recipient's physician of record, of the need for recipient HCV testing 
and counseling. You must notify the recipient's physician of record or a 
legal representative or relative if the recipient is a minor, adjudged 
incompetent by a State court, or if the recipient is competent but State 
law permits a legal representative or relative to receive information on 
behalf of the recipient. You must make reasonable attempts to perform 
the notification within 12 weeks after receiving the results of further 
testing for evidence of HCV infection from the collecting establishment, 
or after receiving the donor's reactive screening test result for HCV if 
further testing is not available, or if under an IND or IDE, is exempted 
for such use by FDA.
    (c) Actions under this section do not constitute a recall as defined 
in Sec.  7.3 of this chapter.

[72 FR 48799, Aug. 24, 2007, as amended at 80 FR 29897, May 22, 2015]



Sec.  610.48  [Reserved]



                   Subpart F_Dating Period Limitations



Sec.  610.50  Date of manufacture for biological products.

    (a) When the dating period begins. The dating period for a product 
must begin on the date of manufacture as described in paragraphs (b) and 
(c) of this section. The dating period for a combination of two or more 
products must be no longer than the dating period of the component with 
the shortest dating period.
    (b) Determining the date of manufacture for biological products 
other than Whole Blood and blood components. The date of manufacture for 
biological products, other than Whole Blood and blood components, must 
be identified in the approved biologics license application as one of 
the following, whichever is applicable: The date of:
    (1) Potency test or other specific test as described in a biologics 
license application or supplement to the application;
    (2) Removal from animals or humans;
    (3) Extraction;
    (4) Solution;
    (5) Cessation of growth;
    (6) Final sterile filtration of a bulk solution;
    (7) Manufacture as described in part 660 of this chapter; or
    (8) Other specific manufacturing activity described in a biologics 
license application or supplement to the biologics license application.
    (c) Determining the date of manufacture for Whole Blood and blood 
components. (1) The date of manufacture for Whole Blood and blood 
components must be one of the following, whichever is applicable:

[[Page 79]]

    (i) Collection date and/or time;
    (ii) Irradiation date;
    (iii) The time the red blood cell product was removed from frozen 
storage for deglycerolization;
    (iv) The time the additive or rejuvenation solution was added;
    (v) The time the product was entered for washing or removing plasma 
(if prepared in an open system);
    (vi) As specified in the instructions for use by the blood 
collection, processing, and storage system approved or cleared for such 
use by FDA; or
    (vii) As approved by the Director, Center for Biologics Evaluation 
and Research, in a biologics license application or supplement to the 
application.
    (2) For licensed Whole Blood and blood components, the date of 
manufacture must be identified in the approved biologics license 
application or supplement to the application.

[81 FR 26691, May 4, 2016]



Sec.  610.53  Dating periods for Whole Blood and blood components.

    (a) General. Dating periods for Whole Blood and blood components are 
specified in the table in paragraph (b) of this section.
    (b) Table of dating periods. In using the table in this paragraph, 
when a product in column A is stored at the storage temperature 
prescribed in column B, storage of a product must not exceed the dating 
period specified in column C, unless a different dating period is 
specified in the instructions for use by the blood collection, 
processing and storage system approved or cleared for such use by FDA. 
Container labels for each product must include the recommended storage 
temperatures.

Whole Blood and Blood Components Storage Temperatures and Dating Periods
------------------------------------------------------------------------
              A                         B                     C
------------------------------------------------------------------------
           Product             Storage temperature      Dating period
------------------------------------------------------------------------
                               Whole Blood
------------------------------------------------------------------------
ACD, CPD, CP2D..............  Between 1 and 6       21 days from date of
                               [deg]C.               collection.
CPDA-1......................  do \1\..............  35 days from date of
                                                     collection.
------------------------------------------------------------------------
                             Red Blood Cells
------------------------------------------------------------------------
ACD, CPD, CP2D..............  Between 1 and 6       21 days from date of
                               [deg]C.               collection.
CPDA-1......................  do..................  35 days from date of
                                                     collection.
Additive solutions..........  do..................  42 days from date of
                                                     collection.
Open system.................  do..................  24 hours after
(e.g., deglycerolized,                               entering bag.
 washed).
Deglycerolized in closed      do..................  14 days after
 system with additive                                entering bag.
 solution added.
Irradiated..................  do..................  28 days from date of
                                                     irradiation or
                                                     original dating,
                                                     whichever is
                                                     shorter.
Frozen......................  -65 [deg]C or colder  10 years from date
                                                     of collection.
------------------------------------------------------------------------
                                Platelets
------------------------------------------------------------------------
Platelets...................  Between 20 and 24     5 days from date of
                               [deg]C.               collection.
Platelets...................  Other temperatures    As specified in the
                               according to          instructions for
                               storage bag           use by the blood
                               instructions.         collection,
                                                     processing and
                                                     storage system
                                                     approved or cleared
                                                     for such use by
                                                     FDA.
------------------------------------------------------------------------
                                 Plasma
------------------------------------------------------------------------
Fresh Frozen Plasma.........  -18 [deg]C or colder  1 year from date of
                                                     collection.
Plasma Frozen Within 24       do..................  1 year from date of
 Hours After Phlebotomy.                             collection.
Plasma Frozen Within 24       do..................  1 year from date of
 Hours After Phlebotomy Held                         collection.
 at Room Temperature Up To
 24 Hours After Phlebotomy.
Plasma Cryoprecipitate        do..................  1 year from date of
 Reduced.                                            collection.
Plasma......................  do..................  5 years from date of
                                                     collection.
Liquid Plasma...............  Between 1 and 6       5 days from end of
                               [deg]C.               Whole Blood dating
                                                     period.
Source Plasma (frozen         -20 [deg]C or colder  10 years from date
 injectable).                                        of collection.

[[Page 80]]

 
Source Plasma Liquid          10 [deg]C or colder.  According to
 (injectable).                                       approved biologics
                                                     license
                                                     application.
Source Plasma                 Temperature           10 years from date
 (noninjectable).              appropriate for       of collection.
                               final product.
Therapeutic Exchange Plasma.  -20 [deg]C or colder  10 years from date
                                                     of collection.
------------------------------------------------------------------------
                          Cryoprecipitated AHF
------------------------------------------------------------------------
Cryoprecipitated AHF........  -18 [deg]C or colder  1 year from date of
                                                     collection of
                                                     source blood or
                                                     from date of
                                                     collection of
                                                     oldest source blood
                                                     in pre-storage
                                                     pool.
------------------------------------------------------------------------
                            Source Leukocytes
------------------------------------------------------------------------
Source Leukocytes...........  Temperature           In lieu of
                               appropriate for       expiration date,
                               final product.        the collection date
                                                     must appear on the
                                                     label.
------------------------------------------------------------------------
\1\ The abbreviation ``do.'' for ditto is used in the table to indicate
  that the previous line is being repeated.


[81 FR 26691, May 4, 2016]



                      Subpart G_Labeling Standards



Sec.  610.60  Container label.

    (a) Full label. The following items shall appear on the label 
affixed to each container of a product capable of bearing a full label:
    (1) The proper name of the product;
    (2) The name, address, and license number of manufacturer;
    (3) The lot number or other lot identification;
    (4) The expiration date;
    (5) The recommended individual dose, for multiple dose containers.
    (6) The statement: `` `Rx only' '' for prescription biologicals.
    (7) If a Medication Guide is required under part 208 of this 
chapter, the statement required under Sec.  208.24(d) of this chapter 
instructing the authorized dispenser to provide a Medication Guide to 
each patient to whom the drug is dispensed and stating how the 
Medication Guide is provided, except where the container label is too 
small, the required statement may be placed on the package label.
    (b) Package label information. If the container is not enclosed in a 
package, all the items required for a package label shall appear on the 
container label.
    (c) Partial label. If the container is capable of bearing only a 
partial label, the container shall show as a minimum the name (expressed 
either as the proper or common name), the lot number or other lot 
identification and the name of the manufacturer; in addition, for 
multiple dose containers, the recommended individual dose. Containers 
bearing partial labels shall be placed in a package which bears all the 
items required for a package label.
    (d) No container label. If the container is incapable of bearing any 
label, the items required for a container label may be omitted, provided 
the container is placed in a package which bears all the items required 
for a package label.
    (e) Visual inspection. When the label has been affixed to the 
container a sufficient area of the container shall remain uncovered for 
its full length or circumference to permit inspection of the contents.

[38 FR 32056, Nov. 20, 1973, as amended at 47 FR 22518, May 25, 1982; 63 
FR 66400, Dec. 1, 1998; 67 FR 4907, Feb. 1, 2002]



Sec.  610.61  Package label.

    The following items shall appear on the label affixed to each 
package containing a product:
    (a) The proper name of the product;
    (b) The name, address, and license number of manufacturer;
    (c) The lot number or other lot identification;
    (d) The expiration date;
    (e) The preservative used and its concentration, or if no 
preservative is used and the absence of a preservative is a

[[Page 81]]

safety factor, the words ``no preservative'';
    (f) The number of containers, if more than one;
    (g) The amount of product in the container expressed as (1) the 
number of doses, (2) volume, (3) units of potency, (4) weight, (5) 
equivalent volume (for dried product to be reconstituted), or (6) such 
combination of the foregoing as needed for an accurate description of 
the contents, whichever is applicable;
    (h) The recommended storage temperature;
    (i) The words ``Shake Well'', ``Do not Freeze'' or the equivalent, 
as well as other instructions, when indicated by the character of the 
product;
    (j) The recommended individual dose if the enclosed container(s) is 
a multiple-dose container;
    (k) The route of administration recommended, or reference to such 
directions in an enclosed circular;
    (l) Known sensitizing substances, or reference to an enclosed 
circular containing appropriate information;
    (m) The type and calculated amount of antibiotics added during 
manufacture;
    (n) The inactive ingredients when a safety factor, or reference to 
an enclosed circular containing appropriate information;
    (o) The adjuvant, if present;
    (p) The source of the product when a factor in safe administration;
    (q) The identity of each microorganism used in manufacture, and, 
where applicable, the production medium and the method of inactivation, 
or reference to an enclosed circular containing appropriate information;
    (r) Minimum potency of product expressed in terms of official 
standard of potency or, if potency is a factor and no U.S. standard of 
potency has been prescribed, the words ``No U.S. standard of potency.''
    (s) The statement: `` `Rx only' '' for prescription biologicals.

[38 FR 32056, Nov. 20, 1973, as amended at 47 FR 22518, May 25, 1982; 55 
FR 10423, Mar. 21, 1990; 67 FR 4907, Feb. 1, 2002]



Sec.  610.62  Proper name; package label; legible type.

    (a) Position. The proper name of the product on the package label 
shall be placed above any trademark or trade name identifying the 
product and symmetrically arranged with respect to other printing on the 
label.
    (b) Prominence. The point size and typeface of the proper name shall 
be at least as prominent as the point size and typeface used in 
designating the trademark and trade name. The contrast in color value 
between the proper name and the background shall be at least as great as 
the color value between the trademark and trade name and the background. 
Typography, layout, contrast, and other printing features shall not be 
used in a manner that will affect adversely the prominence of the proper 
name.
    (c) Legible type. All items required to be on the container label 
and package label shall be in legible type. ``Legible type'' is type of 
a size and character which can be read with ease when held in a good 
light and with normal vision.



Sec.  610.63  Divided manufacturing responsibility to be shown.

    If two or more licensed manufacturers participate in the manufacture 
of a biological product, the name, address, and license number of each 
must appear on the package label, and on the label of the container if 
capable of bearing a full label.

[64 FR 56453, Oct. 20, 1999]



Sec.  610.64  Name and address of distributor.

    The name and address of the distributor of a product may appear on 
the label provided that the name, address, and license number of the 
manufacturer also appears on the label and the name of the distributor 
is qualified by one of the following phrases: ``Manufactured for 
_____'', ``Distributed by ______'', ``Manufactured by _____ for _____'', 
``Manufactured for _____ by ____'', ``Distributor: _____'', or 
``Marketed by _____''. The qualifying phrases may be abbreviated.

[61 FR 57330, Nov. 6, 1996]



Sec.  610.65  Products for export.

    Labels on packages or containers of products for export may be 
adapted to meet specific requirements of the regulations of the country 
to which the

[[Page 82]]

product is to be exported provided that in all such cases the minimum 
label requirements prescribed in Sec.  610.60 are observed.



Sec.  610.67  Bar code label requirements.

    Biological products must comply with the bar code requirements at 
Sec.  201.25 of this chapter. However, the bar code requirements do not 
apply to devices regulated by the Center for Biologics Evaluation and 
Research or to blood and blood components intended for transfusion. For 
blood and blood components intended for transfusion, the requirements at 
Sec.  606.121(c)(13) of this chapter apply instead.

[69 FR 9171, Feb. 26, 2004]



Sec.  610.68  Exceptions or alternatives to labeling requirements for
biological 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 biological 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 biological 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 
biological 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 the biological product that 
are or will be included 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 biological 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.  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.  
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 chapter, to the extent 
that the requirements in these provisions are not explicitly required by 
statute:
    (1) Sec.  610.60;

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    (2) Sec.  610.61(c) and (e) through (r);
    (3) Sec.  610.62;
    (4) Sec.  610.63;
    (5) Sec.  610.64;
    (6) Sec.  610.65; and
    (7) Sec.  312.6.

[72 FR 73600, Dec. 28, 2007]



PART 630_REQUIREMENTS FOR BLOOD AND BLOOD COMPONENTS INTENDED FOR
TRANSFUSION OR FOR FURTHER MANUFACTURING USE--Table of Contents



                      Subpart A_General Provisions

630.1 Purpose and scope.
630.3 Definitions.

                Subpart B_Donor Eligibility Requirements

630.5 Medical supervision.
630.10 General donor eligibility requirements.
630.15 Donor eligibility requirements specific to Whole Blood, Red Blood 
          Cells and Plasma collected by apheresis.
630.20 Exceptions for certain ineligible donors.
630.25 Exceptions from certain donor eligibility requirements for 
          infrequent plasma donors.
630.30 Donation suitability requirements.
630.35 Requalification of previously deferred donors.

                      Subpart C_Donor Notification

630.40 Requirements for notifying deferred donors.

    Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 371; 42 U.S.C. 
216, 262, 264.

    Source: 66 FR 31176, June 11, 2001, unless otherwise noted.



                      Subpart A_General Provisions

    Source: 80 FR 29898, May 22, 2015, unless otherwise noted.



Sec.  630.1  Purpose and scope.

    (a) What is the purpose of subparts A, B, and C of this part? The 
purpose of these subparts, together with Sec. Sec.  610.40 and 610.41 of 
this chapter, is to provide certain minimum criteria for each donation 
of blood and blood components, for:
    (1) Determining the eligibility of a donor of blood and blood 
components;
    (2) Determining the suitability of the donation of blood and blood 
components; and
    (3) Notifying a donor who is deferred from donation.
    (b) Who must comply with subparts A, B, and C of this part? Blood 
establishments that manufacture blood and blood components, as defined 
in Sec.  630.3(a) and (b), must comply with subparts A, B, and C of this 
part.



Sec.  630.3  Definitions.

    As used in this part and in part 610, subpart E, and part 640 of 
this chapter:
    (a) Blood means a product that is a fluid containing dissolved and 
suspended elements which was collected from the vascular system of a 
human.
    (b) Blood component means a product containing a part of blood 
separated by physical or mechanical means.
    (c) Donor means a person who: (1) Donates blood or blood components 
for transfusion or for further manufacturing use; or
    (2) Presents as a potential candidate for such donation.
    (d) Eligibility of a donor means the determination that the donor is 
qualified to donate blood and blood components.
    (e) Infrequent plasma donor means a donor who has:
    (1) Not donated plasma by plasmapheresis or a co-collection of 
plasma with another blood component in the preceding 4 weeks; and
    (2) Not donated more than 12.0 liters of plasma (14.4 liters of 
plasma for donors weighing more than 175 pounds) in the past year.
    (f) Intimate contact with risk for a relevant transfusion-
transmitted infection means having engaged in an activity that could 
result in the transfer of potentially infectious body fluids from one 
person to another.
    (g) Physician substitute means a trained and qualified person(s) who 
is:
    (1) A graduate of an education program for health care workers that 
includes clinical training;
    (2) Currently licensed or certified as a health care worker in the 
jurisdiction where the collection establishment is located;
    (3) Currently certified in cardiopulmonary resuscitation; and

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    (4) Trained and authorized under State law, and/or local law when 
applicable, to perform the specified functions under the direction of 
the responsible physician.
    (h) Relevant transfusion-transmitted infection means:
    (1) Any of the following transfusion-transmitted infections:
    (i) Human immunodeficiency virus, types 1 and 2 (referred to, 
collectively, as HIV);
    (ii) Hepatitis B virus (referred to as HBV);
    (iii) Hepatitis C virus (referred to as HCV);
    (iv) Human T-lymphotropic virus, types I and II (referred to, 
collectively, as HTLV);
    (v) Treponema pallidum (referred to as syphilis);
    (vi) West Nile virus;
    (vii) Trypanosoma cruzi (referred to as Chagas disease);
    (viii) Creutzfeldt-Jakob disease (referred to as CJD);
    (ix) Variant Creutzfeldt-Jakob disease (referred to as vCJD); and
    (x) Plasmodium species (referred to as malaria).
    (2) A transfusion-transmitted infection not listed in paragraph 
(h)(1) of this section when the following conditions are met:
    (i) Appropriate screening measures for the transfusion-transmitted 
infection have been developed and/or an appropriate screening test has 
been licensed, approved, or cleared for such use by FDA and is 
available; and
    (ii) The disease or disease agent:
    (A) May have sufficient incidence and/or prevalence to affect the 
potential donor population; or
    (B) May have been released accidentally or intentionally in a manner 
that could place potential donors at risk of infection.
    (i) Responsible physician means an individual who is:
    (1) Licensed to practice medicine in the jurisdiction where the 
collection establishment is located;
    (2) Adequately trained and qualified to direct and control personnel 
and relevant procedures concerning the determination of donor 
eligibility; collection of blood and blood components; the immunization 
of a donor; and the return of red blood cells or other blood components 
to the donor during collection of blood component(s) by apheresis; and
    (3) Designated by the collection establishment to perform the 
activities described in paragraph (i)(2) of this section.
    (j) Suitability of the donation means a determination of whether the 
donation is acceptable for transfusion or for further manufacturing use.
    (k) Trained person means an individual, including a physician 
substitute, who is authorized under State law, and/or local law when 
applicable, and adequately instructed and qualified to perform the 
specified functions under the direction of the responsible physician.
    (l) Transfusion-transmitted infection means a disease or disease 
agent:
    (1) That could be fatal or life-threatening, could result in 
permanent impairment of a body function or permanent damage to a body 
structure, or could necessitate medical or surgical intervention to 
preclude permanent impairment of body function or permanent damage to a 
body structure; and
    (2) For which there may be a risk of transmission by blood or blood 
components, or by a blood derivative product manufactured from blood or 
blood components, because the disease or disease agent is potentially 
transmissible by that blood, blood component, or blood derivative 
product.



                Subpart B_Donor Eligibility Requirements

    Source: 80 FR 29898, May 22, 2015, unless otherwise noted.



Sec.  630.5  Medical supervision.

    (a) Who must determine the eligibility of a donor? The responsible 
physician must determine the eligibility of a donor of blood or blood 
components in accordance with this subchapter.
    (b) Which activities related to the collection of blood and blood 
components, other than Source Plasma and plasma collected by 
plasmapheresis, may the responsible physician delegate?
    (1) The responsible physician may delegate the following activities 
to a

[[Page 85]]

physician substitute or other trained person:
    (i) Determining the eligibility of a donor and documenting 
assessments related to that determination, except the responsible 
physician must not delegate:
    (A) The examination and determination of the donor's health required 
in Sec.  630.10(f)(2) for donors with blood pressure measurements 
outside specified limits, or for certain more frequent donations under 
Sec.  630.15(a)(1)(ii);
    (B) The determination of the health of the donor required in 
Sec. Sec.  630.10(f)(4), 630.20(a), and 640.21(e)(4) of this chapter. 
The responsible physician may make this determination by telephonic or 
other offsite consultation; or
    (C) The determination of the health of the donor and the 
determination that the blood or blood component collected would present 
no undue medical risk to the transfusion recipient, as required in Sec.  
630.20(c). The responsible physician may make these determinations by 
telephonic or other offsite consultation.
    (ii) Collecting blood or blood components;
    (iii) Returning red blood cells to the donor during apheresis;
    (iv) Obtaining the informed consent of a plateletpheresis donor as 
described in Sec.  640.21(g) of this chapter; or
    (v) Other activities provided that the Director, Center for 
Biologics Evaluation and Research, determines that delegating the 
activities would present no undue medical risk to the donor or to the 
transfusion recipient, and authorizes the delegation of such activities.
    (2) The responsible physician need not be present at the collection 
site when activities delegated under paragraph (b)(1) of this section 
are performed, provided that the responsible physician has delegated 
oversight of these activities to a trained person who is adequately 
trained and experienced in the performance of these activities and is 
also adequately trained and experienced in the recognition of and 
response to the known adverse responses associated with blood collection 
procedures.
    (c) Which activities related to the collection of Source Plasma and 
plasma collected by plasmapheresis may the responsible physician 
delegate?
    (1) Donor eligibility and blood component collection activities. (i) 
The responsible physician may delegate to a physician substitute or 
other trained person any of the activities described in paragraph 
(c)(1)(i)(A) of this section, provided that the responsible physician or 
a physician substitute is on the premises at the collection site:
    (A) The activities listed in paragraphs (b)(1)(i) through (iii) and 
(b)(1)(v) of this section, with respect to Source Plasma and plasma 
collected by plasmapheresis. However, the responsible physician must not 
delegate:
    (1) The examination and determination of the donor's health required 
in Sec.  630.10(f)(2) for donors with blood pressure measurements 
outside specified limits, or in Sec.  630.15(b)(7) for certain donors 
who have experienced red blood cell loss;
    (2) The determination of the health of the donor required in 
Sec. Sec.  630.10(f)(4) and 630.20(a) and (b). The responsible physician 
may make this determination by telephonic or other offsite consultation;
    (3) The determination of the health of the donor and the 
determination that the blood component would present no undue medical 
risk to the transfusion recipient, as required in Sec.  630.20(c). The 
responsible physician may make this determination by telephonic or other 
offsite consultation.
    (4) The determination related to a donor's false-positive reaction 
to a serologic test for syphilis in accordance with Sec.  
640.65(b)(2)(iii) of this chapter; and
    (5) The determination to permit plasmapheresis of a donor with a 
reactive serological test for syphilis in accordance with Sec.  
640.65(b)(2)(iv) of this chapter.
    (B) The collection of Source Plasma in an approved collection 
program from a donor who is otherwise determined to be ineligible.
    (C) The collection of a blood sample in accordance with Sec.  
640.65(b)(1)(i) of this chapter.
    (ii) The responsible physician, who may or may not be present when 
these activities are performed, may delegate

[[Page 86]]

to a physician substitute the following activities:
    (A) Approval and signature for a plasmapheresis procedure as 
provided in Sec.  640.65(b)(1)(ii) of this chapter; and
    (B) Review and signature for accumulated laboratory data, the 
calculated values of each component, and the collection records in 
accordance with Sec.  640.65(b)(2)(i) of this chapter. However, the 
responsible physician must not delegate the decision to reinstate the 
deferred donor in accordance with that provision.
    (2) Donor immunization. The responsible physician must not delegate 
activities performed in accordance with Sec.  640.66 of this chapter, 
except that:
    (i) The responsible physician may delegate to a physician substitute 
or other trained person the administration of an immunization other than 
red blood cells to a donor in an approved collection program, provided 
that the responsible physician or a physician substitute is on the 
premises at the collection site when the immunization is administered.
    (ii) The responsible physician may delegate to a physician 
substitute the administration of red blood cells to a donor in an 
approved collection program, provided that the responsible physician has 
approved the procedure and is on the premises at the collection site 
when the red blood cells are administered.
    (3) Medical history, physical examination, informed consent, and 
examination before immunization. Provided that such activities are 
performed under the supervision of the responsible physician, the 
responsible physician may delegate to a physician substitute the 
activities described in Sec.  630.15(b)(1), (2), and (5). The 
responsible physician is not required to be present at the collection 
site when the physician substitute performs these activities under 
supervision.
    (4) Infrequent plasma donors. (i) For infrequent plasma donors other 
than those described in paragraph (c)(4)(ii) of this section, the 
responsible physician may delegate to a trained person the activities 
listed in paragraphs (b)(1)(i) through (iii) and (b)(1)(v) of this 
section and the informed consent requirements described in Sec.  
630.15(b)(2). The responsible physician or a physician substitute need 
not be present at the collection site when any of these activities are 
performed, provided that the responsible physician has delegated 
oversight of these activities to a trained person who is not only 
adequately trained and experienced in the performance of these 
activities but also adequately trained and experienced in the 
recognition of and response to the known adverse responses associated 
with blood collection procedures. However, the responsible physician 
must not delegate:
    (A) The examination and determination of the donor's health required 
in Sec.  630.10(f)(2) for donors with blood pressure measurements 
outside specified limits, or in Sec.  630.15(b)(7) for certain donors 
who have experienced red blood cell loss; or
    (B) The determination of the health of the donor required in Sec.  
630.10(f)(4).
    (ii) For infrequent plasma donors who are otherwise ineligible or 
are participating in an approved immunization program, the responsible 
physician may delegate only in accordance with paragraphs (c)(1) through 
(3) of this section.
    (d) Must rapid emergency medical services be available? 
Establishments that collect blood or blood components must establish, 
maintain, and follow standard operating procedures for obtaining rapid 
emergency medical services for donors when medically necessary. In 
addition, establishments must assure that an individual (responsible 
physician, physician substitute, or trained person) who is currently 
certified in cardiopulmonary resuscitation is located on the premises 
whenever collections of blood or blood components are performed.



Sec.  630.10  General donor eligibility requirements.

    (a) What factors determine the eligibility of a donor? You, an 
establishment that collects blood or blood components, must not collect 
blood or blood components before determining that the donor is eligible 
to donate or before determining that an exception to this provision 
applies. To be eligible, the donor must be in good health and free

[[Page 87]]

from transfusion-transmitted infections as can be determined by the 
processes in this subchapter. A donor is not eligible if the donor is 
not in good health or if you identify any factor(s) that may cause the 
donation to adversely affect:
    (1) The health of the donor; or
    (2) The safety, purity, or potency of the blood or blood component.
    (b) What educational material must you provide to the donor before 
determining eligibility? You must provide educational material 
concerning relevant transfusion-transmitted infections to donors before 
donation when donor education about that relevant transfusion-
transmitted infection, such as HIV, is necessary to assure the safety, 
purity, and potency of blood and blood components. The educational 
material must include an explanation of the readily identifiable risk 
factors closely associated with exposure to the relevant transfusion-
transmitted infection. You must present educational material in an 
appropriate form, such as oral, written or multimedia, and in a manner 
designed to be understood by the donor. The educational material must 
instruct the donor not to donate blood and blood components when a risk 
factor is present. When providing educational material to donors under 
this section, you may include in those materials the information 
required to be provided to donors under paragraph (g)(2)(ii)(E) of this 
section.
    (c) When must you determine the eligibility of a donor? You must 
determine donor eligibility on the day of donation, and before 
collection. Except:
    (1) When a donor is donating blood components that cannot be stored 
for more than 24 hours, you may determine the donor's eligibility and 
collect a sample for testing required under Sec.  610.40 of this 
chapter, no earlier than 2 calendar days before the day of donation, 
provided that your standard operating procedures address these 
activities.
    (2) In the event that, upon review, you find that a donor's 
responses to the donor questions before collection were incomplete, 
within 24 hours of the time of collection, you may clarify a donor's 
response or obtain omitted information required under paragraph (e) of 
this section, provided that your standard operating procedures address 
these activities.
    (d) How must you determine the eligibility of a donor? You must 
determine the donor's eligibility before collection of blood or blood 
components, by the following procedures:
    (1) You must consult the records of deferred donors maintained under 
Sec.  606.160(e)(1) and (2) of this chapter. Exception: If pre-
collection review of the record described in Sec.  606.160(e)(2) of this 
chapter is not feasible because you cannot consult the cumulative record 
at the collection site, you must consult the cumulative record prior to 
release of any blood or blood component prepared from the collection.
    (2) Assure that the interval since the donor's last donation is 
appropriate;
    (3) Assess the donor's medical history; and
    (4) Perform a physical assessment of the donor.
    (e) How do you assess the donor's medical history? Before collection 
you must conduct a medical history interview as described in this 
section to determine if the donor is in good health; to identify risk 
factors closely associated with exposure to, or clinical evidence of a 
relevant transfusion-transmitted infection; and to determine if there 
are other conditions that may adversely affect the health of the donor 
or the safety, purity, or potency of the blood or blood components or 
any product manufactured from the blood or blood components. Your 
assessment must include each of the following factors:
    (1) Factors that make the donor ineligible to donate because of an 
increased risk for, or evidence of, a relevant transfusion-transmitted 
infection. A donor is ineligible to donate when information provided by 
the donor or other reliable evidence indicates possible exposure to a 
relevant transfusion-transmitted infection if that risk of exposure is 
still applicable at the time of donation. Information and evidence 
indicating possible exposure to a relevant transfusion-transmitted 
infection include:
    (i) Behaviors associated with a relevant transfusion-transmitted 
infection;

[[Page 88]]

    (ii) Receipt of blood or blood components or other medical 
treatments and procedures associated with possible exposure to a 
relevant transfusion-transmitted infection;
    (iii) Signs and/or symptoms of a relevant transfusion-transmitted 
infection;
    (iv) Institutionalization for 72 hours or more consecutively in the 
past 12 months in a correctional institution;
    (v) Intimate contact with risk for a relevant transfusion-
transmitted infection; and
    (vi) Nonsterile percutaneous inoculation.
    (2) Other factors that make the donor ineligible to donate. A donor 
is ineligible to donate when donating could adversely affect the health 
of the donor, or when the safety, purity, or potency of the blood or 
blood component could be affected adversely. Your assessment of the 
donor must include each of the following factors:
    (i) Symptoms of a recent or current illness;
    (ii) Certain medical treatments or medications;
    (iii) Travel to, or residence in, an area endemic for a transfusion-
transmitted infection, when such screening is necessary to assure the 
safety, purity, and potency of blood and blood components due to the 
risks presented by donor travel and the risk of transmission of that 
transfusion-transmitted infection by such donors;
    (iv) Exposure or possible exposure to an accidentally or 
intentionally released disease or disease agent relating to a 
transfusion-transmitted infection, if you know or suspect that such a 
release has occurred;
    (v) Pregnancy at the time of, or within 6 weeks prior to, donation;
    (vi) Whether, in the opinion of the interviewer, the donor appears 
to be under the influence of any drug, alcohol or for any reason does 
not appear to be providing reliable answers to medical history 
questions, or if the donor says that the purpose of donating is to 
obtain test results for a relevant transfusion-transmitted infection; 
and
    (vii) The donor is a xenotransplantation product recipient.
    (f) How do you perform a physical assessment of the donor? You must 
determine on the day of donation, and before collection that the donor 
is in good health based on the following, at a minimum:
    (1) Temperature. The donor's oral body temperature must not exceed 
37.5 [deg]C (99.5 [deg]F), or the equivalent if measured at another body 
site;
    (2) Blood pressure. The donor's systolic blood pressure must not 
measure above 180 mm of mercury, or below 90 mm of mercury, and the 
diastolic blood pressure must not measure above 100 mm of mercury or 
below 50 mms of mercury. A donor with measurements outside these limits 
may be permitted to donate only when the responsible physician examines 
the donor and determines and documents that the health of the donor 
would not be adversely affected by donating.
    (3) Hemoglobin or hematocrit determination. You must determine the 
donor's hemoglobin level or hematocrit value by using a sample of blood 
obtained by fingerstick, venipuncture, or by a method that provides 
equivalent results. Blood obtained from the earlobe is not acceptable.
    (i) Allogeneic donors must have a hemoglobin level or hematocrit 
value that is adequate to assure donor safety and product potency. The 
following minimum standards apply.
    (A) Female allogeneic donors must have a hemoglobin level that is 
equal to or greater than 12.5 grams of hemoglobin per deciliter of 
blood, or a hematocrit value that is equal to or greater than 38 
percent. Recognizing that lower levels are also within normal limits for 
female donors, you may collect blood from female allogeneic donors who 
have a hemoglobin level between 12.0 and 12.5 grams per deciliter of 
blood, or a hematocrit value between 36 and 38 percent, provided that 
you have taken additional steps to assure that this alternative standard 
is adequate to ensure that the health of the donor will not be adversely 
affected due to the donation, in accordance with a procedure that has 
been found acceptable for this purpose by FDA.
    (B) Male allogeneic donors must have a hemoglobin level that is 
equal to or greater than 13.0 grams of hemoglobin

[[Page 89]]

per deciliter of blood, or a hematocrit value that is equal to or 
greater than 39 percent.
    (ii) An autologous donor must have a hemoglobin level no less than 
11.0 grams of hemoglobin per deciliter of blood, or a hematocrit value 
no less than 33 percent.
    (4) Pulse. The donor's pulse must be regular and between 50 and 100 
beats per minute. A donor with an irregular pulse or measurements 
outside these limits may be permitted to donate only when the 
responsible physician determines and documents that the health of the 
donor would not be adversely affected by donating.
    (5) Weight. The donor must weigh a minimum of 50 kilograms (110 
pounds).
    (6) Skin examination. (i) The donor's phlebotomy site must be free 
of infection, inflammation, and lesions; and
    (ii) The donor's arms and forearms must be free of punctures and 
scars indicative of injected drugs of abuse.
    (g) Are there additional requirements for determining the 
eligibility of the donor? You must obtain the following from the donor 
on the day of donation:
    (1) Proof of identity and postal address. You must obtain proof of 
identity of the donor and a postal address where the donor may be 
contacted for 8 weeks after donation; and
    (2) Donor's acknowledgement. (i) Prior to each donation, you must 
provide information to the donor addressing the elements specified in 
paragraphs (g)(2)(ii)(A) through (E) of this section and obtain the 
donor's acknowledgement that the donor has reviewed the information. You 
must establish procedures in accordance with Sec.  606.100 of this 
chapter to assure that the donor has reviewed this material, and provide 
for a signature or other documented acknowledgement.
    (ii) The donor acknowledgement must not include any exculpatory 
language through which the donor is made to waive or appear to waive any 
of the donor's legal rights. It must, at a minimum clearly address the 
following:
    (A) The donor has reviewed the educational material provided under 
paragraph (b) of this section regarding relevant transfusion-transmitted 
infections;
    (B) The donor agrees not to donate if the donation could result in a 
potential risk to recipients as described in the educational material;
    (C) A sample of the donor's blood will be tested for specified 
relevant transfusion-transmitted infections;
    (D) If the donation is determined to be not suitable under Sec.  
630.30(a) or if the donor is deferred from donation under Sec.  610.41 
of this chapter, the donor's record will identify the donor as 
ineligible to donate and the donor will be notified under Sec.  630.40 
of the basis for the deferral and the period of deferral;
    (E) The donor has been provided and reviewed information regarding 
the risks and hazards of the specific donation procedure; and
    (F) The donor has the opportunity to ask questions and withdraw from 
the donation procedure.
    (h) What must you do when a donor is not eligible? You must not 
collect blood or blood components from a donor found to be ineligible 
prior to collection based on criteria in Sec. Sec.  630.10 or 630.15, or 
deferred under Sec.  610.41 of this chapter or Sec.  630.30(b)(2), 
unless this subchapter provides an exception. You must defer donors 
found to be ineligible and you must notify the donor of their deferral 
under Sec.  630.40.



Sec.  630.15  Donor eligibility requirements specific to Whole Blood,
Red Blood Cells and Plasma collected by apheresis.

    (a) What additional donor eligibility requirements apply when you, 
an establishment that collects blood or blood components, collect Whole 
Blood or Red Blood Cells by apheresis?
    (1) Donation frequency must be consistent with protecting the health 
of the donor.
    (i) For a collection resulting in a single unit of Whole Blood or 
Red Blood Cells collected by apheresis, donation frequency must be no 
more than once in 8 weeks, and for apheresis collections resulting in 
two units of Red Blood Cells, the donor must not donate more than once 
in 16 weeks.
    (ii) The limitations in paragraph (a)(1)(i) of this section apply 
unless the responsible physician examines the donor at the time of 
donation and one of the following conditions exists:

[[Page 90]]

    (A) The donation is for autologous use as prescribed by the donor's 
physician and the responsible physician determines and documents that 
the donation may proceed; or
    (B) The donation is a dedicated donation based on the intended 
recipient's documented exceptional medical need and the responsible 
physician determines and documents that the health of the donor would 
not be adversely affected by donating.
    (2) Therapeutic phlebotomy. When a donor who is determined to be 
eligible under Sec.  630.10 undergoes a therapeutic phlebotomy under a 
prescription to promote the donor's health, you may collect from the 
donor more frequently than once in 8 weeks for collections resulting in 
a single unit of Whole Blood or Red Blood Cells, or once in 16 weeks for 
apheresis collections resulting in two units of Red Blood Cells, 
provided that the container label conspicuously states the disease or 
condition of the donor that necessitated phlebotomy. However, no 
labeling for the disease or condition is required under this section if:
    (i) The donor meets all eligibility criteria;
    (ii) The donor undergoes a therapeutic phlebotomy as prescribed by a 
licensed health care provider treating the donor for:
    (A) Hereditary hemochromatosis; or
    (B) Another disease or condition, when the health of a donor with 
that disease or condition will not be adversely affected by donating, 
and the donor's disease or condition will not adversely affect the 
safety, purity, and potency of the blood and blood components, or any 
products manufactured from them, and the collection is in accordance 
with a procedure that has been found acceptable for this purpose by FDA; 
and
    (iii) You perform without charge therapeutic phlebotomies for all 
individuals with that disease or condition.
    (b) What additional donor eligibility requirements apply when you, 
an establishment that collects blood or blood components, collect Source 
Plasma or plasma by plasmapheresis?
    (1) Medical history and physical examination. Except as provided in 
Sec.  630.25:
    (i) The responsible physician must conduct an appropriate medical 
history and physical examination of the donor on the day of the first 
donation or no more than 1 week before the first donation and at 
subsequent intervals of no longer than 1 year.
    (ii) The responsible physician must examine the donor for medical 
conditions that would place the donor at risk from plasmapheresis. If 
the donor is determined to be at risk, you must defer the donor from 
donating.
    (iii) The responsible physician must conduct a new medical history 
and physical examination of a donor who does not return for 6 months.
    (2) What requirements apply to obtaining informed consent?
    (i) The responsible physician must obtain the informed consent of a 
plasma donor on the first day of donation or no more than 1 week before 
the first donation, and at subsequent intervals of no longer than 1 
year.
    (ii) The responsible physician must obtain the informed consent of a 
plasma donor who does not return within 6 months of the last donation.
    (iii) The responsible physician must explain the risks and hazards 
of the procedure to the donor. The explanation must include the risks of 
a hemolytic transfusion reaction if the donor is given the cells of 
another donor and the risks involved if the donor is immunized. The 
explanation must be made in such a manner that the donor may give their 
consent and has a clear opportunity to refuse the procedure.
    (iv) If a donor is enrolled in a new program, such as an 
immunization or special collection program, the responsible physician 
must again obtain an informed consent specific for that program.
    (3) Weight. You must weigh a donor at each donation.
    (4) Total protein level. You must determine the donor's total plasma 
protein level before each plasmapheresis procedure. The donor must have 
a total plasma protein level of no less than 6.0 grams per deciliter and 
no more than 9.0 grams per deciliter in a plasma sample or a serum 
sample.
    (5) Examination before immunization. (i) No more than 1 week before 
the first

[[Page 91]]

immunization injection for the production of high-titer antibody plasma, 
the responsible physician must conduct an appropriate medical history 
and physical examination, as described in paragraph (b)(1) of this 
section, in addition to assessing the general donor eligibility 
requirements under Sec.  630.10. It is not necessary to repeat the 
medical history and physical examination requirement in paragraph (b)(1) 
of this section, if the immunized donor's plasma is collected within 3 
weeks of the first immunization injection.
    (ii) You are not required to repeat the medical history and physical 
examination required under paragraph (b)(1) of this section for a donor 
currently participating in a plasmapheresis collection program and 
determined to be eligible under Sec.  630.10 unless the medical history 
and physical examination are due under paragraph (b)(1)(i) or 
(b)(1)(iii) of this section.
    (6) Deferral of donors due to red blood cell loss. (i) You must 
defer a donor from donating plasma by plasmapheresis for 8 weeks if the 
donor has donated a unit of Whole Blood, or a single unit of Red Blood 
Cells by apheresis. However, you may collect plasma by plasmapheresis 
after a donation of Whole Blood or a single unit of Red Blood Cells by 
apheresis after at least 2 calendar days have passed, provided that the 
extracorporeal volume of the apheresis device is less than 100 
milliliters.
    (ii) You must defer a donor from donating plasma by plasmapheresis 
for a period of 16 weeks if the donor donates two units of Red Blood 
Cells during a single apheresis procedure;
    (iii) You must defer a donor for 8 weeks or more if the cumulative 
red blood cell loss in any 8 week period could adversely affect donor 
health.
    (7) Exceptions to deferral due to red blood cell loss. You are not 
required to defer a Source Plasma donor from donating plasma by 
plasmapheresis due to red blood cell loss if the following conditions 
are met:
    (i) The responsible physician examines the donor at the time of the 
current donation and determines and documents that the donor is in good 
health and the donor's health permits the plasmapheresis;
    (ii) The donor's plasma possesses a property, such as an antibody, 
antigen, or protein deficiency that is transitory, of a highly unusual 
or infrequent specificity, or of an unusually high titer;
    (iii) The special characteristics of the donor's plasma and the need 
for plasmapheresis of the donor under Sec.  630.20(b) are documented at 
your establishment; and
    (iv) The extracorporeal volume of the apheresis device is less than 
100 milliliters.
    (8) Malaria. Freedom from risk of malaria is not required for a 
donor of Source Plasma.
    (9) You must comply with other requirements for collection of plasma 
in part 640 of this chapter and this part including restrictions on 
frequency of collection as specified in Sec. Sec.  640.32 and 640.65 of 
this chapter.



Sec.  630.20  Exceptions for certain ineligible donors.

    After assessing donor eligibility under Sec. Sec.  630.10 and 
630.15, an establishment may collect blood and blood components from a 
donor who is determined to be not eligible to donate under any provision 
of Sec.  630.10(e) and (f) or Sec.  630.15(a) if one of the following 
sets of conditions are met:
    (a) The donation is for autologous use only as prescribed by the 
donor's physician, the donor has a hemoglobin level no less than 11.0 
grams of hemoglobin per deciliter of blood or a hematocrit value no less 
than 33 percent, and the responsible physician determines and documents 
that the donor's health permits the collection procedure; or
    (b) The donation is collected under a Source Plasma collection 
program which has received prior written approval from the Director, 
Center for Biologics Evaluation and Research, to collect plasma for 
further manufacturing use into in vitro products for which there are no 
alternative sources, the donor meets the criteria in Sec.  630.10(f)(1) 
through (6), and the responsible physician determines and documents for 
each donation that the donor's health permits the collection procedure, 
and the collection takes place under the medical oversight specified

[[Page 92]]

in the approved plasmapheresis program.
    (c) The donation is restricted for use solely by a specific 
transfusion recipient based on documented exceptional medical need, and 
the responsible physician determines and documents that the donor's 
health permits the collection procedure, and that the donation presents 
no undue medical risk to the transfusion recipient.



Sec.  630.25  Exceptions from certain donor eligibility requirements for
infrequent plasma donors.

    For an infrequent plasma donor who is not participating in an 
immunization program, establishments are not required to:
    (a) Perform a medical history and physical examination of the donor 
under Sec.  630.15(b)(1);
    (b) Perform a test for total protein under Sec.  630.15(b)(4);
    (c) Determine the total plasma or serum protein and immunoglobulin 
composition under Sec.  640.65(b)(1)(i) of this chapter; or
    (d) Review the data and records as required in Sec.  640.65(b)(2)(i) 
of this chapter.



Sec.  630.30  Donation suitability requirements.

    (a) When is a donation suitable? A donation is suitable when:
    (1) The donor is not currently deferred from donation as determined 
by review of the records of deferred donors required under Sec.  
606.160(e) of this chapter;
    (2) The results in accordance with Sec. Sec.  630.10 through 630.25 
indicate that the donor is in good health and procedures were followed 
to ensure that the donation would not adversely affect the health of the 
donor;
    (3) The results in accordance with Sec.  630.10(e) indicate that the 
donor is free from risk factors for, or evidence of, relevant 
transfusion-transmitted infections and other factors that make the donor 
ineligible to donate;
    (4) The donor's blood is tested in accordance with Sec.  610.40 of 
this chapter, and is negative or nonreactive, unless an exception 
applies under Sec.  610.40(h) of this chapter; and
    (5) The donation meets other requirements in this subchapter.
    (b) What must you do when the donation is not suitable? (1) You must 
not release the donation for transfusion or further manufacturing use 
unless it is an autologous donation, or an exception is provided in this 
chapter.
    (2) You must defer the donor when a donation is determined to be 
unsuitable based on the criteria in paragraphs (a)(1) through (4) of 
this section.
    (3) You must defer the donor of bacterially contaminated platelets 
when the contaminating organism is identified in accordance with Sec.  
606.145(d) of this chapter as likely to be associated with a bacterial 
infection that is endogenous to the bloodstream of the donor.
    (4) You must notify the deferred donor in accordance with the 
notification requirements in Sec.  630.40.



Sec.  630.35  Requalification of previously deferred donors.

    Establishments may determine a deferred donor to be eligible as a 
donor of blood and blood components if, at the time of the current 
collection, the donor meets the eligibility criteria in this part, 
except for the record of the previous deferral, and you determine that 
the criteria that were the basis for the previous deferral are no longer 
applicable. Criteria for the previous deferral are no longer applicable 
if the following conditions are met:
    (a) The previous deferral was for a defined period of time and that 
time period has passed, or the deferral was otherwise temporary, such as 
a deferral based on eligibility criteria described in Sec. Sec.  
630.10(f)(1) through (5) or 630.15(b)(4); or
    (b) For a donor deferred for reasons other than under Sec.  
610.41(a) of this chapter, you determine that the donor has met criteria 
for requalification by a method or process found acceptable for such 
purpose by FDA.



                      Subpart C_Donor Notification

    Source: 80 FR 29898, May 22, 2015, unless otherwise noted.



Sec.  630.40  Requirements for notifying deferred donors.

    (a) Notification of donors. You, an establishment that collects 
blood or

[[Page 93]]

blood components, must make reasonable attempts to notify any donor, 
including an autologous donor, who has been deferred based on the 
results of tests for evidence of infection with a relevant transfusion-
transmitted infection(s) as required by Sec.  610.41(a) of this chapter; 
any donor who has been deferred as required under Sec.  630.30(b)(3) 
because their donated platelets have been determined under Sec.  
606.145(d) of this chapter to be contaminated with an organism that is 
identified as likely to be associated with a bacterial infection that is 
endogenous to the bloodstream of the donor; and any donor who has been 
determined not to be eligible as a donor based on eligibility criteria 
under Sec. Sec.  630.10 and 630.15. You must attempt to obtain the 
results of further testing required under Sec.  610.40(e) of this 
chapter prior to notifying a donor of the deferral. If notification 
occurs prior to receipt of such results, you must also notify a deferred 
donor of the results of the further testing. You must notify a donor as 
described in paragraph (b) of this section.
    (b) Content of notification. You must provide the following 
information to a donor deferred or determined not to be eligible as a 
donor as described in paragraph (a) of this section:
    (1) That the donor is deferred or determined not to be eligible for 
donation and the reason for that decision;
    (2) Where appropriate, the types of donation of blood or blood 
components that the donor should not donate in the future;
    (3) Where applicable, the results of tests for evidence of infection 
due to relevant transfusion-transmitted infection(s) that were a basis 
for deferral under Sec.  610.41 of this chapter, including results of 
further testing as required in Sec.  610.40(e) of this chapter; and,
    (4) Where appropriate, information concerning medical followup and 
counseling.
    (c) Time period for notification. You must make reasonable attempts 
to notify the donor within 8 weeks after determining that the donor is 
deferred or determined not to be eligible for donation as described in 
paragraph (a) of this section. You must document that you have 
successfully notified the donor or when you are unsuccessful that you 
have made reasonable attempts to notify the donor.
    (d) Autologous donors. (1) You also must provide the following 
information to the referring physician of an autologous donor who is 
deferred based on the results of tests for evidence of infection with a 
relevant transfusion-transmitted infection(s) or whose platelets 
indicate evidence of a bacterial infection that is endogenous to the 
bloodstream of the donor as described in paragraph (a) of this section:
    (i) Information that the autologous donor is deferred based on the 
results of tests for evidence of infection due to relevant transfusion-
transmitted infection(s), as required under Sec.  610.41 of this 
chapter, and the reason for that decision;
    (ii) Where appropriate, the types of donation of blood or blood 
components that the autologous donor should not donate in the future; 
and
    (iii) The results of tests for evidence of infection due to relevant 
transfusion-transmitted infection(s), that were a basis for deferral 
under Sec.  610.41 of this chapter, including results of further testing 
as required in Sec.  610.40(e) of this chapter.
    (2) You must make reasonable attempts to notify the autologous 
donor's referring physician within 8 weeks after determining that the 
autologous donor is deferred as described in paragraph (a) of this 
section. You must document that you have successfully notified the 
autologous donor's referring physician or when you are unsuccessful that 
you have made reasonable attempts to notify the physician.

[66 FR 31176, June 11, 2001. Redesignated and amended at 80 FR 29898, 
May 22, 2015]



PART 640_ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS-
-Table of Contents



                          Subpart A_Whole Blood

Sec.
640.1 Whole Blood.
640.2 General requirements.
640.4 Collection of the blood.
640.5 Testing the blood.
640.6 Modifications of Whole Blood.

[[Page 94]]

                        Subpart B_Red Blood Cells

640.10 Red Blood Cells.
640.11 General requirements.
640.12 Eligibility of donor.
640.13 Collection of the blood.
640.14 Testing the blood.
640.15 Segments for testing.
640.16 Processing.
640.17 Modifications for specific products.

                           Subpart C_Platelets

640.20 Platelets.
640.21 Eligibility of donors.
640.22 Collection of source material.
640.23 Testing the blood.
640.24 Processing.
640.25 General requirements.

                            Subpart D_Plasma

640.30 Plasma.
640.31 Eligibility of donors.
640.32 Collection of source material.
640.33 Testing the blood.
640.34 Processing.

Subpart E [Reserved]

                        Subpart F_Cryoprecipitate

640.50 Cryoprecipitate AHF.
640.51 Eligibility of donors.
640.52 Collection of source material.
640.53 Testing the blood.
640.54 Processing.
640.55 U.S. Standard preparation.
640.56 Quality control test for potency.

                         Subpart G_Source Plasma

640.60 Source Plasma.
640.64 Collection of blood for Source Plasma.
640.65 Plasmapheresis.
640.66 Immunization of donors.
640.67 Laboratory tests.
640.68 Processing.
640.69 General requirements.
640.71 Manufacturing responsibility.
640.72 Records.
640.73 Reporting of fatal donor reactions.
640.74 Modification of Source Plasma.
640.76 Products stored or shipped at unacceptable temperatures.

                        Subpart H_Albumin (Human)

640.80 Albumin (Human).
640.81 Processing.
640.82 Tests on final product.
640.83 General requirements.
640.84 Labeling.

                Subpart I_Plasma Protein Fraction (Human)

640.90 Plasma Protein Fraction (Human).
640.91 Processing.
640.92 Tests on final product.
640.93 General requirements.
640.94 Labeling.

                    Subpart J_Immune Globulin (Human)

640.100 Immune Globulin (Human).
640.101 General requirements.
640.102 Manufacture of Immune Globulin (Human).
640.103 The final product.
640.104 Potency.

Subpart K [Reserved]

                    Subpart L_Alternative Procedures

640.120 Alternative procedures.

              Subpart M_Definitions and Medical Supervision

640.125 Definitions.
640.130 Medical supervision.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 U.S.C. 
216, 262, 263, 263a, 264.

    Source: 38 FR 32089, Nov. 20, 1973, unless otherwise noted.

    Cross References: For U.S. Customs Service regulations relating to 
viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal 
Service regulations relating to the admissibility to the United States 
mails see parts 124 and 125 of the Domestic Mail Manual, that is 
incorporated by reference in 39 CFR part 111.



                          Subpart A_Whole Blood



Sec.  640.1  Whole Blood.

    The proper name of this product shall be Whole Blood. Whole Blood is 
defined as blood collected from human donors for transfusion to human 
recipients.

[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985]



Sec.  640.2  General requirements.

    (a) Manufacturing responsibility. All manufacturing of Whole Blood, 
including donor examination, blood collection, laboratory tests, 
labeling, storage and issue, shall be done under the supervision and 
control of the same licensed establishment except that the Director, 
Center for Biologics Evaluation and Research, may approve arrangements, 
upon joint request of two or more licensed establishments, which

[[Page 95]]

he finds are of such a nature as to assure compliance otherwise with the 
provisions of this subchapter.
    (b) Blood container. The blood container shall not be entered prior 
to issue for any purpose except for blood collection or when the method 
of processing requires use of a different container. The container shall 
be uncolored and transparent to permit visual inspection of the contents 
and any closure shall be such as will maintain a hermetic seal and 
prevent contamination of the contents. The container material shall not 
interact with the contents under the customary conditions of storage and 
use, in such a manner as to have an adverse effect upon the safety, 
purity, or potency of the blood.
    (c) Reissue of blood. Blood that has been removed from storage 
controlled by a licensed establishment shall not be reissued by a 
licensed establishment unless the following conditions are observed:
    (1) The container has a tamper-proof seal when originally issued and 
this seal remains unbroken;
    (2) A segment is properly attached and has not been removed, except 
that blood lacking a properly attached segment may be reissued in an 
emergency provided it is accompanied by instructions for sampling and 
for use within 6 hours after entering the container for sampling;
    (3) The blood has been stored continuously at 1 to 6 [deg]C and 
shipped between 1 and 10 [deg]C;
    (4) The blood is held for observation until a significant inspection 
consistent with the requirements of Sec.  640.5(e) can be made.

[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 4015, Jan. 28, 1976; 42 
FR 59878, Nov. 22, 1977; 43 FR 34460, Aug. 4, 1978; 49 FR 15187, Apr. 
18, 1984; 49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 1985; 53 FR 
116, Jan. 5, 1988; 55 FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6, 
1998; 64 FR 45371, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 
31165, June 11, 2001; 66 FR 40889, Aug. 6, 2001; 67 FR 9587, Mar. 4, 
2002]



Sec.  640.4  Collection of the blood.

    (a) [Reserved]
    (b) The donor center. The pertinent requirements of Sec. Sec.  
600.10 and 600.11 of this chapter shall apply at both the blood 
establishment and at any other place where the bleeding is performed.
    (c) Blood containers. Blood containers and donor sets shall be 
pyrogen-free, sterile and identified by lot number. The amount of 
anticoagulant required for the quantity of blood to be collected shall 
be in the blood container when it is sterilized. In addition, all 
container and donor set surfaces that come in contact with blood used in 
the processing of Heparin Whole Blood shall be water repellent.
    (d) The anticoagulant solution. The anticoagulant solution shall be 
sterile and pyrogen-free. Anticoagulant solutions shall be compounded 
and used according to a formula approved by the Director, Center for 
Biologics Evaluation and Research.
    (e) Donor identification. Each unit of blood shall be so marked or 
identified by number or other symbol as to relate it to the individual 
donor whose identity shall be established to the extent necessary for 
compliance with Sec.  630.10 of this chapter.
    (f) Prevention of contamination of the blood. The skin of the donor 
at the site of phlebotomy shall be prepared thoroughly and carefully by 
a method that gives maximum assurance of a sterile container of blood. 
The blood shall be collected by aseptic methods in a sterile system 
which may be closed or may be vented if the vent protects the blood 
against contamination.
    (g) Samples and segments for laboratory tests. Samples and segments 
for laboratory tests shall meet the following standards:
    (1) One or more segments shall be provided with each unit of blood 
when issued or reissued except as provided in Sec.  640.2(c)(2) and all 
segments shall be from the donor who is the source of the unit of blood.
    (2) All samples for laboratory tests performed by the manufacturer 
and all segments accompanying a unit of blood shall be collected at the 
time of filling the original blood container.
    (3) All containers for all samples shall bear the donor's 
identification before collecting the samples.
    (4) All segments accompanying a unit of blood shall be attached to 
the whole blood container before blood collection,

[[Page 96]]

in a tamperproof manner that will conspicuously indicate removal and 
reattachment.
    (5) Segments for compatibility testing shall contain blood mixed 
with the appropriate anticoagulant.
    (h) Storage. Whole Blood must be placed in storage at a temperature 
between 1 and 6 [deg]C immediately after collection unless the blood is 
to be further processed into another component or the blood must be 
transported from the donor center to the processing laboratory. If 
transported, the blood must be placed in temporary storage having 
sufficient refrigeration capacity to cool the blood continuously toward 
a temperature range between 1 and 10 [deg]C until arrival at the 
processing laboratory. At the processing laboratory, the blood must be 
stored at a temperature between 1 and 6 [deg]C. Blood from which a 
component is to be prepared must be held in an environment maintained at 
a temperature range specified for that component in the directions for 
use for the blood collecting, processing, and storage system approved 
for such use by the Director, CBER.

[38 FR 32089, Nov. 20, 1973, as amended at 42 FR 59878, Nov. 22, 1977; 
43 FR 34460, Aug. 4, 1978; 49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 
29, 1985; 55 FR 11013, Mar. 26, 1990; 64 FR 45372, Aug. 19, 1999; 66 FR 
1836, Jan. 10, 2001; 66 FR 40889, Aug. 6, 2001; 72 FR 45887, Aug. 16, 
2007; 73 FR 7464, Feb. 8, 2008; 80 FR 29904, May 22, 2015]



Sec.  640.5  Testing the blood.

    All laboratory tests shall be made on a specimen of blood taken from 
the donor, and these tests shall include the following:
    (a) [Reserved]
    (b) Determination of blood group. Each container of Whole Blood 
shall be classified as to ABO blood group. At least two blood group 
tests shall be made and the unit shall not be issued until grouping 
tests by different methods or with different lots of antiserums are in 
agreement. Only those Anti-A and Anti-B Blood Grouping Reagents licensed 
under, or that otherwise meet the requirements of, the regulations of 
this subchapter shall be used, and the technique used shall be that for 
which the serum is specifically designed to be effective.
    (c) Determination of the Rh factors. Each container of Whole Blood 
shall be classified as to Rh type on the basis of tests done on the 
sample. The label shall indicate the extent of typing and the results of 
all tests performed. If the test, using Anti-D Blood Grouping Reagent, 
is positive, the container may be labeled ``Rh Positive.'' If the test 
is negative, the results shall be confirmed by further testing which 
shall include tests for the ``weak D (formerly D\u\).'' Blood may be 
labeled ``Rh Negative'' if further testing is negative. Units testing 
positive after additional more specific testing shall be labeled as ``Rh 
Positive.'' Only Anti-Rh Blood Grouping Reagents licensed under, or that 
otherwise meet the requirements of, this subchapter shall be used, and 
the technique used shall be that for which the reagent is specifically 
designed to be effective.
    (d) Sterility test. Whole Blood intended for transfusion shall not 
be tested for sterility by a method that entails entering the final 
container before the blood is used for transfusion.
    (e) Inspection. Whole Blood shall be inspected visually during 
storage and immediately prior to issue. If the color or physical 
appearance is abnormal or there is any indication or suspicion of 
microbial contamination the unit of Whole Blood shall not be issued for 
transfusion.
    (f) Test for relevant transfusion-transmitted infections. Whole 
Blood shall be tested for evidence of infection due to relevant 
transfusion-transmitted infections as required under Sec.  610.40 of 
this chapter.

[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985; 53 
FR 117, Jan. 5, 1988; 53 FR 12764, Apr. 19, 1988; 64 FR 45372, Aug. 19, 
1999; 66 FR 1836, Jan. 10, 2001; 66 FR 31165, June 11, 2001; 66 FR 
40889, Aug. 6, 2001; 80 FR 29904, May 22, 2015]



Sec.  640.6  Modifications of Whole Blood.

    Upon approval by the Director, Center for Biologics Evaluation and 
Research, of a supplement to the biologics license application for Whole 
Blood a manufacturer may prepare Whole Blood from which the 
antihemophilic factor has been removed, provided the

[[Page 97]]

Whole Blood meets the applicable requirements of this subchapter and the 
following conditions are met:
    (a) The antihemophilic factor shall be removed in accordance with 
paragraphs (a), (b), and (c) of Sec.  640.52.
    (b) Although the closed system between the red blood cells and 
plasma shall be maintained, the red blood cells shall be maintained 
between 1 and 6 [deg]C at all times, including that time when the plasma 
is being frozen for removal of the antihemophilic factor.

[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50 
FR 4138, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 
28, 1994; 64 FR 45372, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999]



                        Subpart B_Red Blood Cells



Sec.  640.10  Red Blood Cells.

    The proper name of this product shall be Red Blood Cells. The 
product is defined as red blood cells remaining after separating plasma 
from human blood.

[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985]



Sec.  640.11  General requirements.

    (a) Storage. Immediately after processing, the Red Blood Cells shall 
be placed in storage and maintained at a temperature between 1 and 6 
[deg]C.
    (b) Inspection. The product shall be inspected immediately after 
separation of the plasma, periodically during storage, and at the time 
of issue. The product shall not be issued if there is any abnormality in 
color or physical appearance or if there is any indication of microbial 
contamination.

[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 18292, May 3, 1976; 42 
FR 59878, Nov. 11, 1977; 50 FR 4139, Jan. 29, 1985]



Sec.  640.12  Eligibility of donor.

    Establishments must determine the eligibility of donors of the 
source blood for Red Blood Cells in accordance with Sec. Sec.  630.10 
and 630.15 of this chapter.

[80 FR 29904, May 22, 2015]



Sec.  640.13  Collection of the blood.

    (a) The source blood shall be collected as prescribed in Sec.  
640.4.
    (b) Source blood may also be derived from Whole Blood manufactured 
in accordance with applicable provisions of this subchapter.

[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4139, Jan. 29, 1985; 64 
FR 45372, Aug. 19, 1999]



Sec.  640.14  Testing the blood.

    Blood from which Red Blood Cells are prepared shall be tested as 
prescribed in Sec.  610.40 of this chapter and Sec.  640.5 (b) and (c).

[53 FR 117, Jan. 5, 1988, as amended at 66 FR 31165, June 11, 2001; 80 
FR 29904, May 22, 2015]



Sec.  640.15  Segments for testing.

    Segments collected in integral tubing shall meet the following 
standards:
    (a) One or more segments shall be provided with each unit of Whole 
Blood or Red Blood Cells when issued or reissued.
    (b) Before they are filled, all segments shall be marked or 
identified so as to relate them to the donor of that unit of red cells.
    (c) All segments accompanying a unit of Red Blood Cells shall be 
filled at the time the blood is collected or at the time the final 
product is prepared.

[66 FR 40890, Aug. 6, 2001]



Sec.  640.16  Processing.

    (a) Separation. Within the timeframe specified in the directions for 
use for the blood collecting, processing, and storage system used, Red 
Blood Cells may be prepared either by centrifugation, done in a manner 
that will not tend to increase the temperature of the blood, or by 
normal undisturbed sedimentation. A portion of the plasma sufficient to 
insure optimal cell preservation shall be left with the red cells except 
when a cryoprotective substance or additive solution is added for 
prolonged storage.
    (b) Sterile system. All surfaces that come in contact with the red 
cells shall be sterile and pyrogen-free.
    (c) Final containers. Final containers used for Red Blood Cells 
shall be the original blood containers unless the method of processing 
requires a different container. The final container shall meet the 
requirements for blood containers prescribed in Sec.  640.2(c). At the 
time of filing, if a different container is used, it shall be marked or

[[Page 98]]

identified by number or other symbol so as to relate it to the donor of 
that unit of red cells.

[38 FR 32089, Nov. 20, 1973, as amended at 43 FR 34460, Aug. 4, 1978; 50 
FR 4139, Jan. 29, 1985; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, 
2001; 66 FR 40890, Aug. 6, 2001]



Sec.  640.17  Modifications for specific products.

    Red Blood Cells Frozen: A cryophylactic substance may be added to 
the Red Blood Cells for extended manufacturers' storage at -65 [deg]C or 
colder, provided the manufacturer submits data considered by the 
Director, Center for Biologics Evaluation and Research, as adequately 
demonstrating through in vivo cell survival and other appropriate tests 
that the addition of the substance, the materials used and the 
processing methods results in a final product that meets the required 
standards of safety, purity, and potency for Red Blood Cells, and that 
the frozen product will maintain those properties for the prescribed 
dating period. Section 640.11 (a) and (b) do not apply while a 
cryophylactic substance is present.

[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 18292, May 3, 1976; 49 
FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26, 
1990; 63 FR 16685, Apr. 6, 1998]



                           Subpart C_Platelets



Sec.  640.20  Platelets.

    (a) Proper name and definition. The proper name of this product 
shall be Platelets. The product is defined as platelets collected from 
one unit of blood and resuspended in an appropriate volume of original 
plasma, as prescribed in Sec.  640.24(d).
    (b) Source. The source material for Platelets is plasma which may be 
obtained by whole blood collection or by plateletpheresis.

[40 FR 4304, Jan. 29, 1975, as amended at 47 FR 49021, Oct. 29, 1982; 50 
FR 4139, Jan. 29, 1985; 72 FR 45887, Aug. 16, 2007]



Sec.  640.21  Eligibility of donors.

    (a) Establishments must determine the eligibility of donors of 
platelets derived from Whole Blood and donors of platelets collected by 
plateletpheresis in accordance with Sec. Sec.  630.10 and 630.15 of this 
chapter, except as provided in this section.
    (b) A plateletpheresis donor must not serve as the source of 
platelets for transfusion if the donor has recently ingested a drug that 
adversely affects platelet function.
    (c) A Whole Blood donor must not serve as the source of platelets 
for transfusion if the donor has recently ingested a drug that adversely 
affects platelet function unless the unit is labeled to identify the 
ingested drug that adversely affects platelet function.
    (d) If you are collecting platelets by plateletpheresis, you must 
assess and monitor the donor's platelet count.
    (1) You must take adequate and appropriate steps to assure that the 
donor's platelet count is at least 150,000 platelets per microliter (/
[micro]L) before plateletpheresis begins. Exception: If you do not have 
records of a donor's platelet count from prior donations and you are not 
able to assess the donor's platelet count either prior to or immediately 
following the initiation of the collection procedure, you may collect 
platelets by plateletpheresis, but you must not collect 9.0 x 10\11\ or 
more platelets from that donor.
    (2) You must defer from platelet donation a donor whose pre-donation 
platelet count is less than 150,000 platelets/[micro]L until a 
subsequent pre-donation platelet count indicates that the donor's 
platelet count is at least 150,000 platelets/[micro]L; and
    (3) You must take appropriate steps to assure that the donor's 
intended post-donation platelet count will be no less than 100,000 
platelets/[micro]L.
    (e) Frequency of plateletpheresis collection. (1) The donor may 
donate no more than a total of 24 plateletpheresis collections during a 
12-month rolling period.
    (2) When you collect fewer than 6 x 10\11\ platelets, you must wait 
at least 2 calendar days before any subsequent plateletpheresis 
collection. You must not attempt to collect more than 2 collections 
within a 7 calendar day period.
    (3) When you collect 6 x 10\11\ or more platelets, you must wait at 
least 7 calendar days before any subsequent plateletpheresis collection.

[[Page 99]]

    (4) Exception. For a period not to exceed 30 calendar days, a donor 
may serve as a dedicated plateletpheresis donor for a single recipient, 
in accordance with Sec.  610.40(c)(1) of this chapter, as often as is 
medically necessary, provided that the donor is in good health, as 
determined and documented by the responsible physician, and the donor's 
platelet count is at least 150,000 platelets/[micro]L, measured at the 
conclusion of the previous donation or before initiating 
plateletpheresis for the current donation.
    (f) Deferral of plateletpheresis donors due to red blood cell loss. 
(1) You must defer a donor from donating platelets by plateletpheresis 
or a co-collection of platelets and plasma by apheresis for 8 weeks if 
the donor has donated a unit of Whole Blood, or a single unit of Red 
Blood Cells by apheresis unless at least 2 calendar days have passed and 
the extracorporeal volume of the apheresis device is less than 100 
milliliters.
    (2) You must defer a donor from donating platelets for a period of 
16 weeks if the donor donates two units of Red Blood Cells during a 
single apheresis procedure.
    (3) You must defer a donor for 8 weeks or more if the cumulative red 
blood cell loss in any 8 week period could adversely affect donor 
health.
    (g) The responsible physician must obtain the informed consent of a 
plateletpheresis donor on the first day of donation, and at subsequent 
intervals no longer than 1 year.
    (1) The responsible physician must explain the risks and hazards of 
the procedure to the donor; and
    (2) The explanation must be made in such a manner that the donor may 
give consent, and has a clear opportunity to refuse the procedure.

[80 FR 29904, May 22, 2015]



Sec.  640.22  Collection of source material.

    (a) Whole blood used as the source of Platelets shall be collected 
as prescribed in Sec.  640.4.
    (b) [Reserved]
    (c) If plateletpheresis is used, the procedure for collection must 
be as prescribed in Sec. Sec.  640.21, 640.64 (except paragraph (c)), 
and 640.65, or as described in an approved biologics license application 
(BLA) or an approved supplement to a BLA.
    (d) The phlebotomy shall be performed by a single uninterrupted 
venipuncture with minimal damage to, and minimal manipulation of, the 
donor's tissue.

[40 FR 4304, Jan. 29, 1975, as amended at 45 FR 27927, Apr. 25, 1980; 49 
FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26, 
1990; 59 FR 49351, Sept. 28, 1994; 64 FR 45372, Aug. 19, 1999; 64 FR 
56453, Oct. 20, 1999; 72 FR 45887, Aug. 16, 2007; 80 FR 29904, May 22, 
2015]



Sec.  640.23  Testing the blood.

    (a) Blood from which plasma is separated for the preparation of 
Platelets shall be tested as prescribed in Sec.  610.40 of this chapter 
and Sec.  640.5 (b) and (c).
    (b) The tests shall be performed on a sample of blood collected at 
the time of collecting the source blood, and such sample container shall 
be labeled with the donor's number before the container is filled.

[40 FR 4304, Jan. 29, 1975, as amended at 50 FR 4139, Jan. 29, 1985; 53 
FR 117, Jan. 5, 1988; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, 
2001; 66 FR 31165, June 11, 2001; 80 FR 29904, May 22, 2015]



Sec.  640.24  Processing.

    (a) Separation of plasma and platelets and resuspension of the 
platelets must be in a closed system. Platelets must not be pooled 
during processing unless the platelets are pooled as specified in the 
directions for use for the blood collecting, processing, and storage 
system approved for such use by the Director, Center for Biologics 
Evaluation and Research.
    (b) Immediately after collection, the whole blood or plasma shall be 
held in storage between 20 and 24 [deg]C unless it must be transported 
from the collection center to the processing laboratory. During such 
transport, all reasonable methods shall be used to maintain the 
temperature as close as possible to a range between 20 and 24 [deg]C 
until it arrives at the processing laboratory where it shall be held 
between 20 and 24 [deg]C until the platelets are separated. The platelet 
concentrate shall be separated within 4 hours or within the timeframe 
specified in the directions

[[Page 100]]

for use for the blood collecting, processing, and storage system.
    (c) The time and speed of centrifugation must have been demonstrated 
to produce an unclumped product, without visible hemolysis, that yields 
a count of not less than 5.5 x 10\10\ platelets per unit in at least 75 
percent of the units tested.
    (d) The volume of original plasma used for resuspension of the 
platelets shall be determined by the maintenance of a pH of not less 
than 6.2 during the storage period. The pH shall be measured on a sample 
of platelets which has been stored for the maximum dating period at the 
selected storage temperature. One of the following storage temperatures 
shall be used continuously:
    (1) 20 to 24 [deg]C.
    (2) 1 to 6 [deg]C.
    (e) Final containers used for Platelets shall be colorless and 
transparent to permit visual inspection of the contents; any closure 
shall maintain a hermetic seal and prevent contamination of the 
contents. The container material shall not interact with the contents, 
under the customary conditions of storage and use, in such a manner as 
to have an adverse effect upon the safety, purity, potency, or efficacy 
of the product. At the time of filling, the final container shall be 
marked or identified by number so as to relate it to the donor.

[40 FR 4304, Jan. 29, 1975, as amended at 42 FR 10983, Feb. 25, 1977; 47 
FR 49021, Oct. 29, 1982; 50 FR 4139, Jan. 29, 1985; 63 FR 16685, Apr. 6, 
1998; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 
40890, Aug. 6, 2001; 72 FR 45887, Aug. 16, 2007; 73 FR 7464, Feb. 8, 
2008]



Sec.  640.25  General requirements.

    (a) Storage. Immediately after resuspension, Platelets shall be 
placed in storage at the selected temperature range. If stored at 20 to 
24 [deg]C, a continuous gentle agitation of the platelet concentrate 
shall be maintained throughout the storage period. Agitation is optional 
if stored at a temperature between 1 and 6 [deg]C.
    (b) Quality control testing. Each month four units prepared from 
different donors shall be tested at the end of the storage period as 
follows:
    (1) Platelet count.
    (2) pH of not less than 6.2 measured at the storage temperature of 
the unit.
    (3) Measurement of actual plasma volume.
    (4) If the results of the quality control testing indicate that the 
product does not meet the prescribed requirements, immediate corrective 
action shall be taken and a record maintained of such action.
    (c) Manufacturing responsibility. All manufacturing of Platelets 
shall be performed at the same licensed establishment, except that the 
quality control testing under paragraph (b) of this section may be 
performed by a clinical laboratory which meets the standards of the 
Clinical Laboratories Improvement Amendments of 1988 (CLIA) (42 U.S.C. 
263a) and is qualified to perform platelet counts. Such arrangements 
must be approved by the Director, Center for Biologics Evaluation and 
Research, Food and Drug Administration. Such testing shall not be 
considered as divided manufacturing, as described in Sec.  610.63 of 
this chapter, provided the following conditions are met:
    (1) The results of each test are received within 10 days of the 
preparation of the platelet concentrate, and are maintained by the 
establishment licensed for Platelets so that they may be reviewed by an 
authorized representative of the Food and Drug Administration.
    (2) The licensed Platelets manufacturer has obtained a written 
agreement that the testing laboratory will permit an authorized 
representative of the Food and Drug Administration to inspect its 
testing procedures and facilities during reasonable business hours.
    (3) The testing laboratory will participate in any proficiency 
testing programs undertaken by the Center for Biologics Evaluation and 
Research, Food and Drug Administration.

[40 FR 4304, Jan. 29, 1975, as amended at 47 FR 49021, Oct. 29, 1982; 49 
FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26, 
1990; 66 FR 1836, Jan. 10, 2001; 72 FR 45888, Aug. 16, 2007]

[[Page 101]]



                            Subpart D_Plasma



Sec.  640.30  Plasma.

    (a) Proper name and definition. The proper name of this component is 
Plasma. The component is defined as:
    (1) The fluid portion of one unit of human blood intended for 
intravenous use which is collected in a closed system, stabilized 
against clotting, and separated from the red cells; or
    (2) The fluid portion of human blood intended for intravenous use 
which is prepared by apheresis methods as specified in the directions 
for use for the blood collecting, processing, and storage system 
including closed and open systems.
    (b) Source. (1) Plasma shall be obtained by separating plasma from 
blood collected from blood donors or by plasmapheresis.
    (2) Plasma may be obtained from a unit of Whole Blood collected by 
another licensed establishment.

[42 FR 59878, Nov. 22, 1977; 48 FR 13026, Mar. 29, 1983, as amended at 
50 FR 4139, Jan. 29, 1985; 72 FR 45888, Aug. 16, 2007]



Sec.  640.31  Eligibility of donors.

    (a) Whole Blood donors must meet the criteria for donor eligibility 
prescribed in Sec. Sec.  630.10 and 630.15 of this chapter.
    (b) Collection establishments must determine the eligibility of 
plasmapheresis donors in accordance with Sec. Sec.  630.10 and 630.15 of 
this chapter.

[80 FR 29904, May 22, 2015]



Sec.  640.32  Collection of source material.

    (a) Whole Blood must be collected, transported, and stored as 
prescribed in Sec.  640.4. When whole blood is intended for Plasma, 
Fresh Frozen Plasma, and Liquid Plasma, until the plasma is removed, the 
whole blood must be maintained at a temperature between 1 and 6 [deg]C 
or as specified in the directions for use for the blood collecting, 
processing, and storage system approved for such use by the Director, 
Center for Biologics Evaluations and Research. Whole blood intended for 
Platelet Rich Plasma must be maintained as prescribed in Sec.  640.24 
until the plasma is removed. The red blood cells must be placed in 
storage at a temperature between 1 and 6 [deg]C immediately after the 
plasma is separated.
    (b) Plasma obtained by plasmapheresis shall be collected as 
prescribed in Sec.  640.64 (except that paragraph (c)(3) of Sec.  640.64 
shall not apply), and Sec.  640.65.

[42 FR 59878, Nov. 22, 1977, as amended at 45 FR 27927, Apr. 25, 1980; 
50 FR 4139, Jan. 29, 1985; 64 FR 45372, Aug. 19, 1999; 72 FR 45888, Aug. 
16, 2007; 80 FR 29905, May 22, 2015]



Sec.  640.33  Testing the blood.

    (a) Blood from which plasma is separated shall be tested as 
prescribed in Sec.  610.40 of this chapter and Sec.  640.5 (b) and (c).
    (b) Manufacturers of Plasma collected by plasmapheresis shall have 
testing and recordkeeping responsibilities equivalent to those 
prescribed in Sec. Sec.  640.71 and 640.72.

[42 FR 59878, Nov. 22, 1977, as amended at 44 FR 17658, Mar. 23, 1979; 
50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 66 FR 31165, June 
11, 2001; 80 FR 29905, May 22, 2015]



Sec.  640.34  Processing.

    (a) Plasma. Plasma shall be separated from the red blood cells and 
shall be stored at -18 [deg]C or colder within 6 hours after transfer to 
the final container or within the timeframe specified in the directions 
for use for the blood collecting, processing, and storage system unless 
the product is to be stored as Liquid Plasma.
    (b) Fresh Frozen Plasma. Fresh frozen plasma shall be prepared from 
blood collected by a single uninterrupted venipuncture with minimal 
damage to and minimal manipulation of the donor's tissue. The plasma 
must be separated from the red blood cells or collected by an apheresis 
procedure, and placed in a freezer within 8 hours or within the 
timeframe specified in the directions for use for the blood collecting, 
processing, and storage system, and stored at -18 [deg]C or colder.
    (c) Liquid Plasma. Liquid Plasma shall be separated from the red 
blood cells and shall be stored at a temperature of 1 to 6 [deg]C within 
4 hours after filling the final container or within the timeframe 
specified in the directions for use for the blood collecting, 
processing, and storage system.

[[Page 102]]

    (d) Platelet Rich Plasma. Platelet rich plasma shall be prepared 
from blood collected by a single uninterrupted venipuncture with minimal 
damage to and manipulation of the donor's tissue. The plasma shall be 
separated from the red blood cells by centrifugation within 4 hours 
after completion of the phlebotomy or within the timeframe specified in 
the directions for use for the blood collecting, processing, and storage 
system. The time and speed of the centrifugation shall have been shown 
to produce a product with at least 250,000 platelets per microliter. The 
plasma shall be stored at a temperature between 20 and 24 [deg]C 
immediately after filling the final container. A gentle and continuous 
agitation of the product shall be maintained throughout the storage 
period, if stored at a temperature of 20 to 24 [deg]C.
    (e) Modifications of Plasma. It is possible to separate Platelets 
and/or Cryoprecipitated AHF from Plasma. When these components are to be 
separated, the plasma shall be collected as described in Sec.  640.32 
for Plasma.
    (1) Platelets shall be separated as prescribed in subpart C of part 
640, prior to freezing the plasma. The remaining plasma may be labeled 
as ``Fresh Frozen Plasma,'' if frozen within 6 hours after filling the 
final container or within the timeframe specified in the directions for 
use for the blood collecting, processing, and storage system.
    (2) Cryoprecipitated AHF shall be removed as prescribed in subpart F 
of part 640. The remaining plasma shall be labeled ``Plasma, 
Cryoprecipitate Reduced.''
    (3) Plasma remaining after both Platelets and Cryoprecipitated AHF 
have been removed may be labeled ``Plasma, Cryoprecipitate Reduced.''
    (f) The final container. (1) The final container shall have no color 
added to the plastic and shall be transparent to permit visual 
inspection of the contents; any closure shall maintain a hermetic seal 
and prevent contamination of the contents.
    (2) The final container material shall not interact with the 
contents, under the customary conditions of storage and use, in such a 
manner as to have an adverse effect upon the safety, purity, potency, 
and effectiveness of the product.
    (3) Prior to filling, the final container shall be identified by 
number so as to relate it to the donor.
    (g) The final product. (1) The final product shall be inspected 
immediately after separation of the plasma and shall not be issued for 
transfusion if there is (i) any abnormality in color or physical 
appearance, or (ii) any indication of contamination.
    (2) With the exception of Platelet Rich Plasma and Liquid Plasma the 
final product shall be inspected for evidence of thawing or breakage at 
the time of issuance, however, the containers need not be stored in a 
manner that shows evidence of thawing if records of continuous 
monitoring of the storage temperature establish that the temperature 
remained at -18 [deg]C or colder. If continuous monitoring of the 
product is not available, the final product shall be stored in a manner 
that will show evidence of thawing and shall not be issued if there is 
any evidence of thawing.
    (3) No preservative shall be added to the final product.

[42 FR 59878, Nov. 22, 1977, as amended at 43 FR 34460, Aug. 4, 1978; 48 
FR 13026, Mar. 29, 1983; 50 FR 4139, Jan. 29, 1985; 64 FR 45373, Aug. 
19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001; 72 FR 
45888, Aug. 16, 2007]

Subpart E [Reserved]



                        Subpart F_Cryoprecipitate



Sec.  640.50  Cryoprecipitated AHF.

    (a) Proper name and definition. The proper name of this product 
shall be Cryoprecipitated AHF. The product is defined as a preparation 
of antihemophilic factor, which is obtained from a single unit of plasma 
collected and processed in a closed system.
    (b) Source. The source material for Cryoprecipitated AHF shall be 
plasma which may be obtained by whole blood collection or by 
plasmapheresis.

[42 FR 21774, Apr. 29, 1977; 48 FR 13026, Mar. 29, 1983, as amended at 
50 FR 4139, Jan. 29, 1985]

[[Page 103]]



Sec.  640.51  Eligibility of donors.

    (a) Whole blood donors must meet the criteria for eligibility 
prescribed in Sec. Sec.  630.10 and 630.15 of this chapter.
    (b) Collection establishments must determine the eligibility of 
plasmapheresis donors in accordance with Sec. Sec.  630.10 and 630.15 of 
this chapter.

[80 FR 29905, May 22, 2015]



Sec.  640.52  Collection of source material.

    (a) Whole blood used as a source of Cryoprecipitated AHF shall be 
collected as prescribed in Sec.  640.4. Whole blood from which both 
Platelets and Cryoprecipitated AHF is derived shall be maintained as 
required under Sec.  640.24 until the platelets are removed.
    (b) If plasmapheresis is used, the procedure for collection shall be 
as prescribed in Sec.  640.64 (except that paragraph (c)(3) of that 
section shall not apply), and 640.65.

[42 FR 21774, Apr. 29, 1977, as amended at 50 FR 4139, Jan. 29, 1985; 64 
FR 45373, Aug. 19, 1999; 80 FR 29905, May 22, 2015]



Sec.  640.53  Testing the blood.

    (a) Blood from which plasma is separated for the preparation of 
Cryoprecipitated AHF shall be tested as prescribed in Sec.  610.40 of 
this chapter and Sec.  640.5 (b) and (c).
    (b) The tests shall be performed on a sample of blood collected at 
the time of collecting the source blood, and such sample container shall 
be labeled with the donor's number before the container is filled.
    (c) Manufacturers of Cryoprecipitated AHF obtained from plasma 
collected by plasmapheresis shall have testing and record-keeping 
responsibilities equivalent to those prescribed in Sec. Sec.  640.71 and 
640.72.

[42 FR 21774, Apr. 29, 1977, as amended at 42 FR 37546, July 22, 1977; 
42 FR 43063, Aug. 26, 1977; 50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan. 
5, 1988; 66 FR 31165, June 11, 2001; 80 FR 29905, May 22, 2015]



Sec.  640.54  Processing.

    (a) Processing the plasma. (1) The plasma shall be separated from 
the red blood cells by centrifugation to obtain essentially cell-free 
plasma.
    (2) The plasma shall be placed in a freezer within 8 hours after 
blood collection or within the timeframe specified in the directions for 
use for the blood collecting, processing, and storage system. A 
combination of dry ice and organic solvent may be used for freezing: 
Provided, That the procedure has been shown not to cause the solvent to 
penetrate the container or leach plasticizer from the container into the 
plasma.
    (3) Immediately after separation and freezing of the plasma, the 
plasma shall be stored and maintained at -18 [deg]C or colder until 
thawing of the plasma for further processing to remove the 
Cryoprecipitated AHF.
    (b) Processing the final product. (1) The Cryoprecipitated AHF shall 
be separated from the plasma by a procedure that has been shown to 
produce an average of no less than 80 units of antihemophilic factor per 
final container.
    (2) No diluent shall be added to the product by the manufacturer 
prior to freezing.
    (3) The final container used for Cryoprecipitated AHF shall be 
colorless and transparent to permit visual inspection of the contents; 
any closure shall maintain a hermetic seal and prevent contamination of 
the contents. The container material shall not interact with the 
contents under customary conditions of storage and use in such a manner 
as to have an adverse effect upon the safety, purity, potency and 
effectiveness of the product. At the time of filling, the final 
container shall be identified by a number so as to relate it to the 
donor.

[42 FR 21774, Apr. 29, 1977, as amended at 47 FR 15330, Apr. 9, 1982; 50 
FR 4139, Jan. 29, 1985; 64 FR 45373, Aug. 19, 1999; 66 FR 1837, Jan. 10, 
2001; 66 FR 40890, Aug. 6, 2001]



Sec.  640.55  U.S. Standard preparation.

    A U.S. Standard Antihemophilic Factor (Factor VIII) preparation may 
be obtained from the Center for Biologics Evaluation and Research, (HFM-
407) (see mailing addresses in Sec.  600.2 of this chapter) for use in 
the preparation of a working reference to be employed in a

[[Page 104]]

quality control potency test of Cryoprecipitated AHF.

[42 FR 21774, Apr. 29, 1977, as amended at 49 FR 23834, June 8, 1984; 50 
FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 70 FR 14985, Mar. 
24, 2005]



Sec.  640.56  Quality control test for potency.

    (a) Quality control tests for potency of antihemophilic factor shall 
be conducted each month on at least four representative containers of 
Cryoprecipitated AHF.
    (b) The results of each test are received by the establishment 
licensed for Cryoprecipitated AHF within 30 days of the preparation of 
the cryoprecipitated antihemophilic factor and are maintained at that 
establishment so that they may be reviewed by an authorized 
representative of the Food and Drug Administration.
    (c) The quality control test for potency may be performed by a 
clinical laboratory which meets the standards of the Clinical 
Laboratories Improvement Amendments of 1988 (CLIA) (42 U.S.C. 263a) and 
is qualified to perform potency tests for antihemophilic factor. Such 
arrangements must be approved by the Director, Center for Biologics 
Evaluation and Research, Food and Drug Administration. Such testing 
shall not be considered as divided manufacturing, as described in Sec.  
610.63 of this chapter, provided the following conditions are met:
    (1) The establishment licensed for Cryoprecipitated AHF has obtained 
a written agreement that the testing laboratory will permit an 
authorized representative of the Food and Drug Administration to inspect 
its testing procedures and facilities during reasonable business hours.
    (2) The testing laboratory will participate in any proficiency 
testing programs undertaken by the Center for Biologics Evaluation and 
Research, Food and Drug Administration.
    (d) If the average potency level of antihemophilic factor in the 
containers tested is less than 80 units of antihemophilic factor per 
container, immediate corrective actions shall be taken and a record 
maintained of such action.

[42 FR 21774, Apr. 29, 1977, as amended at 49 FR 23834, June 8, 1984; 50 
FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 64 FR 45373, Aug. 
19, 1999; 66 FR 1837, Jan. 10, 2001]



                         Subpart G_Source Plasma



Sec.  640.60  Source Plasma.

    The proper name of the product shall be Source Plasma. The product 
is defined as the fluid portion of human blood collected by 
plasmapheresis and intended as source material for further manufacturing 
use. The definition excludes single donor plasma products intended for 
intravenous use.

[41 FR 10768, Mar. 12, 1976, as amended at 50 FR 4140, Jan. 29, 1985]



Sec.  640.64  Collection of blood for Source Plasma.

    (a) [Reserved]
    (b) Blood containers. Blood containers and donor sets must be 
pyrogen-free, sterile, and identified by lot number.
    (c) The anticoagulant solution. The anticoagulant solution must be 
sterile and pyrogen-free. Anticoagulant solutions must be compounded and 
used according to a formula that has been approved for the applicant by 
the Director, Center for Biologics Evaluation and Research.
    (d) Donor identification. Each unit of blood and plasma shall be so 
marked or identified by number or other symbol so as to relate it 
directly to the donor.
    (e) Prevention of contamination of the blood and plasma. The skin of 
the donor at the site of phlebotomy shall be prepared thoroughly and 
carefully by a method that gives maximum assurance of a sterile 
container of blood. The blood shall be collected, the plasma separated, 
and the cells returned to the donor by aseptic methods in a sterile 
system which may be closed, or may be vented if the vent protects the 
blood cells and plasma against contamination.

[38 FR 32089, Nov. 20, 1973; 39 FR 13632, Apr. 16, 1974, as amended at 
41 FR 10768, Mar. 12, 1976; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 
29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 63 FR 
16685, Apr. 6, 1998; 64 FR 56453, Oct. 20, 1999; 72 FR 45888, Aug. 16, 
2007; 80 FR 29905, May 22, 2015]

[[Page 105]]



Sec.  640.65  Plasmapheresis.

    (a) Procedure-general. The plasmapheresis procedure is a procedure 
in which, during a single visit to the establishment, blood is removed 
from a donor, the plasma separated from the formed elements, and at 
least the red blood cells returned to the donor. This procedure shall be 
described in detail in the biologics license application.
    (b) Procedures-specific requirements. The plasmapheresis procedure 
shall meet the following requirements:
    (1)(i) Except as provided under Sec.  630.25 of this chapter, the 
responsible physician must draw a sample of blood from each donor on the 
day of the initial physical examination or plasmapheresis, whichever 
comes first, and at least every 4 months thereafter. A serologic test 
for syphilis, a total plasma or serum protein determination, and a 
plasma or serum protein electrophoresis or quantitative immuno-diffusion 
test or an equivalent test to determine immunoglobulin composition of 
the plasma or serum shall be performed on the sample.
    (ii) A repeat donor who does not return for plasmapheresis at the 
time the 4-month sample is due to be collected may be plasmapheresed on 
the day he appears: Provided, That no longer than 6 months has elapsed 
since the last sample was collected, and the responsible physician 
approves the plasmapheresis procedure and so indicates by signing the 
donor's record before such procedure is performed. The sample for the 4-
month tests shall be collected on the day of the donor's return.
    (iii) A repeat donor from whom the plasmapheresis center is unable 
to obtain a sample for testing as prescribed in paragraph (b)(1)(i) of 
this section for a total period exceeding 6 months shall be processed as 
a new donor.
    (2)(i) Except as provided under Sec.  630.25 of this chapter, the 
responsible physician must review the accumulated laboratory data, 
including any tracings of the plasma or serum protein electrophoresis 
pattern, the calculated values of the protein composition of each 
component, and the collection records within 14 calendar days after the 
sample is drawn to determine whether or not the donor should be deferred 
from further donation. If a determination is not made within 14 calendar 
days, the donor must be deferred pending such a determination. The 
responsible physician must sign the review. If the protein composition 
is not within normal limits established by the testing laboratory, or if 
the total protein level is less than 6.0 grams per deciliter or more 
than 9.0 grams per deciliter in a plasma sample or serum sample, the 
donor must be deferred from donation until the protein composition 
returns to acceptable levels. Reinstatement of the donor into the 
plasmapheresis program when the donor's protein composition values have 
returned to an acceptable level must first be approved by the 
responsible physician.
    (ii) A donor with a reactive serologic test for syphilis shall not 
be plasmapheresed again until the donor's serum is tested and found to 
be nonreactive to a serologic test for syphilis, except as provided in 
paragraph (b)(2) (iii) and (iv) of this section.
    (iii) A donor whose serum is determined to have a biologic false-
positive reaction to a serologic test for syphilis may be 
plasmapheresed: Provided, That the donor's file identifies the serologic 
test for syphilis and results used to confirm the biologic false-
positive reaction and indicates that the responsible physician has 
determined the false-positive reaction is not the result of an 
underlying disorder that would disqualify the donor from participation 
in the plasmapheresis program. If the serologic test for syphilis is 
performed at a facility other than the plasmapheresis center, all 
applicable provisions of Sec.  640.71 shall be met.
    (iv) A donor with a reactive serologic test for syphilis may be 
plasmapheresed only to obtain plasma to be used for further 
manufacturing into control serum for the serologic test for syphilis: 
Provided, That the responsible physician approves the donation, the 
donor's file contains a signed statement from a physician or clinic 
establishing that treatment for syphilis has been initiated and that 
continuance in the plasmapheresis program will not interfere with or 
jeopardize the treatment of the syphilitic donor.
    (3) A donor identification system shall be established that 
positively identifies each donor and relates such

[[Page 106]]

donor directly to his blood and its components as well as to his 
accumulated records and laboratory data. Such system shall include 
either a photograph of each donor which shall be used on each visit to 
confirm the donor's identity, or some other method that provides equal 
or greater assurance of positively identifying the donor.
    (4) The amount of whole blood, not including anticoagulant, removed 
from a donor during a manual plasmapheresis procedure or in any 2-day 
period shall not exceed 1,000 milliliters unless the donor's weight is 
175 pounds or greater, in which case the amount of whole blood, not 
including anticoagulant, removed from the donor during a manual 
plasmapheresis procedure or in any 2-day period shall not exceed 1,200 
milliliters.
    (5) The amount of whole blood, not including anticoagulant, removed 
from a donor during a manual plasmapheresis procedure within a 7-day 
period shall not exceed 2,000 milliliters unless the donor's weight is 
175 pounds or greater, in which case the amount of whole blood, not 
including anticoagulant, removed from a donor during a manual 
plasmapheresis procedure within a 7-day period shall not exceed 2,400 
milliliters.
    (6) No more than 500 milliliters of whole blood shall be removed 
from a donor at one time, unless the donor's weight is 175 pounds or 
greater, in which case no more than 600 milliliters of whole blood shall 
be removed from the donor at one time.
    (7) The plasma shall be separated from the red blood cells 
immediately after blood collection. The maximum feasible volume of red 
blood cells shall be returned to the donor before another unit is 
collected.
    (8) The volume of plasma collected during an automated 
plasmapheresis collection procedure shall be consistent with the volumes 
specifically approved by the Director, Center for Biologics Evaluation 
and Research, and collection shall not occur less than 2 days apart or 
more frequently than twice in a 7-day period.

[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976; 
64 FR 45373, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999; 80 FR 29905, May 
22, 2015]



Sec.  640.66  Immunization of donors.

    If specific immunization of a donor is to be performed, the 
selection, scheduling and administration of the antigen, and the 
evaluation of each donor's clinical response, shall be by the 
responsible physician. Any material used for immunization shall be 
either a product licensed under section 351 of the Public Health Service 
Act for such purpose or one specifically approved by the Director, 
Center for Biologics Evaluation and Research, Food and Drug 
Administration. Immunization procedures shall be on file at each 
plasmapheresis center where immunizations are performed.

[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, Mar. 26, 1990; 80 FR 29905, May 22, 2015]



Sec.  640.67  Laboratory tests.

    Each unit of Source Plasma shall be tested for evidence of infection 
due to relevant transfusion-transmitted infections as required under 
Sec.  610.40 of this chapter.

[66 FR 31165, June 11, 2001, as amended at 80 FR 29905, May 22, 2015]



Sec.  640.68  Processing.

    (a) Sterile system. All administration and transfer sets inserted 
into blood containers used for processing Source Plasma intended for 
manufacturing into injectable or noninjectable products and all interior 
surfaces of plasma containers used for processing Source Plasma intended 
for manufacturing into injectable products shall be sterile, pyrogen-
free, nontoxic, and compatible with the contents under normal conditions 
of use. Only Sodium Chloride Injection USP shall be used as a red blood 
cell diluent. If the method of separation of the plasma intended for 
injectable products involves a system in which an airway must be 
inserted into the plasma container, the airway shall be sterile and 
constructed so as to exclude microorganisms and maintain a sterile 
system.
    (b) Final containers. Final containers used for Source Plasma, 
whether integrally attached or separated from the original blood 
container, shall not be entered prior to issuance for any purpose except 
for filling with the plasma.

[[Page 107]]

Such containers shall be uncolored and hermetically sealed, and shall 
permit clear visibility of the contents. Final containers and their 
components shall not interact with the plasma contents under conditions 
of storage and use so as to alter the safety, quality, purity, or 
potency of the plasma and shall provide adequate protection against 
external factors that may cause deterioration or contamination. Prior to 
filling, the final container shall be marked or identified by number or 
other symbol which will relate it directly to the donor.
    (c) Preservative. Source Plasma shall not contain a preservative.

[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976; 
50 FR 4140, Jan. 29, 1985]



Sec.  640.69  General requirements.

    (a) Pooling. Two units of Source Plasma from the same donor may be 
pooled if such units are collected during one plasmapheresis procedure: 
Provided, That the pooling is done by a procedure that does not 
introduce a risk of contamination of the red blood cells and, for plasma 
intended for injectable products, gives maximum assurance of a sterile 
container of plasma.
    (1) The pooling of plasma from two or more donors is not permitted 
in the manufacture of Source Plasma intended for manufacturing into 
injectable products.
    (2) The pooling of plasma from two or more donors by the 
manufacturer of Source Plasma intended for manufacturing into 
noninjectable products is permitted: Provided, That the plasma from two 
or more donors is pooled after the plasma has been removed from the red 
blood cells, and after the red blood cell containers are sealed.
    (b) Storage. Immediately after filling, plasma intended for 
manufacturing into injectable products shall be stored at a temperature 
not warmer than -20 [deg]C, except for plasma collected as provided in 
Sec.  640.74. Plasma intended for manufacturing into noninjectable 
products may be stored at temperatures appropriate for the intended use 
of the final product, provided these temperatures are included in the 
Source Plasma license application.
    (c) Inspection. Source Plasma intended for manufacturing into 
injectable products shall be inspected for evidence of thawing at the 
time of issuance, except that inspection of individual plasma containers 
need not be made if the records of continuous monitoring of the storage 
temperature establish that the temperature remained at -20 [deg]C or 
colder. If there is evidence that the storage temperature has not been 
maintained at -20 [deg]C or colder, the plasma may be relabeled and 
issued as provided in Sec.  640.76(a).
    (d) Samples. If samples are provided, they shall meet the following 
standards:
    (1) Prior to filling, all samples shall be marked or identified so 
as to relate them directly to the donor of that unit of plasma.
    (2) All samples shall be filled at the time the final product is 
prepared by the person who prepares the final product.
    (3) All samples shall be representative of the contents of the final 
product or be collected from the donor at the time of filling the 
collection container.
    (4) All samples shall be collected in a manner that does not 
contaminate the contents of the final container.
    (e) Restrictions on distribution. Establishments must ensure that 
Source Plasma donated by paid donors not be used for further 
manufacturing into injectable products until the donor has a record of 
being found eligible to donate in accordance with Sec.  630.10 of this 
chapter and a record of negative test results on all tests required 
under Sec.  610.40(a) of this chapter on two occasions in the past 6 
months.
    (f) Hold. Source Plasma donated by paid donors determined to be 
suitable for further manufacturing into injectable products must be held 
in quarantine for a minimum of 60 calendar days before it is released 
for further manufacturing. If, after placing a donation in quarantine 
under this section, the donor is subsequently deferred under Sec.  
610.41 of this chapter, or you subsequently determine a donor to be 
ineligible under Sec.  630.10 of this chapter due to risk factors 
closely associated with exposure to, or clinical evidence of, infection 
due to a relevant transfusion-transmitted infection, you

[[Page 108]]

must not distribute quarantined donations from that donor for further 
manufacturing use to make an injectable product.

[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976; 
41 FR 14367, Apr. 5, 1976; 50 FR 4140, Jan. 29, 1985; 63 FR 16685, Apr. 
6, 1998; 64 FR 45374, Aug. 19, 1999; 80 FR 29905, May 22, 2015]



Sec.  640.71  Manufacturing responsibility.

    (a) All steps in the manufacturing of Source Plasma, including donor 
examination, blood collection, plasmapheresis, laboratory testing, 
labeling, storage, and issuing shall be performed by personnel of the 
establishment licensed to manufacture Source Plasma, except that testing 
performed in accordance with Sec.  610.40 of this chapter and Sec.  
640.65(b) may be performed by personnel of an establishment licensed for 
blood and blood derivatives under section 351(a) of the Public Health 
Service Act, or by a clinical laboratory that meets the standards of the 
Clinical Laboratories Improvement Amendments of 1988 (CLIA) (42 U.S.C. 
263a): Provided, The establishment or clinical laboratory is qualified 
to perform the assigned test(s).
    (b) Such testing shall not be considered divided manufacturing, 
which requires two biologics licenses for Source Plasma: Provided, That
    (1) The results of such tests are maintained by the licensed 
manufacturer of the Source Plasma whereby such results may be reviewed 
by a responsible physician as required in Sec.  640.65(b)(2) of this 
chapter and by an authorized representative of the Food and Drug 
Administration.
    (2) The Source Plasma manufacturer has obtained a written agreement 
that the testing laboratory will permit authorized representatives of 
the Food and Drug Administration to inspect its testing procedures and 
facilities during reasonable business hours.
    (3) The testing laboratory will participate in any proficiency 
testing programs undertaken by the Center for Biologics Evaluation and 
Research, Food and Drug Administration.

[41 FR 10770, Mar. 12, 1976, as amended at 49 FR 23834, June 8, 1984; 50 
FR 4140, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 55 FR 11013, Mar. 26, 
1990; 64 FR 45374, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999; 66 FR 
1837, Jan. 10, 2001; 80 FR 29905, May 22, 2015]



Sec.  640.72  Records.

    (a) In addition to the recordkeeping requirements of this 
subchapter, the following records shall be maintained:
    (1) Documentation shall be available to ensure that the shipping 
temperature requirements of Sec.  600.15 of this title and of Sec.  
640.74(b)(2) are being met for Source Plasma intended for manufacture 
into injectable products.
    (2)(i) For each donor, establishments must maintain records 
including a separate and complete record of initial and periodic 
examinations, tests, laboratory data, and interviews, etc., as required 
in Sec. Sec.  630.10 and 630.15 of this chapter and Sec. Sec.  640.65, 
640.66, and 640.67, except as provided in paragraph (a)(2)(ii) of this 
section.
    (ii) Negative results for testing for evidence of infection due to 
relevant transfusion-transmitted infections required in Sec.  610.40 of 
this chapter, and the volume or weight of plasma withdrawn from a donor 
need not be recorded on the individual donor record if such information 
is maintained on the premises of the plasmapheresis center where the 
donor's plasma has been collected.
    (3) The original or a clear copy or other durable record which may 
be electronic of the donor's consent for participation in the 
plasmapheresis program or for immunization.
    (4) Records of the medical history and physical examination of the 
donor conducted in accordance with Sec.  630.15(b)(1) of this chapter 
and, where applicable, Sec.  630.15(b)(5) of this chapter must document 
the eligibility of the donor as a plasmapheresis donor and, when 
applicable, as an immunized donor.
    (5) If plasma that is reactive to a serologic test for syphilis is 
issued as prescribed in Sec.  640.65(b)(2)(iv), the distribution records 
shall indicate by number those units that are reactive.

[[Page 109]]

    (b) Each donor record must be directly cross-referenced to the 
unit(s) of Source Plasma associated with the donor.
    (c) If a repeat donor is rejected or a donor's plasma is found 
unsuitable, the donor's record shall contain a full explanation for the 
rejection.
    (d) If a donor has a reaction while on the plasmapheresis premises, 
or a donor reaction is reported to the center after the donor has left 
the premises, the donor's record shall contain a full explanation of the 
reaction, including the measures taken to assist the donor and the 
outcome of the incident.

[41 FR 10770, Mar. 12, 1976, as amended at 50 FR 4140, Jan. 29, 1985; 53 
FR 117, Jan. 5, 1988; 64 FR 45374, Aug. 19, 1999; 67 FR 9587, Mar. 4, 
2002; 80 FR 29905, May 22, 2015]



Sec.  640.73  Reporting of fatal donor reactions.

    If a donor has a fatal reaction which, in any way, may be associated 
with plasmapheresis the Director of the Center for Biologics Evaluation 
and Research shall be notified by telephone as soon as possible. If the 
facility is located outside of the continental United States, 
notification by cable or telegram shall be acceptable.

[41 FR 10770, Mar. 12, 1976, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]



Sec.  640.74  Modification of Source Plasma.

    (a) Upon approval by the Director, Center for Biologics Evaluation 
and Research, Food and Drug Administration, of a supplement to the 
biologics license application for Source Plasma, a manufacturer may 
prepare Source Plasma as a liquid product for a licensed blood 
derivative manufacturer who has indicated a need for a liquid product.
    (b) Source Plasma Liquid shall meet all standards of the frozen 
Source Plasma except:
    (1) Source Plasma Liquid shall be stored in nonleachable containers 
so that the containers and their components will not interact with the 
plasma contents under conditions of storage and use so as to alter the 
safety, quality, purity, or potency of the plasma and shall provide 
adequate protection against external factors that may cause 
deterioration or contamination.
    (2) Source Plasma Liquid shall be shipped, stored and labeled for 
storage at a temperature of 10 [deg]C or colder. An exception to the 
shipping or storage temperature shall be approved by the Director, 
Center for Biologics Evaluation and Research, Food and Drug 
Administration, based upon his receipt of substantial evidence to 
support another temperature. Such evidence may be submitted by either 
the licensed manufacturer of the Source Plasma Liquid or the 
manufacturer of the final blood derivative product who has requested the 
Source Plasma Liquid.
    (3) The label for the Source Plasma Liquid shall be easily 
distinguished from that of the frozen product. Color coding shall not be 
used for this purpose.
    (4) The label affixed to each container of Source Plasma Liquid 
shall contain, in addition to the information required by Sec.  606.121 
of this chapter, but excluding Sec.  606.121(e)(5)(ii) of this chapter, 
the name of the manufacturer of the final blood derivative product for 
whom it was prepared.
    (5) Source Plasma Liquid shall be inspected immediately prior to 
issuance. If the color or physical appearance is abnormal, or there is 
any indication or suspicion of microbial contamination, the unit of 
Source Plasma Liquid shall not be issued.

[38 FR 32089, Nov. 20, 1973. Redesignated and amended at 41 FR 10770, 
Mar. 12, 1976; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 
FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 63 FR 16685, Apr. 
6, 1998; 64 FR 56454, Oct. 20, 1999; 77 FR 18, Jan. 3, 2012]



Sec.  640.76  Products stored or shipped at unacceptable temperatures.

    (a) Storage temperature. (1) Except as provided in paragraph (a)(2) 
of this section, Source Plasma intended for manufacture into injectable 
products that is inadvertently exposed (i.e., an unforeseen occurrence 
in spite of compliance with good manufacturing practice) to a storage 
temperature warmer than -20 [deg]C and colder than + 10 [deg]C may be 
issued only if labeled as ``Source Plasma Salvaged.'' The label shall be 
revised before issuance, and

[[Page 110]]

appropriate records shall be maintained identifying the units involved, 
describing their disposition, and explaining fully the conditions that 
caused the inadvertent temperature exposure.
    (2) Source Plasma intended for manufacture into injectable products 
that is exposed inadvertently (i.e., an unforeseen occurrence in spite 
of compliance with good manufacturing practice) to one episode of 
storage temperature fluctuation that is warmer than -20 [deg]C and 
colder than -5 [deg]C for not more than 72 hours is exempt from the 
labeling requirements of paragraph (a)(1) of this section, provided that 
the plasma has been and remains frozen solid. Appropriate records shall 
be maintained identifying the units involved, describing their 
disposition, explaining fully the conditions that caused the inadvertent 
temperature exposure, and documenting that the episode of temperature 
elevation did not exceed 72 hours, that the temperature did not rise to 
warmer than -5 [deg]C in storage, and that the plasma remained frozen 
solid throughout the period of elevated temperature. When requested, 
copies of the records shall be provided to the plasma derivative 
manufacturer.
    (b) Shipping temperature. If Source Plasma for manufacture into 
injectable products is exposed inadvertently (i.e., an unforeseen 
occurrence in spite of compliance with good manufacturing practice) to a 
shipping temperature warmer than -5 [deg]C and colder than + 10 [deg]C, 
the plasma derivative manufacturer shall label it ``Source Plasma 
Salvaged.'' Appropriate records shall be maintained identifying the 
units involved, describing their disposition, and explaining fully the 
conditions that caused the inadvertent temperature exposure.
    (c) Relabeling. If Source Plasma is required to be relabeled as 
``Source Plasma Salvaged'' under paragraph (a)(1) or (b) of this 
section, the person responsible for the relabeling shall cover the 
original label with either (1) a complete new label containing the 
appropriate information or (2) a partial label affixed to the original 
label and containing the appropriate new information, which covers the 
incorrect information regarding storage temperature.

[45 FR 80501, Dec. 5, 1980, as amended at 50 FR 4140, Jan. 29, 1985]



                        Subpart H_Albumin (Human)



Sec.  640.80  Albumin (Human).

    (a) Proper name and definition. The proper name of the product shall 
be Albumin (Human). The product is defined as a sterile solution of the 
albumin derived from human plasma.
    (b) Source material. The source material of Albumin (Human) shall be 
plasma recovered from Whole Blood prepared as prescribed in Sec. Sec.  
640.1 through 640.5, or Source Plasma prepared as prescribed in 
Sec. Sec.  640.60 through 640.76.
    (c) Additives in source material. Source material shall not contain 
an additive unless it is shown that the processing method yields a final 
product free of the additive to such extent that the continued safety, 
purity, potency, and effectiveness of the final product will not be 
adversely affected.

[42 FR 27582, May 31, 1977, as amended at 50 FR 4140, Jan. 29, 1985; 64 
FR 26286, May 14, 1999]



Sec.  640.81  Processing.

    (a) Date of manufacture. The date of manufacture shall be the date 
of final sterile filtration of a uniform pool of bulk solution.
    (b) Processing method. The processing method shall not affect the 
integrity of the product, and shall have been shown to yield 
consistently a product which is safe for intravenous injection.
    (c) Microbial contamination. All processing steps shall be conducted 
in a manner to minimize the risk of contamination from microorganisms, 
pyrogens, or other impurities. Preservatives to inhibit growth of 
microorganisms shall not be used during processing.
    (d) Storage of bulk fraction. Bulk concentrate to be held more than 
1 week prior to further processing shall be stored in clearly identified 
closed vessels at a temperature of -5 [deg]C or colder. Any other bulk 
form of the product, exclusive of the sterile bulk solution, to be held 
more than 1 week prior to further processing shall be stored in

[[Page 111]]

clearly identified closed vessels at a temperature of 5 [deg]C or 
colder. Any bulk fraction to be held one week or less prior to further 
processing shall be stored in clearly identified closed vessels at a 
temperature of 5 [deg]C or colder.
    (e) Heat treatment. Heating of the final containers of Albumin 
(Human) shall begin within 24 hours after completion of filling. Heat 
treatment shall be conducted so that the solution is heated continuously 
for not less than 10, or more than 11 hours, at an attained temperature 
of 600.5 [deg]C.
    (f) Stabilizer. Either 0.080.016 millimole 
sodium caprylate, or 0.080.016 millimole sodium 
acetyltryptophanate and 0.080.016 millimole sodium 
caprylate per gram of protein shall be present as a stabilizer(s). 
Calculations of the stabilizer concentration may employ the labeled 
value for the protein concentration of the product as referred to in 
Sec.  640.84(d).
    (g) Incubation. All final containers of Albumin (Human) shall be 
incubated at 20 to 35 [deg]C for at least 14 days following the heat 
treatment prescribed in paragraph (e) of this section. At the end of 
this incubation period, each final container shall be examined and all 
containers showing any indication of turbidity or microbial 
contamination shall not be issued. The contents of turbid final 
containers shall be examined microscopically and tested for sterility. 
If growth occurs, organisms shall be identified as to genus, and the 
material from such containers shall not be used for further 
manufacturing.

[42 FR 27582, May 31, 1977, as amended at 50 FR 4140, Jan. 29, 1985; 64 
FR 26286, May 14, 1999; 65 FR 13679, Mar. 14, 2000; 65 FR 52018, Aug. 
28, 2000]



Sec.  640.82  Tests on final product.

    Tests shall be performed on the final product to determine that it 
meets the following standards:
    (a) Protein concentration. Final product shall conform to one of the 
following concentrations: 4.0 0.25 percent; 5.0 
0.30 percent; 20.0 1.2 
percent; and 25.0 1.5 percent solution of protein.
    (b) Protein composition. At least 96 percent of the total protein in 
the final product shall be albumin, as determined by a method that has 
been approved for each manufacturer by the Director, Center for 
Biologics Evaluation and Research, Food and Drug Administration.
    (c) pH. The pH shall be 6.9 0.5 when measured 
in a solution of the final product diluted to a concentration of 1 
percent protein with 0.15 molar sodium chloride.
    (d) Sodium concentration. The sodium concentration of the final 
product shall be 130 to 160 milliequivalents per liter.
    (e) Potassium concentration. The potassium concentration of the 
final product shall not exceed 2 milliequivalents per liter.
    (f) Heat stability. A final container sample of Albumin (Human) 
shall remain unchanged, as determined by visual inspection, after 
heating at 57 [deg]C for 50 hours, when compared to its control 
consisting of a sample, from the same lot, which has not undergone this 
heating.

[42 FR 27582, May 31, 1977, as amended at 49 FR 23834, June 8, 1984; 50 
FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 64 FR 26286, May 14, 
1999]



Sec.  640.83  General requirements.

    (a) Preservative. The final product shall not contain a 
preservative.
    (b) Storage of bulk solution. After all processing steps have been 
completed, the sterile bulk solution shall be stored in a manner that 
will ensure the continued sterility of the product, and at a temperature 
that shall not exceed the recommended storage temperature of the final 
product prescribed in Sec.  610.53 of this chapter.

[42 FR 27582, May 31, 1977]



Sec.  640.84  Labeling.

    In addition to the labeling requirements of Sec. Sec.  610.60, 
610.61, and 610.62 of this chapter, the container and package labels 
shall contain the following information:
    (a) The osmotic equivalent in terms of plasma, and the sodium 
concentration in terms of a value or a range in milliequivalents per 
liter;
    (b) The cautionary statement placed in a prominent position on the 
label, ``Do Not Use if Turbid. Do Not Begin Administration More Than 4 
Hours

[[Page 112]]

After the Container Has Been Entered.'';
    (c) The need for additional fluids when 20 percent or 25 percent 
albumin is administered to a patient with marked dehydration;
    (d) The protein concentration, expressed as a 4 percent, 5 percent, 
20 percent, or 25 percent solution.

[42 FR 27582, May 31, 1977, as amended at 49 FR 2244, Jan. 19, 1984; 64 
FR 26286, May 14, 1999]



                Subpart I_Plasma Protein Fraction (Human)

    Source: 42 FR 27583, May 31, 1977, unless otherwise noted.



Sec.  640.90  Plasma Protein Fraction (Human).

    (a) Proper name and definition. The proper name of the product shall 
be Plasma Protein Fraction (Human). The product is defined as a sterile 
solution of protein composed of albumin and globulin, derived from human 
plasma.
    (b) Source material. The source material of Plasma Protein Fraction 
(Human) shall be plasma recovered from Whole Blood prepared as 
prescribed in Sec. Sec.  640.1 through 640.5, or Source Plasma prepared 
as prescribed in Sec. Sec.  640.60 through 640.76.
    (c) Additives in source material. Source material shall not contain 
an additive unless it is shown that the processing method yields a final 
product free of the additive to such extent that the continued safety, 
purity, potency, and effectiveness of the final product will not be 
adversely affected.

[42 FR 27583, May 31, 1977, as amended at 64 FR 26286, May 14, 1999]



Sec.  640.91  Processing.

    (a) Date of manufacture. The date of manufacture shall be the date 
of final sterile filtration of a uniform pool of bulk solution.
    (b) Processing method. The processing method shall not affect the 
integrity of the product, and shall have been shown to yield 
consistently a product which:
    (1) After the heating prescribed in paragraph (e) of this section 
does not show an increase in the components with electrophoretic 
mobility similar to that of alpha globulin that amounts to more than 5 
percent of the total protein.
    (2) Contains less than 5 percent protein with a sedimentation 
coefficient greater than 7.0 S.
    (3) Is safe for intravenous injection.
    (c) Microbial contamination. All processing steps shall be conducted 
in a manner to minimize the risk of contamination from microorganisms, 
pyrogens, or other impurities. Preservatives to inhibit growth of 
microorganisms shall not be used during processing.
    (d) Storage of bulk fraction. Bulk concentrate to be held more than 
1 week prior to further processing shall be stored in clearly identified 
closed vessels at a temperature of -5 [deg]C or colder. Any other bulk 
form of the product (exclusive of the sterile bulk solution) to be held 
more than 1 week prior to further processing, shall be stored in clearly 
identified closed vessels at a temperature of 5 [deg]C or colder. Any 
bulk fraction to be held one week or less prior to further processing 
shall be stored in clearly identified closed vessels at a temperature of 
5 [deg]C or colder.
    (e) Heat treatment. Heating of the final containers of Plasma 
Protein Fraction (Human) shall begin within 24 hours after completion of 
filling. Heat treatment shall be conducted so that the solution is 
heated continuously for not less than 10 or more than 11 hours at an 
attained temperature of 600.5 [deg]C.
    (f) Stabilizer. Either 0.080.016 millimole 
sodium caprylate, or 0.080.016 millimole sodium 
acetyltryptophanate and 0.080.016 millimole sodium 
caprylate per gram of protein shall be present as a stabilizer(s). 
Calculations of the stabilizer concentration may employ the labeled 
value 5 percent for the protein concentration of the product.
    (g) Incubation. All final containers of Plasma Protein Fraction 
(Human) shall be incubated at 20 to 35 [deg]C for at least 14 days 
following the heat treatment prescribed in paragraph (e) of this 
section. At the end of this incubation period, each final container 
shall be examined and all containers showing any indication of turbidity 
or microbial contamination shall not be issued. The contents of turbid 
final containers

[[Page 113]]

shall be examined microscopically and tested for sterility. If growth 
occurs, the types of organisms shall be identified as to genus and the 
material from such containers shall not be used for further 
manufacturing.

[42 FR 27583, May 31, 1977, as amended at 64 FR 26286, May 14, 1999]



Sec.  640.92  Tests on final product.

    Tests shall be performed on the final product to determine that it 
meets the following standards:
    (a) Protein concentration. The final product shall be a 5.0 0.30 percent solution of protein.
    (b) Protein composition. The total protein in the final product 
shall consist of at least 83 percent albumin, and no more than 17 
percent globulins. No more than 1 percent of the total protein shall be 
gamma globulin. The protein composition shall be determined by a method 
that has been approved for each manufacturer by the Director, Center for 
Biologics Evaluation and Research, Food and Drug Administration.
    (c) pH. The pH shall be 7.0 0.3 when measured 
in a solution of the final product diluted to a concentration of 1 
percent protein with 0.15 molar sodium chloride.
    (d) Sodium concentration. The sodium concentration of the final 
product shall be 130 to 160 milliequivalents per liter.
    (e) Potassium concentration. The potassium concentration of the 
final product shall not exceed 2 milliequivalents per liter.
    (f) Heat stability. A final container sample of Plasma Protein 
Fraction (Human) shall remain unchanged, as determined by visual 
inspection, after heating at 57 [deg]C for 50 hours, when compared to 
its control consisting of a sample, from the same lot, which has not 
undergone this heating.

[42 FR 27583, May 31, 1977, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, Mar. 26, 1990; 64 FR 26286, May 14, 1999; 65 FR 13679, Mar. 
14, 2000]



Sec.  640.93  General requirements.

    (a) Preservative. The final product shall not contain a 
preservative.
    (b) Storage of bulk solution. After all processing steps have been 
completed, the sterile bulk solution shall be stored in a manner that 
will ensure the continued sterility of the product, and at a temperature 
that shall not exceed the recommended storage temperature of the final 
product prescribed in Sec.  610.53 of this chapter.



Sec.  640.94  Labeling.

    In addition to the labeling requirements of Sec. Sec.  610.60, 
610.61, and 610.62 of this chapter, the container and package labels 
shall contain the following information:
    (a) The osmotic equivalent in terms of plasma, and the sodium 
concentration in terms of a value or a range in milliequivalents per 
liter.
    (b) The cautionary statement placed in a prominent position on the 
label, ``Do Not Use if Turbid. Do Not Begin Administration More than 4 
Hours After the Container Has Been Entered.''

[42 FR 27583, May 31, 1977, as amended at 49 FR 2244, Jan. 19, 1984; 64 
FR 26286, May 14, 1999]



                    Subpart J_Immune Globulin (Human)



Sec.  640.100  Immune Globulin (Human).

    (a) Proper name and definition. The proper name of this product 
shall be Immune Globulin (Human). The product is defined as a sterile 
solution containing antibodies derived from human plasma.
    (b) Source material. The source material of Immune Globulin (Human) 
shall be plasma recovered from Whole Blood prepared as prescribed in 
Sec. Sec.  640.1 through 640.5, or Source Plasma prepared as prescribed 
in Sec. Sec.  640.60 through 640.76.
    (c) Additives in source material. The source material shall contain 
no additives other than citrate or acid citrate dextrose anticoagulant 
solution, unless it is shown that the processing method yields a product 
free of the additive to such an extent that the safety, purity, and 
potency of the product will not be affected adversely.

[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4140, Jan. 29, 1985; 64 
FR 26287, May 14, 1999]

[[Page 114]]



Sec.  640.101  General requirements.

    (a) Heat stability test. Approximately 2 ml. of completely processed 
material of each lot shall not show any visible sign of gelation after 
heating in a 12 x 75 mm. stoppered glass tube at 57 [deg]C for 4 hours.
    (b) pH. The pH of final container material shall be 6.8 0.4 when measured in a solution diluted to 1 percent 
protein with 0.15 molar sodium chloride.
    (c) Turbidity. The product shall be free of turbidity as determined 
by visual inspection of final containers.
    (d) Date of manufacture. The date of manufacture is the date of 
initiating the last valid measles or poliomyelitis antibody test (Sec.  
640.104(b) (2) and (3)) whichever date is earlier.
    (e) Labeling. In addition to complying with all applicable labeling 
required in this subchapter, labeling shall indicate that:
    (1) There is no prescribed potency for viral hepatitis antibodies.
    (2) The product is not recommended for intravenous administration.

[38 FR 32089, Nov. 20, 1973; 48 FR 13026, Mar. 29, 1983, as amended at 
49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 51 FR 15611, Apr. 
25, 1986; 55 FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6, 1998; 64 FR 
26287, May 14, 1999]



Sec.  640.102  Manufacture of Immune Globulin (Human).

    (a) Processing method. The processing method shall be one that has 
been shown: (1) To be capable of concentrating tenfold from source 
material at least two different antibodies; (2) not to affect the 
integrity of the globulins; (3) to consistently yield a product which is 
safe for subcutaneous and intramuscular injection and (4) not to 
transmit viral hepatitis.
    (b) Microbial contamination. Low temperatures or aseptic techniques 
shall be used to minimize contamination by microorganisms. Preservatives 
to inhibit growth of microorganisms shall not be used during processing.
    (c) Bulk storage. The globulin fraction may be stored in bulk prior 
to further processing provided it is stored in clearly identified 
hermetically closed vessels. Globulin as either a liquid concentrate or 
a solid and containing alcohol or more than 5 percent moisture shall be 
stored at a temperature of -10 [deg]C or lower. Globulin as a solid free 
from alcohol and containing less than 5 percent moisture, shall be 
stored at a temperature of 0 [deg]C or lower.
    (d) Determination of the lot. Each lot of Immune Globulin (Human) 
shall represent a pooling of approximately equal amounts of material 
from not less than 1,000 donors.
    (e) Sterilization and heating. The final product shall be sterilized 
promptly after solution. At no time during processing shall the product 
be exposed to temperatures above 45 [deg]C, and after sterilization the 
product shall not be exposed to temperatures above 32 [deg]C for more 
than 72 hours.

[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4140, Jan. 29, 1985; 63 
FR 16685, Apr. 6, 1998; 64 FR 26287, May 14, 1999; 65 FR 13679, Mar. 14, 
2000; 65 FR 52018, Aug. 28, 2000]



Sec.  640.103  The final product.

    (a) Final solution. The final product shall be a 16.5 1.5 percent solution of globulin containing 0.3 molar 
glycine and a preservative.
    (b) Protein composition. At least 96 percent of the total protein 
shall be immunoglobulin G (IgG), as determined by a method that has been 
approved for each manufacturer by the Director, Center for Biologics 
Evaluation and Research, Food and Drug Administration.

[38 FR 32089, Nov. 20, 1973, as amended at 64 FR 26287, May 14, 1999]



Sec.  640.104  Potency.

    (a) Antibody levels and tests. Each lot of final product shall 
contain at least the minimum levels of antibodies for diphtheria, 
measles, and for at least one type of poliomyelitis. In the event the 
final bulk solution is stored at a temperature above 5 [deg]C the 
antibody level tests shall be performed after such storage with a sample 
of the stored material.
    (b) Minimum levels. The minimum antibody levels are as follows:
    (1) No less than 2 units of diphtheria antitoxin per ml.
    (2) A measles neutralizing antibody level that, when compared with 
that of a reference material designated by the Center for Biologics 
Evaluation and Research (CBER), Food and Drug Administration, as 
indicated in paragraph

[[Page 115]]

(c) of this section, demonstrates adequate potency. The Director, CBER, 
shall notify manufacturers when a new reference material will be used 
and will advise manufacturers of an appropriate antibody level taking 
into account a comparison of the new reference material to the previous 
reference material.
    (3) A poliomyelitis Type 1, Type 2, or Type 3 neutralizing antibody 
level that, when compared with that of a reference material designated 
by the Center for Biologics Evaluation and Research, Food and Drug 
Administration, as indicated in paragraph (c) of this section, 
demonstrates adequate potency. The Director, CBER, shall notify 
manufacturers when a new reference material will be used and will advise 
manufacturers of an appropriate antibody level taking into account a 
comparison of the new reference material to the previous reference 
material.
    (c) Reference materials. The following reference materials shall be 
obtained from the Center for Biologics Evaluation and Research:
    (1) Reference Immune Globulin for correlation of measles antibody 
titers.
    (2) Reference Immune Globulin for correlation of poliomyelitis 
antibody titers, Types 1, 2, and 3.

[38 FR 32089, Nov. 20, 1973, as amended at 39 FR 9661, Mar. 13, 1974; 49 
FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 
1990; 63 FR 16685, Apr. 6, 1998; 64 FR 26287, May 14, 1999]

Subpart K [Reserved]



                    Subpart L_Alternative Procedures



Sec.  640.120  Alternative procedures.

    (a) The Director, Center for Biologics Evaluation and Research, may 
issue an exception or alternative to any requirement in subchapter F of 
chapter I of title 21 of the Code of Federal Regulations regarding 
blood, blood components, or blood products. The Director may issue such 
an exception or alternative in response to:
    (1) A written request from an establishment. Licensed establishments 
must submit such requests in accordance with Sec.  601.12 of this 
chapter;
    (2) An oral request from an establishment, if there are difficult 
circumstances and submission of a written request is not feasible. 
Establishments must follow up such oral request by submitting written 
requests under paragraph (a)(1) of this section within 5 working days.
    (b) To respond to a public health need, the Director may issue a 
notice of exception or alternative to any requirement in subchapter F of 
chapter I of title 21 of the Code of Federal Regulations regarding 
blood, blood components, or blood products, if a variance under this 
section is necessary to assure that blood, blood components, or blood 
products will be available in a specified location or locations to 
address an urgent and immediate need for blood, blood components, or 
blood products or to provide for appropriate donor screening and 
testing.
    (c) If the Director issues such an exception or alternative orally, 
the Director will follow up by issuing a written notice of the exception 
or alternative. Periodically, FDA will provide a list of approved 
exceptions and alternative procedures on the FDA Center for Biologics 
Evaluation and Research Web site.

[80 FR 29906, May 22, 2015]



              Subpart M_Definitions and Medical Supervision

    Source: 80 FR 29906, May 22, 2015, unless otherwise noted.



Sec.  640.125  Definitions.

    The definitions set out in Sec.  630.3 of this chapter apply to the 
use of those defined terms in this part.



Sec.  640.130  Medical supervision.

    The requirements for medical supervision established in Sec.  630.5 
of this chapter supplement the regulations in this part.

[[Page 116]]



PART 660_ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY
TESTS--Table of Contents



            Subpart A_Antibody to Hepatitis B Surface Antigen

Sec.
660.1 Antibody to Hepatitis B Surface Antigen.
660.2 General requirements.
660.3 Reference panel.
660.4 Potency test.
660.5 Specificity.
660.6 Samples; protocols; official release.

Subpart B [Reserved]

                    Subpart C_Blood Grouping Reagent

660.20 Blood Grouping Reagent.
660.21 Processing.
660.22 Potency requirements with reference preparations.
660.25 Potency tests without reference preparations.
660.26 Specificity tests and avidity tests.
660.28 Labeling.

                    Subpart D_Reagent Red Blood Cells

660.30 Reagent Red Blood Cells.
660.31 Eligibility of donor.
660.32 Collection of source material.
660.33 Testing of source material.
660.34 Processing.
660.35 Labeling.
660.36 Samples and protocols.

                  Subpart E_Hepatitis B Surface Antigen

660.40 Hepatitis B Surface Antigen.
660.41 Processing.
660.43 Potency test.
660.44 Specificity.
660.45 Labeling.
660.46 Samples; protocols; official release.

                      Subpart F_Anti-Human Globulin

660.50 Anti-Human Globulin.
660.51 Processing.
660.52 Reference preparations.
660.53 Controls for serological procedures.
660.54 Potency tests, specificity tests, tests for heterospecific 
          antibodies, and additional tests for nonspecific properties.
660.55 Labeling.

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 360d, 
360h, 360i, 371, 372; 42 U.S.C. 216, 262, 263, 263a, 264.

    Cross References: For U.S. Customs Service regulations relating to 
viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal 
Service regulations relating to the admissibility to the United States 
mails see parts 124 and 125 of the Domestic Mail Manual, that is 
incorporated by reference in 39 CFR part 111.



            Subpart A_Antibody to Hepatitis B Surface Antigen



Sec.  660.1  Antibody to Hepatitis B Surface Antigen.

    (a) Proper name and definition. The proper name of this product 
shall be Antibody to Hepatitis B Surface Antigen. The product is defined 
as a preparation of serum containing antibody to hepatitis B surface 
antigen.
    (b) Source. The source of this product shall be plasma or blood, 
obtained aseptically from animals immunized with hepatitis B surface 
antigen, which have met the applicable requirements of Sec.  600.11 of 
this chapter, or from human donor whose blood is positive for hepatitis 
B surface antigen.

[40 FR 29711, July 15, 1975]



Sec.  660.2  General requirements.

    (a) Processing. The processing method shall be one that has been 
shown to consistently yield a specific and potent final product free of 
properties which would adversely affect the test results when the 
product is tested by the methods recommended by the manufacturer in the 
package enclosure.
    (b) Ancillary reagents and materials. All ancillary reagents and 
materials supplied in the package with the product shall meet generally 
accepted standards of purity and quality and shall be effectively 
segregated and otherwise manufactured in a manner (such as heating at 60 
[deg]C. for 10 hours) that will reduce the risk of contaminating the 
product and other biological products. Ancillary reagents and materials 
accompanying the product which are used in the performance of the test 
as described by the manufacturer's recommended test procedures shall 
have been shown not to adversely affect the product within the 
prescribed dating period.
    (c) Labeling. (1) In addition to the items required by other 
applicable labeling provisions of this subchapter, the following shall 
also be included:
    (i) Indication of the source of the product immediately following 
the

[[Page 117]]

proper name on both the final container and package label, e.g., human, 
guinea pig.
    (ii) Name of the test method(s) recommended for the product on the 
package label and on the final container label when capable of bearing a 
full label (see Sec.  610.60(a) of this chapter).
    (iii) A warning on the package label and on the final container 
label if capable of bearing a full label (see Sec.  610.60(a) of this 
chapter) indicating that the product and antigen if supplied, shall be 
handled as if capable of transmitting hepatitis.
    (iv) If the product is dried, the final container label shall 
indicate ``Reconstitution date: ___'' and a statement indicating the 
period within which the product may be used after reconstitution.
    (v) The package shall include a package enclosure providing:
    (A) Adequate instructions for use;
    (B) A description of all recommended test methods; and
    (C) Warnings as to possible hazards, including hepatitis, in 
handling the product and any ancillary reagents and materials 
accompanying the product.
    (2) The applicant may provide the labeling information referenced in 
paragraph (c)(1) of this section in the form of:
    (i) A symbol accompanied by explanatory text adjacent to the symbol;
    (ii) A symbol not accompanied by adjacent explanatory text that:
    (A) Is contained in a standard that FDA recognizes under its 
authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act;
    (B) Is used according to the specifications for use of the symbol 
set forth in FDA's section 514(c) recognition; and
    (C) Is explained in a paper or electronic symbols glossary that is 
included in the labeling for the device and the labeling on or within 
the package containing the device bears a prominent and conspicuous 
statement identifying the location of the symbols glossary that is 
written in English or, in the case of articles distributed solely in 
Puerto Rico or in a Territory where the predominant language is one 
other than English, the predominant language may be used; or
    (iii) A symbol not accompanied by adjacent explanatory text that:
    (A) Is established in a standard developed by a standards 
development organization (SDO);
    (B) Is not contained in a standard that is recognized by FDA under 
its authority in section 514(c) of the Federal Food, Drug, and Cosmetic 
Act or is contained in a standard that is recognized by FDA but is not 
used according to the specifications for use of the symbol set forth in 
FDA's section 514(c) recognition;
    (C) Is determined by the manufacturer to be likely to be read and 
understood by the ordinary individual under customary conditions of 
purchase and use in compliance with section 502(c) of the Federal Food, 
Drug, and Cosmetic Act;
    (D) Is used according to the specifications for use of the symbol 
set forth in the SDO-developed standard; and
    (E) Is explained in a paper or electronic symbols glossary that is 
included in the labeling for the device and the labeling on or within 
the package containing the device bears a prominent and conspicuous 
statement identifying the location of the symbols glossary that is 
written in English or, in the case of articles distributed solely in 
Puerto Rico or in a Territory where the predominant language is one 
other than English, the predominant language may be used.
    (3) The use of symbols to provide the labeling information 
referenced in paragraph (c)(1) of this section which do not meet the 
requirements of paragraph (c)(2) of this section renders a device 
misbranded under section 502(c) of the Federal Food, Drug, and Cosmetic 
Act.
    (4) For purposes of paragraph (c)(2) of this section:
    (i) An SDO is an organization that is nationally or internationally 
recognized and that follows a process for standard development that is 
transparent, (i.e., open to public scrutiny), where the participation is 
balanced, where an appeals process is included, where the standard is 
not in conflict with any statute, regulation, or policy under which FDA 
operates, and where the standard is national or international in scope.

[[Page 118]]

    (ii) The term ``symbols glossary'' means a compiled listing of:
    (A) Each SDO-established symbol used in the labeling for the device;
    (B) The title and designation number of the SDO-developed standard 
containing the symbol;
    (C) The title of the symbol and its reference number, if any, in the 
standard; and
    (D) The meaning or explanatory text for the symbol as provided in 
the FDA recognition or, if FDA has not recognized the standard or 
portion of the standard in which the symbol is located or the symbol is 
not used according to the specifications for use of the symbol set forth 
in FDA's section 514(c) recognition, the explanatory text as provided in 
the standard.
    (d) Final container. A final container shall be sufficiently 
transparent to permit visual inspection of the contents for presence of 
particulate matter and increased turbidity. The effectiveness of the 
contents of a final container shall be maintained throughout its dating 
period.
    (e) Date of manufacture. The date of manufacture of Antibody to 
Hepatitis B surface Antigen that has been iodinated with radioactive 
iodine (\125\I) shall be the day of labeling the antibody with the 
radionuclide.
    (f) Retention samples. Each manufacturer shall retain representative 
samples of the product in accordance with Sec.  600.13 of this chapter 
except for that which has been iodinated with radioactive iodine. 
Retention samples of Antibody to Hepatitis B Surface Antigen iodinated 
with \125\I shall consist of a minimum of two complete finished packages 
of each lot of the diagnostic test kit and shall be retained for a 
period of at least 90 days from the date of manufacture.

[38 FR 32098, Nov. 20, 1973, as amended at 40 FR 29711, July 15, 1975; 
46 FR 36134, July 14, 1981; 49 FR 1684, Jan. 13, 1984; 81 FR 38924, June 
15, 2016]



Sec.  660.3  Reference panel.

    A Reference Hepatitis B Surface Antigen Panel shall be obtained from 
the Food and Drug Administration, Center for Biologics Evaluation and 
Research, Reagents and Standards Shipping, 10903 New Hampshire Ave., 
Bldg. 75, Rm. G704, Silver Spring, MD 20993-0002 and shall be used for 
determining the potency and specificity of Antibody to Hepatitis B 
Surface Antigen.

[40 FR 29711, July 15, 1975, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, Mar. 26, 1990; 70 FR 14985, Mar. 24, 2005; 80 FR 18093, Apr. 
3, 2015]



Sec.  660.4  Potency test.

    To be satisfactory for release, each filling of Antibody to 
Hepatitis B Surface Antigen shall be tested against the Reference 
Hepatitis B Surface Antigen Panel and shall be sufficiently potent to 
detect the antigen in the appropriate sera of the reference panel by all 
test methods recommended by the manufacturer in the package insert.

[40 FR 29711, July 15, 1975]



Sec.  660.5  Specificity.

    Each filling of the product shall be specific for antibody to 
hepatitis B surface antigen, as determined by specificity tests found 
acceptable by the Director, Center for Biologics Evaluation and 
Research.

[40 FR 29712, July 15, 1975, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]



Sec.  660.6  Samples; protocols; official release.

    (a) Samples. (1) For the purposes of this section, a sample of 
product not iodinated with \125\I means a sample from each filling of 
each lot packaged as for distribution, including all ancillary reagents 
and materials; and a sample of product iodinated with \125\I means a 
sample from each lot of diagnostic test kits in a finished package, 
including all ancillary reagents and materials.
    (2) Unless the Director, Center for Biologics Evaluation and 
Research, determines that the reliability and consistency of the 
finished product can be assured with a smaller quantity of sample or no 
sample and specifically reduces or eliminates the required quantity of 
sample, each manufacturer shall submit the following samples to the 
Director, Center for Biologics Evaluation and Research (see mailing 
addresses in Sec.  600.2(c) of this chapter),

[[Page 119]]

within 5 working days after the manufacturer has satisfactorily 
completed all tests on the samples:
    (i) One sample until written notification of official release is no 
longer required under paragraph (c)(2) of this section.
    (ii) One sample at periodic intervals of 90 days, beginning after 
written notification of official release is no longer required under 
paragraph (c)(2) of this section. The sample submitted at the 90-day 
interval shall be from the first lot or filling, as applicable, released 
by manufacturer, under the requirements of Sec.  610.1 of this chapter, 
after the end of the previous 90-day interval. The sample shall be 
identified as ``surveillance sample'' and shall include the date of 
manufacture.
    (iii) Samples may at any time be required to be submitted to the 
Director, Center for Biologics Evaluation and Research, if the Director 
finds that continued evaluation is necessary to ensure the potency, 
quality, and reliability of the product.
    (b) Protocols. For each sample submitted as required in paragraph 
(a)(1) of this section, the manufacturer shall send a protocol that 
consists of a summary of the history of manufacture of the product, 
including all results of each test for which test results are requested 
by the Director, Center for Biologics Evaluation and Research. The 
protocols submitted with the samples at periodic intervals as provided 
in paragraph (a)(2)(ii) of this section shall be identified by the 
manufacturer as ``surveillance test results.''
    (c) Official release. (1) The manufacturer shall not distribute the 
product until written notification of official release is received from 
the Director, Center for Biologics Evaluation and Research, except as 
provided in paragraph (c)(2) of this section. Official release is 
required for samples from at least five consecutive lots or fillings, as 
applicable, manufactured after licensure of the product.
    (2) After written notification of official release is received from 
the Director, Center for Biologics Evaluation and Research, for at least 
five consecutive lots or fillings, as applicable, manufactured after 
licensure of the product, and after the manufacturer receives from the 
Director, Center for Biologics Evaluation and Research, written 
notification that official release is no longer required, subsequent 
lots or fillings may be released by the manufacturer under the 
requirements of Sec.  610.1 of this chapter.
    (3) The manufacturer shall not distribute lots or fillings, as 
applicable, of products that required sample submission under paragraph 
(a)(2)(iii) of this section until written notification of official 
release or notification that official release is no longer required is 
received from the Director, Center for Biologics Evaluation and 
Research.

[48 FR 20407, May 6, 1983, as amended at 49 FR 23834, June 8, 1984; 51 
FR 15611, Apr. 25, 1986; 55 FR 11013, 11014, Mar. 26, 1990; 70 FR 14985, 
Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015]

Subpart B [Reserved]



                    Subpart C_Blood Grouping Reagent

    Source: 53 FR 12764, Apr. 19, 1988, unless otherwise noted.



Sec.  660.20  Blood Grouping Reagent.

    (a) Proper name and definition. The proper name of this product 
shall be Blood Grouping Reagent and it shall consist of an antibody-
containing fluid containing one or more of the blood grouping antibodies 
listed in Sec.  660.28(a)(4).
    (b) Source. The source of this product shall be blood, plasma, 
serum, or protein-rich fluids, such as those derived from stable 
immunoglobulin-secreting cell lines maintained either in tissue cultures 
or in secondary hosts.

[53 FR 12764, Apr. 19, 1988, as amended at 65 FR 77499, Dec. 12, 2000; 
81 FR 38925, June 15, 2016]



Sec.  660.21  Processing.

    (a) Processing method. (1) The processing method shall be one that 
has been shown to yield consistently a specific, potent final product, 
free of properties that would affect adversely the intended use of the 
product throughout its dating period. Stability testing shall be 
performed on an adequate number of representative samples of

[[Page 120]]

each group of products manufactured in the same fashion.
    (2) Only that material that has been fully processed, thoroughly 
mixed in a single vessel, and filtered shall constitute a lot.
    (3) A lot may be subdivided into sublots. If lots are to be 
subdivided, the manufacturer shall include this information in the 
biologics license application. The manufacturer shall describe the test 
specifications to verify that each sublot is identical to other sublots 
of the lot.
    (4) Each lot of Blood Grouping Reagent shall be identified by a lot 
number. Each sublot shall be identified by that lot number to which a 
distinctive prefix or suffix shall be added. Final container and package 
labels shall bear the lot number and all distinctive prefixes and 
suffixes that have been applied to identify the sublot from which 
filling was accomplished.
    (b) Color coding of reagents. Blood Grouping Reagents may be colored 
provided the added colorant does not adversely affect the safety, 
purity, or potency of the product and the colorant is approved by the 
Director, Center for Biologics Evaluation and Research.
    (c) Final containers and dropper assemblies. Final containers and 
dropper pipettes shall be colorless and sufficiently transparent to 
permit observation of the contents to detect particulate matter or 
increased turbidity during use.
    (d) Volume of final product. Each manufacturer shall identify the 
possible final container volumes in the biologics license application.
    (e) Date of manufacture. The date of manufacture shall be the date 
the manufacturer begins the last entire group of potency tests.

[53 FR 12764, Apr. 19, 1988, as amended at 64 FR 56454, Oct. 20, 1999; 
65 FR 77499, Dec. 12, 2000; 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 
24, 2005]



Sec.  660.22  Potency requirements with reference preparations.

    (a) Potency requirements. Products for which reference Blood 
Grouping Reagents are available shall have a potency titer value at 
least equal to that of the reference preparation.
    (b) Reference preparations. Reference Blood Grouping Reagents shall 
be obtained from the Food and Drug Administration, Center for Biologics 
Evaluation and Research, Reagents and Standards Shipping, 10903 New 
Hampshire Ave., Bldg. 75, Rm. G704, Silver Spring, MD 20993-0002, and 
shall be used as described in the accompanying package insert for 
determining the potency of Blood Grouping Reagents.

[53 FR 12764, Apr. 19, 1988, as amended at 67 FR 9587, Mar. 4, 2002; 70 
FR 14985, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015]



Sec.  660.25  Potency tests without reference preparations.

    Products for which Reference Blood Grouping Reagents are not 
available shall be tested for potency by a method approved by the 
Director, Center for Biologics Evaluation and Research.
    (a) Potency requirements. Blood Grouping Reagents recommended for 
the test tube methods, including the indirect antiglobulin tests, shall 
have the following potency titer values, unless other values are 
approved by the Director, Center for Biologics Evaluation and Research.
    (1) For Anti-K, Anti-k, Anti-Jk \a\, Anti-Fy \a\, Anti-C \w\, at 
least 1 + reaction with a 1:8 dilution of the reagent.
    (2) For Anti-S, Anti-s, Anti-P1, Anti-M, Anti-I, Anti-e 
(saline), Anti-c (saline), and Anti-A1, at least 1 + reaction 
with a 1:4 dilution of the reagent.
    (3) For Anti-U, Anti-Kp\a\, Anti-Kp\b\, Anti-Js\a\, Anti-Js\b\, 
Anti-Fy\b\, Anti-N, Anti-Le\a\, Anti-Le\b\, Anti-Lu\a\, Anti-Lu\b\, 
Anti-Di\a\, Anti-M\g\, Anti-Jk\b\, Anti-Co\b\, Anti-Wr\a\, and Anti-
Xg\a\, at least 2 + reaction with undiluted reagent.
    (b) Products recommended for slide tests or microplate techniques. 
Blood Grouping Reagent recommended for slide test methods or microplate 
techniques shall produce clearly positive macroscopic results when both 
undiluted reagent and reagent diluted with an equal volume of diluent 
are tested by all methods recommended in the manufacturer's package 
insert using red blood cells showing heterozygous or diminished 
expression of the corresponding antigen. The dilution shall be made with 
an equal volume of compatible serum or approved diluent.

[[Page 121]]

    (c) Products recomended for use in an automated system. The 
manufacturer of Blood Grouping Reagent that is recommended for use in an 
automated system shall demonstrate that its product when used both 
undiluted and diluted with an equal volume of diluent satisfactorily 
performs when tested with cells representing heterozygous or diminished 
expression of the corresponding antigen.

[53 FR 12764, Apr. 19, 1988, as amended at 67 FR 9587, Mar. 4, 2002; 70 
FR 14985, Mar. 24, 2005]



Sec.  660.26  Specificity tests and avidity tests.

    Specificity and avidity tests shall be performed using test 
procedures approved by the Director, Center for Biologics Evaluation and 
Research.

[53 FR 12764, Apr. 19, 1988, as amended at 67 FR 9587, Mar. 4, 2002; 70 
FR 14985, Mar. 24, 2005]



Sec.  660.28  Labeling.

    (a) In addition to the applicable labeling requirements of 
Sec. Sec.  610.62 through 610.65 and Sec.  809.10 of this chapter, and 
in lieu of the requirements in Sec. Sec.  610.60 and 610.61 of this 
chapter, the following requirements shall be met:
    (1) Final container label--(i) Color coding. The final container 
label of all Blood Grouping Reagents shall be completely white, except 
that all or a portion of the final container label of the following 
Blood Grouping Reagents may be color coded with the specified color 
which shall be a visual match to a specific color sample designated by 
the Director, Center for Biologics Evaluation and Research. Printing on 
all final container labels shall be in solid black. A logo or company 
name may be placed on the final container label; however, the logo or 
company name shall be located along the bottom or end of the label, 
outside the main panel.

------------------------------------------------------------------------
           Blood grouping reagent                Color of label paper
------------------------------------------------------------------------
Anti-A.....................................  Blue.
Anti-B.....................................  Yellow.
Slide and rapid tube test blood grouping
 reagents only:
    Anti-C.................................  Pink.
    Anti-D.................................  Gray.
    Anti-E.................................  Brown.
    Anti-CDE...............................  Orange.
    Anti-c.................................  Lavender.
    Anti-e.................................  Green.
------------------------------------------------------------------------

    (ii) Required information. The proper name ``Blood Grouping 
Reagent'' need not appear on the final container label provided the 
final container is distributed in a package and the package label bears 
the proper name. The final container label shall bear the following 
information:
    (A) Name of the antibody or antibodies present as set forth in 
paragraph (a)(4) of this section.
    (B) Name, address (including ZIP code), and license number of the 
manufacturer.
    (C) Lot number, including sublot designations.
    (D) Expiration date.
    (E) Source of product if other than human plasma or serum.
    (F) Test method(s) recommended.
    (G) Recommended storage temperature in degrees Celsius.
    (H) Volume of product if a liquid, or equivalent volume for a dried 
product if it is to be reconstituted.
    (I) If a dried product, to remind users to record the reconstitution 
date on the label, the statement ``RECONSTITUTION DATE ___. EXPIRES 1 
YEAR AFTER RECONSTITUTION DATE.''
    (iii) Lettering size. The type size for the specificity of the 
antibody designation on the labels of a final container with a capacity 
of less than 5 milliliters shall be not less than 12 point. The type 
size for the specificity of the antibody designations on the label of a 
container with a capacity of 5 milliliters or more shall be not less 
than 18 point.
    (iv) Visual inspection. When the label has been affixed to the final 
container, a sufficient area of the container shall remain uncovered for 
its full length or no less than 5 millimeters of the lower circumference 
to permit inspection of the contents. The label on a final product 
container for antibodies Anti-c, Anti-k, or Anti-s shall display a bar 
immediately over the specificity letter used in the name, i.e., Anti-c, 
Anti-k, or Anti-s.

[[Page 122]]

    (2) Package label. The following information shall appear either on 
the package label or on the final container label if it is visible 
within the package.
    (i) Proper name of the product.
    (ii) Name of the antibody or antibodies present as set forth in 
paragraph (a)(4) of this section.
    (iii) Name, address (including ZIP Code), and license number of the 
manufacturer.
    (iv) Lot number, including sublot designations.
    (v) Expiration date.
    (vi) Preservative used and its concentration.
    (vii) Number of containers, if more than one.
    (viii) Volume or equivalent volume for dried products when 
reconstituted, and precautions for adequate mixing when reconstituting.
    (ix) Recommended storage temperature in degrees Celsius.
    (x) Source of the product if other than human serum or plasma.
    (xi) Reference to enclosed package insert.
    (xii) If a dried product, a statement indicating the period within 
which the product may be used after reconstitution.
    (xiii) The statement: ``FOR IN VITRO DIAGNOSTIC USE.''
    (xiv) The statement: ``MEETS FDA POTENCY REQUIREMENTS.''
    (xv) If human blood was used in manufacturing the product, the 
statement: ``CAUTION: ALL BLOOD PRODUCTS SHOULD BE TREATED AS 
POTENTIALLY INFECTIOUS. SOURCE MATERIAL FROM WHICH THIS PRODUCT WAS 
DERIVED WAS FOUND NEGATIVE WHEN TESTED IN ACCORDANCE WITH CURRENT FDA 
REQUIRED TESTS. NO KNOWN TEST METHODS CAN OFFER ASSURANCE THAT PRODUCTS 
DERIVED FROM HUMAN BLOOD WILL NOT TRANSMIT INFECTIOUS AGENTS.''
    (xvi) A statement of an observable indication of an alteration of 
the product, e.g., turbidity, color change, precipitate, that may 
indicate possible deterioration of the product.
    (3) Package insert. Each final container of Blood Grouping Reagent 
shall be accompanied by a package insert meeting the requirements of 
Sec.  809.10. If two or more final containers requiring identical 
package inserts are placed in a single package, only one package insert 
per package is required.
    (4) Names of antibodies.

               Blood Group Designation for Container Label
------------------------------------------------------------------------
 
------------------------------------------------------------------------
Anti-A                               Anti-Jk\b\
Anti-A1                              Anti-Js\a\
Anti-A, B                            Anti-Js\b\
Anti-A and B                         Anti-K
Anti-B                               Anti-k
Anti-C                               Anti-Kp\a\
Anti-C\w\                            Anti-Kp\b\
Anti- c                              Anti-Le\a\
Anti-CD                              Anti-Le\b\
Anti-CDE                             Anti-Lu\a\
Anti-Co\b\                           Anti-Lu\b\
Anti-D                               Anti-M
Anti-DE                              Anti-M\g\
Anti-Di\a\                           Anti-N
Anti-E                               Anti-P1
Anti-e                               Anti-S
Anti-Fy\a\                           Anti-s
Anti-Fy\b\                           Anti-U
Anti-I                               Anti-Wr\a\
Anti-Jk\a\                           Anti-Xg\a\
------------------------------------------------------------------------

    (b) The applicant may provide the labeling information referenced in 
paragraph (a) of this section in the form of:
    (1) A symbol accompanied by explanatory text adjacent to the symbol;
    (2) A symbol not accompanied by adjacent explanatory text that:
    (i) Is contained in a standard that FDA recognizes under its 
authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act;
    (ii) Is used according to the specifications for use of the symbol 
set forth in FDA's section 514(c) recognition; and
    (iii) Is explained in a paper or electronic symbols glossary that is 
included in the labeling for the device and the labeling on or within 
the package containing the device bears a prominent and conspicuous 
statement identifying the location of the symbols glossary that is 
written in English or, in the case of articles distributed solely in 
Puerto Rico or in a Territory where the predominant language is one 
other than English, the predominant language may be used; or
    (3) A symbol not accompanied by adjacent explanatory text that:
    (i) Is established in a standard developed by a standards 
development organization (SDO);

[[Page 123]]

    (ii) Is not contained in a standard that is recognized by FDA under 
its authority in section 514(c) of the Federal Food, Drug, and Cosmetic 
Act or is contained in a standard that is recognized by FDA but is not 
used according to the specifications for use of the symbol set forth in 
FDA's section 514(c) recognition;
    (iii) Is determined by the manufacturer to be likely to be read and 
understood by the ordinary individual under customary conditions of 
purchase and use in compliance with section 502(c) of the Federal Food, 
Drug, and Cosmetic Act;
    (iv) Is used according to the specifications for use of the symbol 
set forth in the SDO-developed standard; and
    (v) Is explained in a paper or electronic symbols glossary that is 
included in the labeling for the device and the labeling on or within 
the package containing the device bears a prominent and conspicuous 
statement identifying the location of the symbols glossary that is 
written in English or, in the case of articles distributed solely in 
Puerto Rico or in a Territory where the predominant language is one 
other than English, the predominant language may be used.
    (c) The use of symbols in device labeling to provide the labeling 
information referenced in paragraph (a) of this section which do not 
meet the requirements in paragraph (b) of this section renders a device 
misbranded under section 502(c) of the Federal Food, Drug, and Cosmetic 
Act.
    (d) For purposes of paragraph (b) of this section:
    (1) An SDO is an organization that is nationally or internationally 
recognized and that follows a process for standard development that is 
transparent, (i.e., open to public scrutiny), where the participation is 
balanced, where an appeals process is included, where the standard is 
not in conflict with any statute, regulation, or policy under which FDA 
operates, and where the standard is national or international in scope.
    (2) The term ``symbols glossary'' means a compiled listing of:
    (i) Each SDO-established symbol used in the labeling for the device;
    (ii) The title and designation number of the SDO-developed standard 
containing the symbol;
    (iii) The title of the symbol and its reference number, if any, in 
the standard; and
    (iv) The meaning or explanatory text for the symbol as provided in 
the FDA recognition or, if FDA has not recognized the standard or 
portion of the standard in which the symbol is located or the symbol is 
not used according to the specifications for use of the symbol set forth 
in FDA's section 514(c) recognition, the explanatory text as provided in 
the standard.

[81 FR 38925, June 15, 2016]



                    Subpart D_Reagent Red Blood Cells

    Source: 52 FR 37450, Oct. 7, 1987, unless otherwise noted.



Sec.  660.30  Reagent Red Blood Cells.

    (a) Proper name and definition. The proper name of the product shall 
be Reagent Red Blood Cells, which shall consist of a preparation of 
human red blood cells used to detect or identify human blood-group 
antibodies.
    (b) Source. Reagent Red Blood Cells shall be prepared from human 
peripheral blood meeting the criteria of Sec. Sec.  660.31 and 660.32 of 
this chapter, or from umbilical cord cells which shall be collected and 
prepared according to the manufacturer's biologics license application.

[52 FR 37450, Oct. 7, 1987, as amended at 64 FR 56454, Oct. 20, 1999]



Sec.  660.31  Eligibility of donor.

    Donors of peripheral blood for Reagent Red Blood Cells must meet all 
the criteria for donor eligibility under Sec. Sec.  630.10 and 630.15 of 
this chapter.

[80 FR 29906, May 22, 2015]



Sec.  660.32  Collection of source material.

    Blood for Reagent Red Blood Cells from donors of peripheral blood 
shall be collected as prescribed under Sec.  640.4 of this chapter, 
except that paragraphs (c), (d), (g), and (h) of Sec.  640.4 shall not 
apply.

[[Page 124]]



Sec.  660.33  Testing of source material.

    Except as provided in this section, a sample of each blood 
incorporated into the Reagent Red Blood Cell product shall be 
individually tested, with no fewer than two donor sources of each 
antibody specificity employed, to confirm the identification of all 
blood group antigens specified in the labeling as present or absent. The 
manufacturer shall perform at least one of the required tests for each 
factor. The Reagent Red Blood Cell product may be tested with a single 
donor source of antibody specificity if only one source of antibody is 
available, and the Director, Center for Biologics Evaluation and 
Research, has approved the use of a single donor source of antiserum. 
Each of these tests shall be conducted and interpreted independently, 
and any discrepancy between the results of these two tests shall be 
resolved by testing with at least one additional antiserum before 
concluding that the antigen is present or absent. Where fewer than three 
donor sources of an antibody specificity are available, test 
discrepancies shall be resolved in accordance with the manufacturer's 
biologics license application. Group O Reagent Red Blood Cells used in 
the detection or identification of unexpected antibodies shall include 
at least the following common antigens in each lot of the product: D, C, 
E, c, e, K, k, Fy\a\, Fy\b\, Jk\a\, Jk\b\, Le\a\, Le\b\, P1, 
M, N, S, and s.

[52 FR 37450, Oct. 7, 1987, as amended at 55 FR 11013, Mar. 26, 1990; 64 
FR 56454, Oct. 20, 1999]



Sec.  660.34  Processing.

    (a) Processing method. The processing method shall be one that has 
been shown to yield consistently a product that is capable of detecting, 
throughout the dating period, alloantibodies corresponding to all 
required blood group antigens specified in the labeling as present.
    (b) Products prepared from pooled red blood cells. If the product is 
recommended for the detection of unexpected antibodies, the pool shall 
be prepared by combining equal amounts of cells from no more than two 
donors. Umbilical cord cells are exempt from this requirement. Pooled 
cells shall not be recommended for pretransfusion tests, done in lieu of 
a major crossmatch, to detect unexpected antibodies in patients' 
samples.
    (c) Absence of antibodies. Each lot of final product shall be free 
of demonstrable antibodies, including anti-A and anti-B, unless the 
package insert and container lable include instructions to wash the 
cells before use. The final product shall also be direct antiglobulin 
test negative when tested with polyspecific anti-human globulin.
    (d) Final container. The final containers used for each lot of 
product shall be clean and shall permit observation of the contents for 
hemolysis or a change in color. The final container label, container 
cap, and dropper bulb of a Reagent Red Blood Cell product may be color-
coded with a visual match to a specific color approved by the Director, 
Center for Biologics Evaluation and Research.
    (e) Date of manufacture. The date of manufacture of the product 
shall be the date that the blood is withdrawn from the donor or obtained 
from umbilical cords. The period during which the reagent red blood cell 
source material is kept by the manufacturer in storage in a frozen state 
at -65 [deg]C or colder is excluded from the dating period. If the 
product consists of red blood cells from two or more donors, the date of 
manufacture of the final product shall be the date of withdrawal of 
blood from the donor of the oldest constituent blood. When a product 
consists of more than one container, e.g., cell panel, the date of 
manufacture of each container of the product shall be the earliest date 
that blood was withdrawn from a donor for any container of the product.
    (f) Retention samples. Retention samples shall be maintained as 
required by Sec.  600.13 of this chapter, except that samples must be 
retained only throughout the dating period of the product.

[52 FR 37450, Oct. 7, 1987, as amended at 55 FR 11013, Mar. 26, 1990; 67 
FR 9587, Mar. 4, 2002]



Sec.  660.35  Labeling.

    (a) In addition to the items required by Sec.  809.10 of this 
chapter and other applicable labeling provisions of this chapter, the 
following information shall be included in the labeling:

[[Page 125]]

    (1)(i) A logo or company name may be placed on the final container 
label, however, the logo or company name shall be located along the 
bottom or end of the label, outside of the main panel.
    (ii) If washing the cells is required by the manufacturer, the 
container label shall include appropriate instructions; if the cells 
should not be washed before use, e.g., if washing will adversely affect 
the product, the package insert shall explain.
    (2) The container label of Group O cells shall state:
    ``FOR USE IN DETECTION OF UNEXPECTED ANTIBODIES'' or ``FOR USE IN 
IDENTIFICATION OF UNEXPECTED ANTIBODIES'' or ``NOT FOR USE IN DETECTION 
OR IDENTIFICATION OF UNEXPECTED ANTIBODIES''.
    (3) Except as provided in this section, the container and package 
labels shall state the percentage of red blood cells in the suspension 
either as a discrete figure with a variance of more than [] 1 percentage unit or as a range the extremes of which 
differ by no more than 2 percentage units. If the stated red blood cell 
concentration is less than 2 percent, the variance shall be no more than 
[] 0.5 percentage unit.
    (4) The words ``pooled cells'' shall appear on the container and 
package labels of products prepared from pooled cells. The package label 
or package insert shall state that pooled cells are not recommended for 
pre-transfusion tests, done in lieu of a major crossmatch, to detect 
unexpected antibodies in patients' samples.
    (5) The package insert of a pooled product intended for detection of 
unexpected antibodies shall identify the number of donors contributing 
to the pool. Products designed exclusively for ABO Serum Grouping and 
umbilical cord cells need not identify the number of donors in the pool.
    (6) When the product is a multicontainer product, e.g., a cell 
panel, the container label and package label shall be assigned the same 
identifying lot number, and shall also bear a number or symbol to 
distinguish one container from another. Such number or symbol shall also 
appear on the antigenic constitution matrix.
    (7) The package label or package insert shall state the blood group 
antigens that have been tested for and found present or absent on the 
cells of each donor, or refer to such information in an accompanying 
antigenic constitution matrix. Cells for ABO Serum Grouping are exempt 
from this requirement. The package insert or antigen constitution matrix 
shall list each of the antigens tested with only one source of antibody.
    (8) The package label or package insert shall bear the cautionary 
statement: ``The reactivity of the product may decrease during the 
dating period.''
    (9) The package insert of a product intended for the detection or 
identification of unexpected antibodies shall note that the rate at 
which antigen reactivity (e.g., agglutinability) is lost is partially 
dependent upon individual donor characteristics that are neither 
controlled nor predicted by the manufacturer.
    (10) The package insert shall provide adequate directions for use.
    (11) The package insert shall bear the statement:
    ``CAUTION: ALL BLOOD PRODUCTS SHOULD BE TREATED AS POTENTIALLY 
INFECTIOUS. SOURCE MATERIAL FROM WHICH THIS PRODUCT WAS DERIVED WAS 
FOUND NEGATIVE WHEN TESTED IN ACCORDANCE WITH CURRENT FDA REQUIRED 
TESTS. NO KNOWN TEST METHODS CAN OFFER ASSURANCE THAT PRODUCTS DERIVED 
FROM HUMAN BLOOD WILL NOT TRANSMIT INFECTIOUS AGENTS.''
    (12) The package insert or the antigenic constitution matrix for 
each lot of product shall specify the date of manufacture or the length 
of the dating period.
    (13) Manufacturers shall identify with a permanent donor code in the 
product labeling each donor of peripheral blood used for detection or 
identification of unexpected antibodies.
    (b) The applicant may provide the labeling information referenced in 
paragraph (a) of this section in the form of:
    (1) A symbol accompanied by explanatory text adjacent to the symbol;
    (2) A symbol not accompanied by adjacent explanatory text that:

[[Page 126]]

    (i) Is contained in a standard that FDA recognizes under its 
authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act;
    (ii) Is used according to the specifications for use of the symbol 
set forth in FDA's section 514(c) recognition; and
    (iii) Is explained in a paper or electronic symbols glossary that is 
included in the labeling for the device and the labeling on or within 
the package containing the device bears a prominent and conspicuous 
statement identifying the location of the symbols glossary that is 
written in English or, in the case of articles distributed solely in 
Puerto Rico or in a Territory where the predominant language is one 
other than English, the predominant language may be used; or
    (3) A symbol not accompanied by adjacent explanatory text that:
    (i) Is established in a standard developed by a standards 
development organization (SDO);
    (ii) Is not contained in a standard that is recognized by FDA under 
its authority in section 514(c) of the Federal Food, Drug, and Cosmetic 
Act or is contained in a standard that is recognized by FDA but is not 
used according to the specifications for use of the symbol set forth in 
FDA's section 514(c) recognition;
    (iii) Is determined by the manufacturer to be likely to be read and 
understood by the ordinary individual under customary conditions of 
purchase and use in compliance with section 502(c) of the Federal Food, 
Drug, and Cosmetic Act;
    (iv) Is used according to the specifications for use of the symbol 
set forth in the SDO-developed standard; and
    (v) Is explained in a paper or electronic symbols glossary that is 
included in the labeling for the device and the labeling on or within 
the package containing the device bears a prominent and conspicuous 
statement identifying the location of the symbols glossary that is 
written in English or, in the case of articles distributed solely in 
Puerto Rico or in a Territory where the predominant language is one 
other than English, the predominant language may be used.
    (c) The use of symbols in device labeling to provide the labeling 
information referenced in paragraph (a) of this section which do not 
meet the requirements of paragraph (b) of this section renders a device 
misbranded under section 502(c) of the Federal Food, Drug, and Cosmetic 
Act.
    (d) For purposes of paragraph (b) of this section:
    (1) An SDO is an organization that is nationally or internationally 
recognized and that follows a process for standard development that is 
transparent, (i.e., open to public scrutiny), where the participation is 
balanced, where an appeals process is included, where the standard is 
not in conflict with any statute, regulation, or policy under which FDA 
operates, and where the standard is national or international in scope.
    (2) The term ``symbols glossary'' means a compiled listing of:
    (i) Each SDO-established symbol used in the labeling for the device;
    (ii) The title and designation number of the SDO-developed standard 
containing the symbol;
    (iii) The title of the symbol and its reference number, if any, in 
the standard; and
    (iv) The meaning or explanatory text for the symbol as provided in 
the FDA recognition or, if FDA has not recognized the standard or 
portion of the standard in which the symbol is located or the symbol is 
not used according to the specifications for use of the symbol set forth 
in FDA's section 514(c) recognition, the explanatory text as provided in 
the standard.

[81 FR 38926, June 15, 2016]



Sec.  660.36  Samples and protocols.

    (a) The following shall be submitted to the Center for Biologics 
Evaluation and Research Sample Custodian (see mailing addresses in Sec.  
600.2(c) of this chapter), within 30 days after each routine 
establishment inspection by FDA.
    (1) From a lot of final product, samples from a cell panel intended 
for identification of unexpected antibodies. The sample shall be 
packaged as for distribution and shall have at least 14 days remaining 
in the dating period when shipped to the Center for Biologics Evaluation 
and Research.
    (2) A protocol which shall include the following:

[[Page 127]]

    (i) Complete test records of at least two donors of the samples 
submitted, including original and confirmation phenotyping records.
    (ii) Bleeding records or receipt records which indicate collection 
date, volume, and HBsAg test results.
    (iii) Manufacturing records which document all steps involved in the 
preparation of the product.
    (iv) Test results which verify that the final product meets 
specifications.
    (v) Identity test results.
    (b) A copy of the antigenic constitution matrix specifying the 
antigens present or absent shall be submitted to the Director, Center 
for Biologics Evaluation and Research (see mailing addresses in Sec.  
600.2(c) of this chapter), at the time of initial distribution of each 
lot of Reagent Red Blood Cells for detection or identification of 
unexpected antibodies. Products designed exclusively to identify Anti-A, 
Anti-A1, and Anti-B, as well as products composed entirely of 
umbilical cord cells, are excluded from this requirement.
    (c) Except for umbilical cord samples, whenever a new donor is used, 
a sample of red blood cells from each new donor used in a cell panel 
intended for the identification of unexpected antibodies shall be 
submitted by the manufacturer to the Director, Center for Biologics 
Evaluation and Research (see mailing addresses in Sec.  600.2(c) of this 
chapter). The sample should contain a minimum volume of 0.5 milliliter 
of red blood cells.

[52 FR 37450, Oct. 7, 1987, as amended at 55 FR 11013, 11015, Mar. 26, 
1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005; 80 FR 18093, 
Apr. 3, 2015]



                  Subpart E_Hepatitis B Surface Antigen

    Source: 44 FR 36382, June 22, 1979, unless otherwise noted.



Sec.  660.40  Hepatitis B Surface Antigen.

    (a) Proper name and definition. The proper name of this product 
shall be Hepatitis B Surface Antigen (HBsAg), which shall consist of a 
serum or tissue preparation containing one or more subtypes of the 
Hepatitis B Surface Antigen.
    (b) Source. The source of the product shall be blood, plasma, serum, 
or tissue, obtained aseptically from nonhuman primates that have met the 
applicable requirements of Sec.  600.11 of this chapter, or from human 
donors whose blood is positive for the Hepatitis B Surface Antigen.



Sec.  660.41  Processing.

    (a) Method. The processing method shall be one that has been shown 
to yield consistently a specific and potent final product, free of 
properties which would adversely affect the test results when the 
product is tested by the methods recommended by the manufacturer in the 
package insert. The product and all ancillary reagents and materials 
supplied in the package with the product shall be manufactured in a 
manner that will reduce the risk of transmitting type B viral hepatitis.
    (b) Ancillary reagents and materials. All ancillary reagents and 
materials supplied in the package with the product shall meet generally 
accepted standards of purity and quality and shall be effectively 
segregated and otherwise manufactured in a manner that will reduce the 
risk of contaminating the product and other biological products. 
Ancillary reagents and materials accompanying the product, which are 
used in the performance of the test as described by the manufacturer's 
recommended test procedures, shall have been shown not to affect 
adversely the product within the prescribed dating period.
    (c) Final container. A final container shall be sufficiently 
transparent to permit visual inspection of the contents for presence of 
particulate matter and increased turbidity. The effectiveness of the 
contents of a final container shall be maintained throughout its dating 
period.
    (d) Date of manufacture. The date of manufacture of Hepatitis B 
Surface Antigen that has been iodinated with radioactive iodine (\125\I) 
shall be the day of labeling the antibody with the radionuclide.

[44 FR 36382, June 22, 1979, as amended at 49 FR 1685, Jan. 13, 1984]

[[Page 128]]



Sec.  660.43  Potency test.

    To be satisfactory for release, each filling of Hepatitis B Surface 
Antigen shall be tested against the Reference Hepatitis B Antiserum 
Panel and shall be sufficiently potent to be able to detect the antibody 
in the appropriate sera of the reference panel by all test methods 
recommended by the manufacturer in the package insert.



Sec.  660.44  Specificity.

    Each filling of the product shall be specific for Hepatitis B 
Surface Antigen as determined by specificity tests found acceptable to 
the Director, Center for Biologics Evaluation and Research.

[44 FR 36382, June 22, 1979, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]



Sec.  660.45  Labeling.

    (a) In addition to the requirements of Sec. Sec.  610.60, 610.61, 
and 809.10 of this chapter, the labeling shall bear the following:
    (1) The ``d and y'' antigen subtype and the source of the product to 
follow immediately the proper name on both the final container label and 
the package label. If the product is intended to identify antibodies to 
the ``r and w'' antigen subtype, the antigen subtype designation shall 
include the ``r and w'' antigen subtype.
    (2) The name of the test method(s) recommended for use of the 
product on the package label and on the final container label, when 
capable of bearing a full label (see Sec.  610.60(a) of this chapter).
    (3) A warning on the package label and on the final container label 
stating that the product is capable of transmitting hepatitis and should 
be handled accordingly.
    (4) The package shall include a package insert providing:
    (i) Detailed instructions for use,
    (ii) An adequate description of all recommended test methods, and
    (iii) Warnings as to possible hazards, including hepatitis 
transmitted in handling the product and any ancillary reagents and 
materials accompanying the product.
    (b) The applicant may provide the labeling information referenced in 
paragraph (a) of this section in the form of:
    (1) A symbol accompanied by explanatory text adjacent to the symbol;
    (2) A symbol not accompanied by adjacent explanatory text that:
    (i) Is contained in a standard that FDA recognizes under its 
authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act;
    (ii) Is used according to the specifications for use of the symbol 
set forth in FDA's section 514(c) recognition; and
    (iii) Is explained in a paper or electronic symbols glossary that is 
included in the labeling for the device and the labeling on or within 
the package containing the device bears a prominent and conspicuous 
statement identifying the location of the symbols glossary that is 
written in English or, in the case of articles distributed solely in 
Puerto Rico or in a Territory where the predominant language is one 
other than English, the predominant language may be used; or
    (3) A symbol not accompanied by adjacent explanatory text that:
    (i) Is established in a standard developed by a standards 
development organization (SDO);
    (ii) Is not contained in a standard that is recognized by FDA under 
its authority in section 514(c) of the Federal Food, Drug, and Cosmetic 
Act or is contained in a standard that is recognized by FDA but is not 
used according to the specifications for use of the symbol set forth in 
FDA's section 514(c) recognition;
    (iii) Is determined by the manufacturer to be likely to be read and 
understood by the ordinary individual under customary conditions of 
purchase and use in compliance with section 502(c) of the Federal Food, 
Drug, and Cosmetic Act;
    (iv) Is used according to the specifications for use of the symbol 
set forth in the SDO-developed standard; and
    (v) Is explained in a paper or electronic symbols glossary that is 
included in the labeling for the device and the labeling on or within 
the package containing the device bears a prominent and conspicuous 
statement identifying the location of the symbols glossary that is 
written in English or,

[[Page 129]]

in the case of articles distributed solely in Puerto Rico or in a 
Territory where the predominant language is one other than English, the 
predominant language may be used.
    (c) The use of symbols in device labeling to provide the labeling 
information referenced in paragraph (a) of this section which do not 
meet the requirements of paragraph (b) of this section renders a device 
misbranded under section 502(c) of the Federal Food, Drug, and Cosmetic 
Act.
    (d) For purposes of paragraph (b) of this section:
    (1) An SDO is an organization that is nationally or internationally 
recognized and that follows a process for standard development that is 
transparent, (i.e., open to public scrutiny), where the participation is 
balanced, where an appeals process is included, where the standard is 
not in conflict with any statute, regulation, or policy under which FDA 
operates, and where the standard is national or international in scope.
    (2) The term ``symbols glossary'' means a compiled listing of:
    (i) Each SDO-established symbol used in the labeling for the device;
    (ii) The title and designation number of the SDO-developed standard 
containing the symbol;
    (iii) The title of the symbol and its reference number, if any, in 
the standard; and
    (iv) The meaning or explanatory text for the symbol as provided in 
the FDA recognition or, if FDA has not recognized the standard or 
portion of the standard in which the symbol is located or the symbol is 
not used according to the specifications for use of the symbol set forth 
in FDA's section 514(c) recognition, the explanatory text as provided in 
the standard.

[81 FR 38928, June 15, 2016]



Sec.  660.46  Samples; protocols; official release.

    (a) Samples. (1) For the purposes of this section, a sample of 
product not iodinated with \125\I means a sample from each filling of 
each lot packaged as for distribution, including all ancillary reagents 
and materials; and a sample of product iodinated with \125\I or 
unlyophilized HBsAg-coated red blood cells means a sample from each lot 
of diagnostic test kits in a finished package, including all ancillary 
reagents and materials.
    (2) Unless the Director, Center for Biologics Evaluation and 
Research, determines that the reliability and consistency of the 
finished product can be assured with a smaller quantity of sample or no 
sample and specifically reduces or eliminates the required quantity of 
sample, each manufacturer shall submit the following samples to the 
Director, Center for Biologics Evaluation and Research (see mailing 
addresses in Sec.  600.2(c) of this chapter), within 5 working days 
after the manufacturer has satisfactorily completed all tests on the 
samples:
    (i) One sample until written notification of official release is no 
longer required under paragraph (c)(2) of this section.
    (ii) One sample of product at periodic intervals of 90 days, 
beginning after written notification of official release is no longer 
required under paragraph (c)(2) of this section. The sample submitted at 
the 90-day interval shall be from the first lot or filling, as 
applicable, released by the manufacturer, under the requirements of 
Sec.  610.1 of this chapter, after the end of the previous 90-day 
interval. The sample shall be identified as ``surveillance sample'' and 
shall include the date of manufacture.
    (iii) Samples may at any time be required to be submitted to the 
Director, Center for Biologics Evaluation and Research, if the Director 
finds that continued evaluation is necessary to ensure the potency, 
quality, and reliability of the product.
    (b) Protocols. For each sample submitted as required in paragraph 
(a)(1) of this section, the manufacturer shall send a protocol that 
consists of a summary of the history of manufacture of the product, 
including all results of each test for which test results are requested 
by the Director, Center for Biologics Evaluation and Research. The 
protocols submitted with the samples at periodic intervals as provided 
in paragraph (a)(2)(ii) of this section shall be identified by the 
manufacturer as ``surveillance test results.''
    (c) Official release. (1) The manufacturer shall not distribute the 
product

[[Page 130]]

until written notification of official release is received from the 
Director, Center for Biologics Evaluation and Research, except as 
provided in paragraph (c)(2) of this section. Official release is 
required for at least five consecutive lots or fillings, as applicable, 
manufactured after licensure of the product.
    (2) After written notification of official release is received from 
the Director, Center for Biologics Evaluation and Research, for at least 
five consecutive lots or fillings manufactured after licensure of the 
products, and after the manufacturer receives from the Director, Center 
for Biologics Evaluation and Research, written notification that 
official release is no longer required, subsequent lots or fillings may 
be released by the manufacturer under the requirements of Sec.  610.1 of 
this chapter.
    (3) The manufacturer shall not distribute lots or fillings, as 
applicable, of products that require sample submission under paragraph 
(a)(2)(iii) of this section until written notification of official 
release or notification that official release is no longer required is 
received from the Director, Center for Biologics Evaluation and 
Research.

[48 FR 20407, May 6, 1983, as amended at 49 FR 23834, June 8, 1984; 51 
FR 15611, Apr. 25, 1986; 55 FR 11013, 11014, Mar. 26, 1990; 70 FR 14985, 
Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015]



                      Subpart F_Anti-Human Globulin



Sec.  660.50  Anti-Human Globulin.

    (a) Proper name and definition. The proper name of this product 
shall be Anti-Human Globulin which shall consist of one or more 
antiglobulin antibodies identified in Sec.  660.55(a)(4).
    (b) Source. The source of this product shall be either serum from 
animals immunized with one or more human serum globulins or protein-rich 
fluids derived from stable immunoglobulin-secreting cell lines 
maintained either in tissue cultures or in secondary hosts.

[50 FR 5579, Feb. 11, 1985, as amended at 65 FR 77499, Dec. 12, 2000; 81 
FR 38928, June 15, 2016]



Sec.  660.51  Processing.

    (a) Processing method. (1) The processing method shall be one that 
has been shown to yield consistently a specific, potent final product, 
free of properties that would adversely affect the product for its 
intended use throughout its dating period.
    (2) Anti-IgG, -C3d (polyspecific) reagents and anti-IgG products may 
be colored green.
    (3) Only that material which has been fully processed, thoroughly 
mixed in a single vessel, and filtered shall constitute a lot. Each lot 
shall be identified by a lot number.
    (4) A lot may be subdivided into sublots which shall be identified 
by the lot number to which has been added a distinctive prefix or 
suffix. If lots are to be subdivided, the manufacturer shall include 
this information in the license application . The manufacturer shall 
describe the test specifications to verify that each sublot is identical 
to other sublots of the lot.
    (b) Final containers and dropper assemblies. (1) Final containers 
and dropper assemblies shall be clean.
    (2) Final containers and dropper pipettes shall be colorless and 
sufficiently transparent to permit observation of the contents for 
presence of particulate matter or increased turbidity.
    (c) Date of manufacture. The date of manufacture shall be the date 
the manufacturer begins the last entire group of potency tests.

[50 FR 5579, Feb. 11, 1985, as amended at 50 FR 16474, Apr. 26, 1985; 65 
FR 77499, Dec. 12, 2000; 67 FR 9587, Mar. 4, 2002]



Sec.  660.52  Reference preparations.

    Reference Anti-Human Globulin preparations shall be obtained from 
the Food and Drug Administration, Center for Biologics Evaluation and 
Research, Reagents and Standards Shipping, 10903 New Hampshire Ave., 
Bldg. 75, Rm. G704, Silver Spring, MD 20993-0002, and

[[Page 131]]

shall be used as described in the accompanying package insert for 
determining the potency of Anti-Human Globulin.

[50 FR 5579, Feb. 11, 1985, as amended at 50 FR 16474, Apr. 26, 1985; 51 
FR 15611, Apr. 25, 1986; 55 FR 11015, Mar. 26, 1990; 67 FR 9587, Mar. 4, 
2002; 70 FR 14986, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015]



Sec.  660.53  Controls for serological procedures.

    Red blood cells sensitized with complement shall be tested with 
appropriate positive and negative control antisera. All tests shall be 
performed in accordance with serological testing procedures approved by 
the Director, Center for Biologics Evaluation and Research.

[50 FR 5579, Feb. 11, 1985, as amended at 50 FR 16474, Apr. 26, 1985; 51 
FR 15611, Apr. 25, 1986; 55 FR 11014, Mar. 26, 1990; 67 FR 9587, Mar. 4, 
2002; 70 FR 14986, Mar. 24, 2005]



Sec.  660.54  Potency tests, specificity tests, tests for heterospecific
antibodies, and additional tests for nonspecific properties.

    The following tests shall be performed using test procedures 
approved by the Director, Center for Biologics Evaluation and Research:
    (a) Potency tests for determining anti-IgG and anti-complement 
activity.
    (b) Specificity tests, tests for heterospecific antibodies, and 
additional tests for nonspecific properties.

[50 FR 5579, Feb. 11, 1985, as amended at 50 FR 16474, Apr. 26, 1985; 51 
FR 15611, Apr. 25, 1986; 55 FR 11014, Mar. 26, 1990; 67 FR 9587, Mar. 4, 
2002; 70 FR 14986, Mar. 24, 2005]



Sec.  660.55  Labeling.

    (a) In addition to the applicable labeling requirements of 
Sec. Sec.  610.62 through 610.65 and Sec.  809.10 of this chapter, and 
in lieu of the requirements in Sec. Sec.  610.60 and 610.61 of this 
chapter, the following requirements shall be met:
    (1) Final container label--(i) Color coding. The main panel of the 
final container label of all Anti-IgG, -C3d (polyspecific) reagents 
shall be white or colorless and printing shall be solid dark contrasting 
lettering. The main panel of the final container label of all other 
Anti-Human Globulin reagents shall be black with solid white lettering. 
A logo or company name may be placed on the final container label; 
however, the logo or company name shall be located along the bottom or 
end of the label, outside of the main panel.
    (ii) Required information. The proper name ``Anti-Human Globulin'' 
need not appear on the final container label provided the final 
container is distributed in a package and the package label bears the 
proper name. The final container label shall bear the following 
information:
    (A) Name of the antibody or antibodies present as set forth in 
paragraph (a)(4) of this section. Anti-Human Globulin may contain one or 
more antibodies to either immunoglobulins or complement components but 
the name of each significant antibody must appear on the final container 
label (e.g., anti-C3b, -C3d, -C4d). The final container labels of 
polyspecific Anti-Human Globulin are not required to identify antibody 
specificities other than anti-IgG and anti-C3d but the reactivity of the 
Anti-Human Globulin shall be accurately described in the package insert.
    (B) Name, address, and license number of the manufacturer.
    (C) Lot number, including any sublot designations.
    (D) Expiration date.
    (E) Source of the product.
    (F) Recommended storage temperature in degrees Celsius.
    (G) Volume of product.
    (H) Appropriate cautionary statement if the Anti-Human Globulin is 
not polyspecific. For example, ``DOES NOT CONTAIN ANTIBODIES TO 
IMMUNOGLOBULINS'' or ``DOES NOT CONTAIN ANTIBODIES TO COMPLEMENT 
COMPONENTS.''
    (I) If the final container is not enclosed in a package, all items 
required for a package label shall appear on the container label.
    (iii) Lettering size. The type size for the designation of the 
specific antibody on the label of a final container shall be not less 
than 12 point, unless otherwise approved by the Director, Center for 
Biologics Evaluation and Research. The prefix anti- and other parts of 
the

[[Page 132]]

name such as polyspecific may appear in smaller type.
    (iv) Visual inspection. When the label has been affixed to the final 
container, a sufficient area of the container shall remain uncovered for 
its full length or for no less than 5 millimeters of the lower 
circumference to permit inspection of the contents.
    (2) Package label. The following items shall appear either on the 
package label or on the final container label if see-through packaging 
is used:
    (i) Proper name of the product, and the name of the antibody or 
antibodies as listed in paragraph (a)(4) of this section.
    (ii) Name, address (including ZIP code), and license number of the 
manufacturer.
    (iii) Lot number, including any sublot designations.
    (iv) Expiration date.
    (v) Preservative(s) used and its concentration.
    (vi) Number of containers, if more than one.
    (vii) Recommended storage temperature in degrees Celsius.
    (viii) Source of the product.
    (ix) Reference to enclosed package insert.
    (x) The statement: ``For In Vitro Diagnostic Use.''
    (xi) The statement: ``Meets FDA Potency Requirements.''
    (xii) A statement of an observable indication of an alteration of 
the product, e.g., turbidity, color change, precipitate, that may 
indicate possible deterioration of the product.
    (xiii) Appropriate cautions.
    (3) Package insert. Each final container of Anti-Human Globulin 
shall be accompanied by a package insert meeting the requirements of 
Sec.  809.10 of this chapter. If two or more final containers requiring 
identical package inserts are placed in a single package, only one 
package insert per package is required.
    (4) Names of antibodies. Anti-Human Globulin preparations may 
contain one or more of the antibody specificities listed in this 
paragraph as described in paragraph (a)(1)(ii)(A) of this section.

----------------------------------------------------------------------------------------------------------------
    Antibody designation on container label                                 Definition
----------------------------------------------------------------------------------------------------------------
(1) Anti-IgG, -C3d; Polyspecific...............  Contains anti-IgG and anti-C3d (may contain other
                                                  anticomplement and anti-immunoglobulin antibodies).
(2) Anti-IgG...................................  Contains anti-IgG with no anti-complement activity (not
                                                  necessarily gamma chain specific).
(3) Anti-IgG; heavy chains.....................  Contains only antibodies reactive against human gamma chains.
(4) Anti-C3b...................................  Contains only C3b antibodies with no anti-immunoglobulin
                                                  activity. Note: The antibody produced in response to
                                                  immunization is usually directed against the antigenic
                                                  determinant which is located in the C3c subunit; some persons
                                                  have called this antibody ``anti-C3c.'' In product labeling,
                                                  this antibody should be designated anti-C3b.
(5) Anti-C3d...................................  Contains only C3d antibodies with no anti-immunoglobulin
                                                  activity.
(6) Anti-C4b...................................  Contains only C4b antibodies with no anti-immunoglobulin
                                                  activity.
(7) Anti-C4d...................................  Contains only C4d antibodies with no anti-immunoglobulin
                                                  activity.
----------------------------------------------------------------------------------------------------------------

    (b) The applicant may provide the labeling information referenced in 
this section in the form of:
    (1) A symbol accompanied by explanatory text adjacent to the symbol;
    (2) A symbol not accompanied by adjacent explanatory text that:
    (i) Is contained in a standard that FDA recognizes under its 
authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act;
    (ii) Is used according to the specifications for use of the symbol 
set forth in FDA's section 514(c) recognition; and
    (iii) Is explained in a paper or electronic symbols glossary that is 
included in the labeling for the device and the labeling on or within 
the package containing the device bears a prominent and conspicuous 
statement identifying the location of the symbols glossary that is 
written in English or, in the case of articles distributed solely in 
Puerto Rico or in a Territory where the predominant language is one 
other than English, the predominant language may be used; or
    (3) A symbol not accompanied by adjacent explanatory text that:
    (i) Is established in a standard developed by a standards 
development organization (SDO);

[[Page 133]]

    (ii) Is not contained in a standard that is recognized by FDA under 
its authority in section 514(c) or is contained in a standard that is 
recognized by FDA but is not used according to the specifications for 
use of the symbol set forth in FDA's section 514(c) recognition;
    (iii) Is determined by the manufacturer to be likely to be read and 
understood by the ordinary individual under customary conditions of 
purchase and use in compliance with section 502(c) of the Federal Food, 
Drug, and Cosmetic Act;
    (iv) Is used according to the specifications for use of the symbol 
set forth in the SDO-developed standard; and
    (v) Is explained in a paper or electronic symbols glossary that is 
included in the labeling for the device and the labeling on or within 
the package containing the device bears a prominent and conspicuous 
statement identifying the location of the symbols glossary that is 
written in English or, in the case of articles distributed solely in 
Puerto Rico or in a Territory where the predominant language is one 
other than English, the predominant language may be used.
    (c) The use of symbols in device labeling to provide the labeling 
information referenced in paragraph (a) of this section which do not 
meet the requirements of paragraph (b) of this section renders a device 
misbranded under section 502(c) of the Federal Food, Drug, and Cosmetic 
Act.
    (d) For purposes of paragraph (b) of this section:
    (1) An SDO is an organization that is nationally or internationally 
recognized and that follows a process for standard development that is 
transparent, (i.e., open to public scrutiny), where the participation is 
balanced, where an appeals process is included, where the standard is 
not in conflict with any statute, regulation, or policy under which FDA 
operates, and where the standard is national or international in scope.
    (2) The term ``symbols glossary'' means a compiled listing of:
    (i) Each SDO-established symbol used in the labeling for the device;
    (ii) The title and designation number of the SDO-developed standard 
containing the symbol;
    (iii) The title of the symbol and its reference number, if any, in 
the standard; and
    (iv) The meaning or explanatory text for the symbol as provided in 
the FDA recognition or, if FDA has not recognized the standard or 
portion of the standard in which the symbol is located or the symbol is 
not used according to the specifications for use of the symbol set forth 
in FDA's section 514(c) recognition, the explanatory text as provided in 
the standard.

[81 FR 38928, June 15, 2016]



PART 680_ADDITIONAL STANDARDS FOR MISCELLANEOUS PRODUCTS--Table of Contents



Sec.
680.1 Allergenic Products.
680.2 Manufacture of Allergenic Products.
680.3 Tests.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 U.S.C. 
216, 262, 263, 263a, 264.

    Source: 38 FR 32100, Nov. 20, 1973, unless otherwise noted.

    Cross References: For U.S. Customs Service regulations relating to 
viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal 
Service regulations relating to the admissibility to the United States 
mails see parts 124 and 125 of the Domestic Mail Manual, that is 
incorporated by reference in 39 CFR part 111.



Sec.  680.1  Allergenic Products.

    (a) Definition. Allergenic Products are products that are 
administered to man for the diagnosis, prevention or treatment of 
allergies.
    (b) Source materials--(1) Criteria for source material. Only 
specifically identified allergenic source materials that contain no more 
than a total of 1.0 percent of detectable foreign materials shall be 
used in the manufacture of Allergenic Products, except that this 
requirement shall not apply to molds and animals described under 
paragraphs (b) (2) and (3) of this section, respectively. Source 
materials such as pelts, feathers, hairs, and danders shall be collected 
in a manner that will minimize contamination of the source material.

[[Page 134]]

    (2) Molds. (i) Molds (excluding rusts and smuts) used as source 
material in the manufacture of Allergenic Products shall meet the 
requirements of Sec.  610.18 of this chapter and Sec.  680.2 (a) and 
(b).
    (ii) Mold cultures shall be free of contaminating materials 
(including microorganisms) prior to harvest, and care shall be taken to 
minimize contamination during harvest and subsequent processing.
    (iii) Mold manufacturers shall maintain written standard operating 
procedures, developed by a qualified individual, that will ensure the 
identity of the seed culture, prescribe adequate processing of the mold, 
and specify the acceptable limits and kinds of contamination. These 
limits shall be based on results of appropriate tests performed by the 
manufacturer on at least three consecutive lots of a mold that is a 
representative species of mold subject to the standard operating 
procedures. The tests shall be performed at each manufacturing step 
during and subsequent to harvest, as specified in the standard operating 
procedures. Before use of the mold as a source material for Allergenic 
Products, in accordance with 21 CFR 601.2, the standard operating 
procedures and test data from the three representative lots described 
above shall be submitted to and approved by the Director, Center for 
Biologics Evaluation and Research (see mailing address in Sec.  600.2(a) 
of this chapter).
    (3) Mammals and birds--(i) Care of animals. Animals intended as a 
source material for Allergenic Products shall be maintained by competent 
personnel in facilities or designated areas that will ensure adequate 
care. Competent veterinary care shall be provided as needed.
    (ii) Health of animals. Only animals in good health and free from 
detectable skin diseases shall be used as a source material for 
Allergenic Products. The determination of good health prior to 
collection of the source material shall be made by a licensed 
veterinarian or a competent individual under the supervision and 
instruction of a licensed veterinarian provided that the licensed 
veterinarian certifies in writing that the individual is capable of 
determining the good health of the animals.
    (iii) Immunization against tetanus. Animals of the equine genus 
intended as a source material for Allergenic Products shall be treated 
to maintain immunity to tetanus.
    (iv) Reporting of certain diseases. In cases of actual or suspected 
infection with foot and mouth disease, glanders, tetanus, anthrax, gas 
gangrene, equine infectious anemia, equine encephalomyelitis, or any of 
the pock diseases among animals intended for use or used as source 
material in the manufacture of Allergenic Products, the manufacturer 
shall immediately notify the Director, Center for Biologics Evaluation 
and Research (see mailing address in Sec.  600.2(a) of this chapter).
    (v) Dead animals. Dead animals may be used as source material in the 
manufacture of Allergenic Products: Provided, That (a) the carcasses 
shall be frozen or kept cold until the allergen can be collected, or 
shall be stored under other acceptable conditions so that the postmortal 
decomposition processes do not adversely affect the allergen, and (b) 
when alive, the animal met the applicable requirements prescribed in 
paragraphs (b)(3) (i), (ii), and (iii) of this section.
    (vi) Mammals and birds inspected by the U.S. Department of 
Agriculture. Mammals and birds, subject to inspection by the U.S. 
Department of Agriculture at the time of slaughter and found suitable as 
food, may be used as a source material, and the requirements of 
paragraph (b)(3) (i) through (iv) of this section do not apply in such a 
case. Notwithstanding U.S. Department of Agriculture inspection, the 
carcasses of such inspected animals shall be frozen or kept cold until 
the allergen is collected, or shall be stored under other acceptable 
conditions so that the postmortal decomposition processes do not 
adversely affect the allergen.
    (c) Listing of source materials and suppliers. Each licensed 
manufacturer shall initially list with the Director, Center for 
Biologics Evaluation and Research (see mailing address in Sec.  600.2(a) 
of this chapter), the name and address of each of the manufacturer's

[[Page 135]]

source material suppliers. The listing shall identify each source 
material obtained from each source material supplier. The licensed 
manufacturers shall update the listing annually to include new source 
material suppliers or to delete those no longer supplying source 
materials.
    (d) Exemptions. (1) Exemptions or modifications from the 
requirements under paragraph (b) of this section shall be made only upon 
written approval by the Director, Center for Biologics Evaluation and 
Research.
    (2) Nonlicensed source material suppliers are exempt from drug 
registration.

[38 FR 32100, Nov. 20, 1973, as amended at 49 FR 25432, June 21, 1984; 
49 FR 31395, Aug. 7, 1984; 55 FR 11014, Mar. 26, 1990; 67 FR 9587, Mar. 
4, 2002; 70 FR 14986, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015]



Sec.  680.2  Manufacture of Allergenic Products.

    (a) Extraneous allergenic substances. All manufacturing steps shall 
be performed so as to insure that the product will contain only the 
allergenic and other substances intended to be included in the final 
product.
    (b) Cultures derived from microorganisms. Culture media into which 
organisms are inoculated for the manufacture of Allergenic Products 
shall contain no allergenic substances other than those necessary as a 
growth requirement. Neither horse protein nor any allergenic derivative 
of horse protein shall be used in culture media.
    (c) Liquid products for oral administration. Liquid products 
intended for oral administration that are filled in multiple dose final 
containers shall contain a preservative in a concentration adequate to 
inhibit microbial growth.
    (d) Residual pyridine. Products for which pyridine is used in 
manufacturing shall have no more residual pyridine in the final product 
than 25 micrograms per milliliter.
    (e) [Reserved]
    (f) Records. A record of the history of the manufacture or 
propagation of each lot of source material intended for manufacture of 
final Allergenic Products shall be available at the establishment of the 
manufacturer of the source material, as required by Sec.  211.188 of 
this chapter. A summary of the history of the manufacture or propagation 
of the source material shall be available at the establishment of the 
manufacturer of the final product.

[38 FR 32100, Nov. 20, 1973, as amended at 49 FR 25433, June 21, 1984; 
67 FR 9587, Mar. 4, 2002]



Sec.  680.3  Tests.

    (a) Identity. When a specific identity test meeting the provisions 
of Sec.  610.14 of this chapter cannot be performed, the manufacture of 
each lot shall be separated from the manufacture of other products in a 
manner that will preclude adulteration, and records made in the course 
of manufacture shall be in sufficient detail to verify the identity of 
the product.
    (b) [Reserved]
    (c) Sterility. A sterility test shall be performed on each lot of 
each Allergenic Product as required by Sec.  610.12 of this chapter.
    (d) [Reserved]
    (e) Potency. The potency of each lot of each Allergenic Product 
shall be determined as prescribed in Sec.  610.10 of this chapter. 
Except as provided in this section, the potency test methods shall 
measure the allergenic activity of the product. Until manufacturers are 
notified by the Director, Center for Biologics Evaluation and Research, 
of the existence of a potency test that measures the allergenic activity 
of an allergenic product, manufacturers may continue to use 
unstandardized potency designations.
    (f) Records. The records related to the testing requirements of this 
section shall be prepared and maintained as required by Sec. Sec.  
211.165, 211.167, 211.188, and 211.194 of this chapter.

[38 FR 32100, Nov. 20, 1973, as amended at 39 FR 19777, June 6, 1974; 41 
FR 4015, Jan. 28, 1976; 52 FR 37607, Oct. 8, 1987; 55 FR 11013, Mar. 26, 
1990; 67 FR 9587, Mar. 4, 2002; 77 FR 26175, May 3, 2012; 77 FR 30884, 
May 24, 2012; 80 FR 37974, July 2, 2015]

[[Page 136]]



                         SUBCHAPTER G_COSMETICS





PART 700_GENERAL--Table of Contents



                      Subpart A_General Provisions

Sec.
700.3 Definitions.

          Subpart B_Requirements for Specific Cosmetic Products

700.11 Cosmetics containing bithionol.
700.13 Use of mercury compounds in cosmetics including use as 
          skinbleaching agents in cosmetic preparations also regarded as 
          drugs.
700.14 Use of vinyl chloride as an ingredient, including propellant of 
          cosmetic aerosol products.
700.15 Use of certain halogenated salicylanilides as ingredients in 
          cosmetic products.
700.16 Use of aerosol cosmetic products containing zirconium.
700.18 Use of chloroform as an ingredient in cosmetic products.
700.19 Use of methylene chloride as an ingredient of cosmetic products.
700.23 Chlorofluorocarbon propellants.
700.25 Tamper-resistant packaging requirements for cosmetic products.
700.27 Use of prohibited cattle materials in cosmetic products.
700.35 Cosmetics containing sunscreen ingredients.

    Authority: 21 U.S.C. 321, 331, 352, 355, 361, 362, 371, 374.

    Source: 39 FR 10054, Mar. 15, 1974, unless otherwise noted.



                      Subpart A_General Provisions



Sec.  700.3  Definitions.

    As used in this subchapter:
    (a) The term act means the Federal Food, Drug, and Cosmetic Act.
    (b) The term cosmetic product means a finished cosmetic the 
manufacture of which has been completed. Any cosmetic product which is 
also a drug or device or component thereof is also subject to the 
requirements of Chapter V of the act.
    (c) The term flavor means any natural or synthetic substance or 
substances used solely to impart a taste to a cosmetic product.
    (d) The term fragrance means any natural or synthetic substance or 
substances used solely to impart an odor to a cosmetic product.
    (e) The term ingredient means any single chemical entity or mixture 
used as a component in the manufacture of a cosmetic product.
    (f) The term proprietary ingredient means any cosmetic product 
ingredient whose name, composition, or manufacturing process is 
protected from competition by secrecy, patent, or copyright.
    (g) The term chemical description means a concise definition of the 
chemical composition using standard chemical nomenclature so that the 
chemical structure or structures of the components of the ingredient 
would be clear to a practicing chemist. When the composition cannot be 
described chemically, the substance shall be described in terms of its 
source and processing.
    (h) The term cosmetic raw material means any ingredient, including 
an ingredient that is a mixture, which is used in the manufacture of a 
cosmetic product for commercial distribution and is supplied to a 
cosmetic product manufacturer, packer, or distributor by a cosmetic raw 
material manufacturer or supplier.
    (i) The term commercial distribution of a cosmetic product means 
annual gross sales in excess of $1,000 for that product.
    (j) Establishment means a place of business where cosmetic products 
are manufactured or packaged.
    (k) The term manufacture of a cosmetic product means the making of 
any cosmetic product by chemical, physical, biological, or other 
procedures, including manipulation, sampling, testing, or control 
procedures applied to the product.
    (l) The term packaging of a cosmetic product means filling or 
labeling the product container, including changing the immediate 
container or label (but excluding changing other labeling) at any point 
in the distribution of the cosmetic product from the original place of 
manufacture to the person who makes final delivery or sale to the 
ultimate consumer.

[[Page 137]]

    (m) The term all business trading names used by the establishment 
means any name which is used on a cosmetic product label and owned by 
the cosmetic product manufacturer or packer, but is different from the 
principal name under which the cosmetic product manufacturer or packer 
is registered.
    (n) The definitions and interpretations contained in sections 201, 
601, and 602 of the act shall be applicable to such terms when used in 
the regulations in this subchapter.
    (o) System of commercial distribution of a cosmetic product means 
any distribution outside the establishment manufacturing the product, 
whether for sale, to promote future sales (including free samples of the 
product), or to gage consumer acceptance through market testing, in 
excess of $1,000 in cost of goods.
    (p) Filed screening procedure means a procedure that is:
    (1) On file with the Food and Drug Administration and subject to 
public inspection;
    (2) Designed to determine that there is a reasonable basis for 
concluding that an alleged injury did not occur in conjunction with the 
use of the cosmetic product; and
    (3) Which is subject, upon request by the Food and Drug 
Administration, to an audit conducted by the Food and Drug 
Administration at reasonable times and, where an audit is conducted, 
such audit shows that the procedure is consistently being applied and 
that the procedure is not disregarding reportable information.
    (q) Reportable experience means an experience involving any allergic 
reaction, or other bodily injury, alleged to be the result of the use of 
a cosmetic product under the conditions of use prescribed in the 
labeling of the product, under such conditions of use as are customary 
or reasonably foreseeable for the product or under conditions of misuse, 
that has been reported to the manufacturer, packer, or distributor of 
the product by the affected person or any other person having factual 
knowledge of the incident, other than an alleged experience which has 
been determined to be unfounded or spurious when evaluated by a filed 
screening procedure.

[39 FR 10054, Mar. 15, 1974, as amended at 46 FR 38073, July 24, 1981]



          Subpart B_Requirements for Specific Cosmetic Products



Sec.  700.11  Cosmetics containing bithionol.

    (a) Bithionol has been used to some extent as an antibacterial agent 
in cosmetic preparations such as detergent bars, shampoos, creams, 
lotions, and bases used to hide blemishes. New evidence of clinical 
experience and photopatch tests indicate that bithionol is capable of 
causing photosensitivity in man when used topically and that in some 
instances the photosensitization may persist for prolonged periods as 
severe reactions without further contact with sensitizing articles. 
Also, there is evidence to indicate that bithionol may produce cross-
sensitization with other commonly used chemicals such as certain 
halogenated salicylanilides and hexachlorophene. It is, therefore, the 
view of the Food and Drug Administration that bithionol is a deleterious 
substance which may render any cosmetic product that contains it 
injurious to users. Accordingly, any cosmetic containing bithionol is 
deemed to be adulterated under section 601(a) of the Federal Food, Drug, 
and Cosmetic Act.
    (b) Regulatory proceedings may be initiated with respect to any 
cosmetic preparation containing bithionol shipped within the 
jurisdiction of the act after March 15, 1968.



Sec.  700.13  Use of mercury compounds in cosmetics including use as 
skinbleaching agents in cosmetic preparations also regarded as drugs.

    (a) Mercury-containing cosmetic preparations have been represented 
for many years as skin-bleaching agents or as preparations to remove or 
prevent freckles and/or brown spots (so-called age spots). Preparations 
intended for such use are regarded as drugs as well as cosmetics. In 
addition to such use as skin-bleaching agents, mercury compounds have 
also been widely used as preservatives in cosmetics such as

[[Page 138]]

hand and body creams and lotions; hair shampoos, hair sets and rinses, 
hair straighteners, hair coloring, and other preparations; bath oils, 
bubble bath, and other bath preparations; makeup; antiperspirants and 
deodorants; and eye-area cosmetics.
    (b) The toxicity of mercury compounds is extensively documented in 
scientific literature. It is well known that mercury compounds are 
readily absorbed through the unbroken skin as well as through the lungs 
by inhalation and by intestinal absorption after ingestion. Mercury is 
absorbed from topical application and is accumulated in the body, giving 
rise to numerous adverse effects. Mercury is a potent allergen and 
sensitizer, and skin irritation is common after topical application. 
Cosmetic preparations containing mercury compounds are often applied 
with regularity and frequency for prolonged periods. Such chronic use of 
mercury-containing skin-bleaching preparations has resulted in the 
accumulation of mercury in the body and the occurrence of severe 
reactions. Recently it has also been determined that microorganisms in 
the environment can convert various forms of mercury into highly toxic 
methyl mercury which has been found in the food supply and is now 
considered to be a serious environmental problem.
    (c) The effectiveness of mercury-containing preparations as skin-
bleaching agents is questionable. The Food and Drug Administration has 
not been provided with well controlled studies to document the 
effectiveness of these preparations. Although mercurial preservatives 
are recognized as highly effective, less toxic and satisfactory 
substitutes are available except in the case of certain eye-area 
cosmetics.
    (d) Because of the known hazards of mercury, its questionable 
efficacy as a skin-bleaching agent, and the availability of effective 
and less toxic nonmercurial preservatives, there is no justification for 
the use of mercury in skin-bleaching preparations or its use as a 
preservative in cosmetics, with the exception of eye-area cosmetics for 
which no other effective and safe nonmercurial preservative is 
available. The continued use of mercurial preservatives in such eye-area 
cosmetics is warranted because mercury compounds are exceptionally 
effective in preventing Pseudomonas contamination of cosmetics and 
Pseudomonas infection of the eye can cause serious injury, including 
blindness. Therefore:
    (1) The Food and Drug Administration withdraws the opinion expressed 
in trade correspondence TC-9 (issued May 13, 1939) and concludes that 
any product containing mercury as a skin-bleaching agent and offered for 
sale as skin-bleaching, beauty, or facial preparation is misbranded 
within the meaning of sections 502(a), 502(f)(1) and (2), and 502(j), 
and may be a new drug without approval in violation of section 505 of 
the Federal Food, Drug, and Cosmetic Act. Any such preparation shipped 
within the jurisdiction of the Act after January 5, 1973 will be the 
subject of regulatory action.
    (2) The Food and Drug Administration withdraws the opinion expressed 
in trade correspondence TC-412 (issued Feb. 11, 1944) and will regard as 
adulterated within the meaning of section 601(a) of the Act any cosmetic 
containing mercury unless the cosmetic meets the conditions of paragraph 
(d)(2) (i) or (ii) of this section.
    (i) It is a cosmetic containing no more than a trace amount of 
mercury and such trace amount is unavoidable under conditions of good 
manufacturing practice and is less than 1 part per million (0.0001 
percent), calculated as the metal; or
    (ii) It is a cosmetic intended for use only in the area of the eye, 
it contains no more than 65 parts per million (0.0065 percent) of 
mercury, calculated as the metal, as a preservative, and there is no 
effective and safe nonmercurial substitute preservative available for 
use in such cosmetic.



Sec.  700.14  Use of vinyl chloride as an ingredient, including propellant
of cosmetic aerosol products.

    (a) Vinyl chloride has been used as an ingredient in cosmetic 
aerosol products including hair sprays. Where such aerosol products are 
used in the confines of a small room, as is often the case, the level of 
vinyl chloride to which the

[[Page 139]]

individual may be exposed could be significantly in excess of the safe 
level established in connection with occupational exposure. Evidence 
indicates that vinyl chloride inhalation can result in acute toxicity, 
manifested by dizziness, headache, disorientation, and unconsciousness 
where inhaled at high concentrations. Studies also demonstrate 
carcinogenic effects in animals as a result of inhalation exposure to 
vinyl chloride. Furthermore, vinyl chloride has recently been linked to 
liver disease, including liver cancer, in workers engaged in the 
polymerization of vinyl chloride. It is the view of the Commissioner 
that vinyl chloride is a deleterious substance which may render any 
cosmetic aerosol product that contains it as an ingredient injurious to 
users. Accordingly, any cosmetic aerosol product containing vinyl 
chloride as an ingredient is deemed to be adulterated under section 
601(a) of the Federal Food, Drug, and Cosmetic Act.
    (b) Any cosmetic aerosol product containing vinyl chloride as an 
ingredient shipped within the jurisdiction of the Act is subject to 
regulatory action.

[39 FR 30830, Aug. 26, 1974]



Sec.  700.15  Use of certain halogenated salicylanilides as ingredients
in cosmetic products.

    (a) Halogenated salicylanilides (tribromsalan (TBS,3,4',5-
tribromosalicylanilide), dibromsalan (DBS,4'5-dibromosalicylanilide), 
metabromsalan (MBS, 3,5-dibromosalicylanilide) and 3,3',4,5'-
tetrachlorosalicylanilide (TCSA)) have been used as antimicrobial agents 
for a variety of purposes in cosmetic products. These halogenated 
salicylanilides are potent photosensitizers and cross-sensitizers and 
can cause disabling skin disorders. In some instances, the 
photosensitization may persist for prolonged periods as a severe 
reaction without further exposure to these chemicals. Safer alternative 
antimicrobial agents are available.
    (b) These halogenated salicylanilides are deleterious substances 
which render any cosmetic that contains them injurious to users. 
Therefore, any cosmetic product that contains such a halogenated 
salicylanilide as an ingredient at any level for any purpose is deemed 
to be adulterated under section 601(a) of the Federal Food, Drug, and 
Cosmetic Act.
    (c) Any cosmetic product containing these halogenated 
salicylanilides as an ingredient that is initially introduced into 
interstate commerce after December 1, 1975, that is not in compliance 
with this section is subject to regulatory action.

[40 FR 50531, Oct. 30, 1975]



Sec.  700.16  Use of aerosol cosmetic products containing zirconium.

    (a) Zirconium-containing complexes have been used as an ingredient 
in cosmetics and/or cosmetics that are also drugs, as, for example, 
aerosol antiperspirants. Evidence indicates that certain zirconium 
compounds have caused human skin granulomas and toxic effects in the 
lungs and other organs of experimental animals. When used in aerosol 
form, some zirconium will reach the deep portions of the lungs of users. 
The lung is an organ, like skin, subject to the development of 
granulomas. Unlike the skin, the lung will not reveal the presence of 
granulomatous changes until they have become advanced and, in some 
cases, permanent. It is the view of the Commissioner that zirconium is a 
deleterious substance that may render any cosmetic aerosol product that 
contains it injurious to users.
    (b) Any aerosol cosmetic product containing zirconium is deemed to 
be adulterated under section 601(a) of the Federal Food, Drug, and 
Cosmetic Act.
    (c) Any such cosmetic product introduced in interstate commerce 
after September 15, 1977 is subject to regulatory action.

[42 FR 41376, Aug. 16, 1977]



Sec.  700.18  Use of chloroform as an ingredient in cosmetic products.

    (a) Chloroform has been used as an ingredient in cosmetic products. 
Recent information has become available associating chloroform with 
carcinogenic effects in animals. Studies conducted by the National 
Cancer Institute have demonstrated that the oral administration of 
chloroform to mice

[[Page 140]]

and rats induced hepatocellular carcinomas (liver cancer) in mice and 
renal tumors in male rats. Scientific literature indicates that 
chloroform is absorbed from the gastrointestinal tract, through the 
respiratory system, and through the skin. The Commissioner concludes 
that, on the basis of these findings, chloroform is a deleterious 
substance which may render injurious to users any cosmetic product that 
contains chloroform as an ingredient.
    (b) Any cosmetic product containing chloroform as an ingredient is 
adulterated and is subject to regulatory action under sections 301 and 
601(a) of the Federal Food, Drug, and Cosmetic Act. Any cosmetic product 
containing chloroform in residual amounts from its use as a processing 
solvent during manufacture, or as a byproduct from the synthesis of an 
ingredient, is not, for the purpose of this section, considered to 
contain chloroform as an ingredient.

[41 FR 26845, June 29, 1976]



Sec.  700.19  Use of methylene chloride as an ingredient of cosmetic
products.

    (a) Methylene chloride has been used as an ingredient of aerosol 
cosmetic products, principally hair sprays, at concentrations generally 
ranging from 10 to 25 percent. In a 2-year animal inhalation study 
sponsored by the National Toxicology Program, methylene chloride 
produced a significant increase in benign and malignant tumors of the 
lung and liver of male and female mice. Based on these findings and on 
estimates of human exposure from the customary use of hair sprays, the 
Food and Drug Administration concludes that the use of methylene 
chloride in cosmetic products poses a significant cancer risk to 
consumers, and that the use of this ingredient in cosmetic products may 
render these products injurious to health.
    (b) Any cosmetic product that contains methylene chloride as an 
ingredient is deemed adulterated and is subject to regulatory action 
under sections 301 and 601(a) of the Federal Food, Drug, and Cosmetic 
Act.

[54 FR 27342, June 29, 1989]



Sec.  700.23  Chlorofluorocarbon propellants.

    The use of chlorofluorocarbons in cosmetics as propellants in self-
pressurized containers is prohibited as provided in Sec.  2.125 of this 
chapter.

[43 FR 11317, Mar. 17, 1978]



Sec.  700.25  Tamper-resistant packaging requirements for cosmetic
products.

    (a) General. Because most cosmetic liquid oral hygiene products and 
vaginal products are not now packaged in tamper-resistant retail 
packages, there is the opportunity for the malicious adulteration of 
those cosmetic products with health risks to individuals who unknowingly 
purchase adulterated products and with loss of consumer confidence in 
the security of cosmetic product packages. The Food and Drug 
Administration has the authority and responsibility under the Federal 
Food, Drug, and Cosmetic Act (the act) to establish a uniform national 
requirement for tamper-resistant packaging of cosmetic liquid oral 
hygiene products or products used vaginally that will improve the 
packaging security and help assure the safety of those products. Such a 
cosmetic 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 601 of the act or misbranded under section 602 
of the act, or both.
    (b) Requirement for tamper-resistant package. Each manufacturer and 
packer who packages a cosmetic liquid oral hygiene product or vaginal 
product for retail sale shall package the product in a tamper-resistant 
package, if this product is accessible to the public while held for 
sale. A tamper-resistant package is one having an indicator or barrier 
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 substitution of a tamper-resistant feature 
after tampering, the indicator or barrier to entry is required to be 
distinctive by design (e.g., an aerosol product container) or by the use 
of an identifying characteristic (e.g., a pattern, name, registered 
trademark, logo, or picture). For purposes of

[[Page 141]]

this section, the term ``distinctive by design'' means the packaging 
cannot be duplicated with commonly available materials or through 
commonly available processes. For purposes of this section, the term 
``aerosol product'' means a product which depends upon the power of a 
liquified or compressed gas to expel the contents from the container. A 
tamper-resistant 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-resistant feature shall be designed to and shall remain 
intact when handled in a reasonable manner during manufacture, 
distribution, and retail display.
    (c) Labeling. Each retail package of a cosmetic product covered by 
this section, except aerosol products as defined in paragraph (b) of 
this section, is required to bear a statement that is prominently placed 
so that consumers are alerted to the specific tamper-resistant feature 
of the package. The labeling statement is also required to be so placed 
that it will be unaffected if the tamper-resistant feature of the 
package is breached or missing. If the tamper-resistant feature chosen 
to meet the requirement in paragraph (b) of this section is one that 
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) Requests 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 Tamper-resistant Rule.'' 
The petition is required to contain the following:
    (1) The name of the product.
    (2) The reasons that the product's compliance with the tamper-
resistant 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 will be the subject of malicious adulteration.
    (4) Other information justifying an exemption.

This information collection requirement has been approved by the Office 
of Management and Budget under number 0910-0149.
    (e) Effective date. Cosmetic products covered by this section are 
required to comply with the requirements of this section on the dates 
listed below except to the extent that a product's manufacturer or 
packer has obtained an exemption from a packaging or labeling 
requirement.
    (1) Initial effective date for packaging requirements. (i) The 
packaging requirement in paragraph (b) of this section is effective on 
Feburary 7, 1983 for each affected cosmetic product (except vaginal 
tablets) packaged for retail sale on or after that date, except for the 
requirement in paragraph (b) of this section for a distinctive indicator 
or barrier to entry.
    (ii) The packaging requirement in paragraph (b) of this section is 
effective on May 5, 1983 for each cosmetic product that is a vaginal 
tablet packaged for retail sale on or after that date.
    (2) Initial effective date for labeling requirements. The 
requirement in paragraph (b) of this section that the indicator or 
barrier to entry be distinctive by design and the requirement in 
paragraph (c) of this section for a labeling statement are effective on 
May 5, 1983 for each affected cosmetic product packaged for retail sale 
on or after that date, except that the requirement for a specific label 
reference to any identifying characteristic is effective on February 6, 
1984 for each affected cosmetic product packaged for retail sale on or 
after that date.
    (3) Retail level effective date. The tamper-resistant packaging 
requirement of paragraph (b) of this section is effective February 6, 
1984 for each affected cosmetic product held for sale on or after that 
date that was packaged for retail sale before May 5, 1983. This does

[[Page 142]]

not include the requirement in paragraph (b) of this section that the 
indicator or barrier to entry be distinctive by design. Products 
packaged for retail sale after May 5, 1983, as required to be in 
compliance with all aspects of the regulations without regard to the 
retail level effective date.

[47 FR 50451, Nov. 5, 1982; 48 FR 1707, Jan. 14, 1983; 48 FR 11427, Mar. 
18, 1983, as amended at 48 FR 16664, Apr. 19, 1983; 48 FR 37624, Aug. 
19, 1983]

    Effective Date Note: See 48 FR 41579, Sept. 16, 1983, for a document 
announcing an interim stay of the effective date of certain provisions 
in paragraph (e)(3) of Sec.  700.25.



Sec.  700.27  Use of prohibited cattle materials in cosmetic products.

    (a) Definitions. The definitions and interpretations of terms 
contained in section 201 of the Federal Food, Drug, and Cosmetic Act 
(the FD&C Act) apply to such terms when used in this part. The following 
definitions also apply:
    (1) Prohibited cattle materials mean specified risk materials, small 
intestine of all cattle except as provided in paragraph (b)(2) of this 
section, material from nonambulatory disabled cattle, material from 
cattle not inspected and passed, or mechanically separated (MS) (Beef). 
Prohibited cattle materials do not include the following:
    (i) Tallow that contains no more than 0.15 percent insoluble 
impurities, tallow derivatives, gelatin, hides and hide-derived 
products, and milk and milk products, and
    (ii) Cattle materials inspected and passed from a country designated 
under paragraph (e) of this section.
    (2) Inspected and passed means that the product has been inspected 
and passed for human consumption by the appropriate regulatory 
authority, and at the time it was inspected and passed, it was found to 
be not adulterated.
    (3) Mechanically separated (MS) (Beef) means a meat food product 
that is finely comminuted, resulting from the mechanical separation and 
removal of most of the bone from attached skeletal muscle of cattle 
carcasses and parts of carcasses that meets the specifications contained 
in 9 CFR 319.5, the U.S. Department of Agriculture regulation that 
prescribes the standard of identity for MS (Species).
    (4) Nonambulatory disabled cattle means cattle that cannot rise from 
a recumbent position or that cannot walk, including, but not limited to, 
those with broken appendages, severed tendons or ligaments, nerve 
paralysis, fractured vertebral column, or metabolic conditions.
    (5) Specified risk material means the brain, skull, eyes, trigeminal 
ganglia, spinal cord, vertebral column (excluding the vertebrae of the 
tail, the transverse processes of the thoracic and lumbar vertebrae, and 
the wings of the sacrum), and dorsal root ganglia of cattle 30 months of 
age and older and the tonsils and distal ileum of the small intestine of 
all cattle.
    (6) Tallow means the rendered fat of cattle obtained by pressing or 
by applying any other extraction process to tissues derived directly 
from discrete adipose tissue masses or to other carcass parts and 
tissues. Tallow must be produced from tissues that are not prohibited 
cattle materials or must contain no more than 0.15 percent insoluble 
impurities as determined by the method entitled ``Insoluble Impurities'' 
(AOCS Official Method Ca 3a-46), American Oil Chemists' Society (AOCS), 
5th Edition, 1997, incorporated by reference in accordance with 5 U.S.C. 
552(a) and 1 CFR part 51, or another method equivalent in accuracy, 
precision, and sensitivity to AOCS Official Method Ca 3a-46. You may 
obtain copies of the method from AOCS (http://www.aocs.org) 2211 W. 
Bradley Ave. Champaign, IL 61821. Copies may be examined at the Food and 
Drug Administration's Main Library, 10903 New Hampshire Ave., Bldg. 2, 
Third Floor, Silver Spring, MD 20993, 301-796-2039 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.
    (7) Tallow derivative means any chemical obtained through initial 
hydrolysis, saponification, or trans-esterification of tallow; chemical 
conversion of material obtained by hydrolysis, saponification, or trans-

[[Page 143]]

esterification may be applied to obtain the desired product.
    (8) Gelatin means a product that has been obtained by the partial 
hydrolysis of collagen derived from hides, connective tissue, and/or 
bone bones of cattle and swine. Gelatin may be either Type A (derived 
from an acid-treated precursor) or Type B (derived from an alkali-
treated precursor) that has gone through processing steps that include 
filtration and sterilization or an equivalent process in terms of 
infectivity reduction.
    (b) Requirements. (1) No cosmetic shall be manufactured from, 
processed with, or otherwise contain, prohibited cattle materials.
    (2) The small intestine is not considered prohibited cattle material 
if the distal ileum is removed by a procedure that removes at least 80 
inches of the uncoiled and trimmed small intestine, as measured from the 
caeco-colic junction and progressing proximally towards the jejunum, or 
by a procedure that the establishment can demonstrate is equally 
effective in ensuring complete removal of the distal ileum.
    (c) Records. (1) Manufacturers and processors of a cosmetic that is 
manufactured from, processed with, or otherwise contains, material from 
cattle must establish and maintain records sufficient to demonstrate 
that the cosmetic is not manufactured from, processed with, or does not 
otherwise contain, prohibited cattle materials.
    (2) Records must be retained for 2 years after the date they were 
created.
    (3) Records must be retained at the manufacturing or processing 
establishment or at a reasonably accessible location.
    (4) The maintenance of electronic records is acceptable. Electronic 
records are considered to be reasonably accessible if they are 
accessible from an onsite location.
    (5) Records required by this section and existing records relevant 
to compliance with this section must be available to FDA for inspection 
and copying.
    (6) When filing entry with U.S. Customs and Border Protection, the 
importer of record of a cosmetic manufactured from, processed with, or 
otherwise containing, cattle material must affirm that the cosmetic was 
manufactured from, processed with, or otherwise contains, cattle 
material and must affirm that the cosmetic was manufactured in 
accordance with this section. If a cosmetic is manufactured from, 
processed with, or otherwise contains, cattle material, then the 
importer of record must, if requested, provide within 5 days records 
sufficient to demonstrate that the cosmetic is not manufactured from, 
processed with, or does not otherwise contain, prohibited cattle 
material.
    (7) Records established or maintained to satisfy the requirements of 
this subpart that meet the definition of electronic records in Sec.  
11.3(b)(6) of this chapter are exempt from the requirements of part 11 
of this chapter. Records that satisfy the requirements of this subpart 
but that are also required under other applicable statutory provisions 
or regulations remain subject to part 11 of this chapter.
    (d) Adulteration. Failure of a manufacturer or processor to operate 
in compliance with the requirements of paragraph (b) or (c) of this 
section renders a cosmetic adulterated under section 601(c) of the act.
    (e) Process for designating countries. A country seeking designation 
must send a written request to the Director, Office of the Center 
Director, Center for Food Safety and Applied Nutrition, Food and Drug 
Administration, at the address designated in 21 CFR 5.1100. The request 
shall include information about a country's bovine spongiform 
encephalopathy (BSE) case history, risk factors, measures to prevent the 
introduction and transmission of BSE, and any other information relevant 
to determining whether specified risk materials, the small intestine of 
cattle except as provided in paragraph (b)(2) of this section, material 
from nonambulatory disabled cattle, or MS (Beef) from cattle from the 
country should be considered prohibited cattle materials. FDA shall 
respond in writing to any such request and may impose conditions in 
granting any such request. A country designation granted by FDA under 
this paragraph will be subject to future review by FDA, and

[[Page 144]]

may be revoked if FDA determines that it is no longer appropriate.

[70 FR 53068, Sept. 7, 2005, as amended at 71 FR 59668, Oct. 11, 2006; 
73 FR 20794, Apr. 17, 2008; 81 FR 5596, Feb. 3, 2016; 81 FR 14732, Mar. 
18, 2016]



Sec.  700.35  Cosmetics containing sunscreen ingredients.

    (a) A product that includes the term ``sunscreen'' in its labeling 
or in any other way represents or suggests that it is intended to 
prevent, cure, treat, or mitigate disease or to affect a structure or 
function of the body comes within the definition of a drug in section 
201(g)(1) of the act. Sunscreen active ingredients affect the structure 
or function of the body by absorbing, reflecting, or scattering the 
harmful, burning rays of the sun, thereby altering the normal 
physiological response to solar radiation. These ingredients also help 
to prevent diseases such as sunburn and may reduce the chance of 
premature skin aging, skin cancer, and other harmful effects due to the 
sun when used in conjunction with limiting sun exposure and wearing 
protective clothing. When consumers see the term ``sunscreen'' or 
similar sun protection terminology in the labeling of a product, they 
expect the product to protect them in some way from the harmful effects 
of the sun, irrespective of other labeling statements. Consequently, the 
use of the term ``sunscreen'' or similar sun protection terminology in a 
product's labeling generally causes the product to be subject to 
regulation as a drug. However, sunscreen ingredients may also be used in 
some products for nontherapeutic, nonphysiologic uses (e.g., as a color 
additive or to protect the color of the product). To avoid consumer 
misunderstanding, if a cosmetic product contains a sunscreen ingredient 
and uses the term ``sunscreen'' or similar sun protection terminology 
anywhere in its labeling, the term must be qualified by describing the 
cosmetic benefit provided by the sunscreen ingredient.
    (b) The qualifying information required under paragraph (a) of this 
section shall appear prominently and conspicuously at least once in the 
labeling in conjunction with the term ``sunscreen'' or other similar sun 
protection terminology used in the labeling. For example: ``Contains a 
sunscreen--to protect product color.''

[64 FR 27693, May 21, 1999]



PART 701_COSMETIC LABELING--Table of Contents



                      Subpart A_General Provisions

Sec.
701.1 Misbranding.
701.2 Form of stating labeling requirements.
701.3 Designation of ingredients.
701.9 Exemptions from labeling requirements.

                         Subpart B_Package Form

701.10 Principal display panel.
701.11 Identity labeling.
701.12 Name and place of business of manufacturer, packer, or 
          distributor.
701.13 Declaration of net quantity of contents.

               Subpart C_Labeling of Specific Ingredients

701.20 Detergent substances, other than soap, intended for use in 
          cleansing the body.
701.30 Ingredient names established for cosmetic ingredient labeling.

    Authority: 21 U.S.C. 321, 352, 361, 362, 363, 371, 374; 15 U.S.C. 
1454, 1455.

    Source: 39 FR 10056, Mar. 15, 1974, unless otherwise noted.



                      Subpart A_General Provisions



Sec.  701.1  Misbranding.

    (a) Among representations in labeling of a cosmetic which render 
such cosmetic misbranded is a false or misleading representation with 
respect to another cosmetic or a food, drug, or device.
    (b) The labeling of a cosmetic which contains two or more 
ingredients may be misleading by reason (among other reasons) of the 
designation of such cosmetic 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.

[[Page 145]]



Sec.  701.2  Form of stating labeling requirements.

    (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 602(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;
    (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)(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.



Sec.  701.3  Designation of ingredients.

    (a) The label on each package of a cosmetic shall bear a declaration 
of the name of each ingredient in descending order of predominance, 
except that fragrance or flavor may be listed as fragrance or flavor. An 
ingredient which is both fragrance and flavor shall be designated by 
each of the functions it performs unless such ingredient is identified 
by name. No ingredient may be designated as fragrance or flavor unless 
it is within the meaning of such term as commonly understood by 
consumers. Where one or more ingredients is accepted by the Food and 
Drug Administration as exempt from public disclosure pursuant to the 
procedure established in Sec.  720.8(a) of this chapter, in lieu of 
label declaration of identity the phrase ``and other ingredients'' may 
be used at the end of the ingredient declaration.
    (b) The declaration of ingredients shall appear with such prominence 
and conspicuousness as to render it likely to be read and understood by 
ordinary individuals under normal conditions of purchase. The 
declaration shall appear on any appropriate information panel in letters 
not less than \1/16\ of an inch in height and without obscuring design, 
vignettes, or crowding. In the absence of sufficient space for such 
declaration on the package, or where the manufacturer or distributor 
wishes to use a decorative container, the declaration may appear on a 
firmly affixed tag, tape, or card. In those cases where there is 
insufficient space for such declaration on the package, and it is not 
practical to firmly affix a tag, tape, or card, the Commissioner may 
establish

[[Page 146]]

by regulation an acceptable alternate, e.g., a smaller type size. A 
petition requesting such a regulation as an amendment to this paragraph 
shall be submitted pursuant to part 10 of this chapter.
    (c) A cosmetic ingredient shall be identified in the declaration of 
ingredients by:
    (1) The name specified in Sec.  701.30 as established by the 
Commissioner for that ingredient for the purpose of cosmetic ingredient 
labeling pursuant to paragraph (e) of this section;
    (2) In the absence of the name specified in Sec.  701.30, the name 
adopted for that ingredient in the following editions and supplements of 
the following compendia, listed in order as the source to be utilized:
    (i) CTFA (Cosmetic, Toiletry and Fragrance Association, Inc.) 
Cosmetic Ingredient Dictionary, Second Ed., 1977 (available from the 
Cosmetic, Toiletry and Fragrance Association, Inc. 1110 Vermont Ave. 
NW., Suite 800, Washington, DC 20005, or at the National Archives and 
Records Administration (NARA), which is incorporated by reference, 
except for the following deletions and revisions. (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.)
    (a) The following names are not adopted for the purpose of cosmetic 
ingredient labeling:

Acid Black 58
Acid Black 107
Acid Black 139
Acid Blue 168
Acid Blue 170
Acid Blue 188
Acid Blue 209
Acid Brown 19
Acid Brown 30
Acid Brown 44
Acid Brown 45
Acid Brown 46
Acid Brown 48
Acid Brown 224
Acid Orange 80
Acid Orange 85
Acid Orange 86
Acid Orange 88
Acid Orange 89
Acid Orange 116
Acid Red 131
Acid Red 213
Acid Red 252
Acid Red 259
Acid Violet 73
Acid Violet 76
Acid Violet 99
Acid Yellow 114
Acid Yellow 127
Direct Yellow 81
Solvent Black 5
Solvent Brown 43
Solvent Yellow 63
Solvent Yellow 90

    (b) The following names are adopted for the purpose of cosmetic 
ingredient labeling, provided the respective monographs are revised to 
describe their otherwise disclosed chemical compositions, or describe 
their chemical compositions more precisely, and such revised monographs 
are published in supplements to this dictionary edition by July 18, 
1980.

Acid Black 2
Benzophenone-11
Carbomer 934
Carbomer 934P
Carbomer 940
Carbomer 941
Carbomer 960
Carbomer 961
Chlorofluorocarbon 11S
Dimethicone Copolyol
Disperse Red 17
Pigment Green 7
Polyamino Sugar Condensate
SD Alcohol (all 27 alphanumeric designations)
Sodium Chondroitin Sulfate
Synthetic Beeswax

    (c) The following names are adopted for the purpose of cosmetic 
ingredient labeling until January 19, 1981.

Amphoteric (all 20 numeric designations)
Quaternium (all 49 numeric designations)

    (ii) United States Pharmacopeia, 19th Ed., 1975, and Second 
Supplement to the USP XIX and NF XIV, 1976. (Copies are available from 
the U.S. Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, 
Rockville, MD 20852, 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.).
    (iii) National Formulary, 14th Ed., 1975, and Second Supplement to 
the USP XIX and NF XIV, 1976. (Copies are

[[Page 147]]

available from the U.S. Pharmacopeial Convention, Inc., 12601 Twinbrook 
Parkway, Rockville, MD 20852, 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.).
    (iv) Food Chemicals Codex, 2d Ed., 1972; First Supplement, 1974, and 
Second Supplement, 1975, which are incorporated by reference. Copies are 
available from the Center for Food Safety and Applied Nutrition, Food 
and Drug Administration, 5001 Campus Dr., College Park, MD 20740, 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.
    (v) USAN and the USP dictionary of drug names, USAN 1975, 1961-1975 
cumulative list. (Copies are available from the U.S. Pharmacopeial 
Convention, Inc., 12601 Twinbrook Parkway, Rockville, MD 20852, 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.)
    (3) In the absence of such a listing, the name generally recognized 
by consumers.
    (4) In the absence of any of the above, the chemical or other 
technical name or description.
    (d) Where a cosmetic product is also an over-the-counter drug 
product, the declaration shall declare the active drug ingredients as 
set forth in Sec.  201.66(c)(2) and (d) of this chapter, and the 
declaration shall declare the cosmetic ingredients as set forth in Sec.  
201.66(c)(8) and (d) of this chapter.
    (e) Interested persons may submit a petition requesting the 
establishment of a specific name for a cosmetic ingredient pursuant to 
part 10 of this chapter. The Commissioner may also propose such a name 
on his own initiative.
    (f) As an alternative to listing all ingredients in descending order 
of predominance, ingredients may be grouped and the groups listed in the 
following manner and order:
    (1) Ingredients, other than color additives, present at a 
concentration greater than 1 percent, in descending order of 
predominance; followed by
    (2) Ingredients, other than color additives, present at a 
concentration of not more than 1 percent, without respect to order of 
predominance; followed by
    (3) Color additives, without respect to order of predominance. 
Ingredients specified in paragraph (f)(2) of this section may be 
included with those specified in paragraph (f)(1) of this section and 
listed in descending order of predominance.
    (g) A declaration of ingredients may include an ingredient not in 
the product if the ingredient is identified by the phrase ``may 
contain'' and:
    (1) It is a color additive added to some batches of the product for 
purposes of color matching; or
    (2)(i) The same declaration of ingredients is also used for other 
products similar in composition and intended for the same use, including 
products which may be assortments of products similar in composition and 
intended for the same use; and
    (ii) Such products are ``shaded'' products, i.e., those falling 
within the product categories identified in Sec.  720.4 (c)(3), (7) and 
(8)(v) of this chapter; and
    (iii) All products sharing the common declaration of ingredients are 
sold by the labeler under a common trade name or brand designation, and 
no trade name or brand designation not common to all such products 
appears in the labeling of any of them; and
    (iv) The ingredient is a color additive.
    (h) As an alternative to a declaration of color additive ingredients 
for each product, the color additives of an assortment of cosmetic 
products that are sold together in the same package may be declared in a 
single composite list in a manner that is not misleading and that 
indicates that the list pertains to all the products.

[[Page 148]]

    (i) As an alternative to the declaration of ingredients specified in 
paragraph (b) of this section, the declaration of ingredients may appear 
in letters not less than \1/16\ of an inch in height in labeling 
accompanying the product, as for example, on padded sheets or in 
leaflets, if the total surface area of the package is less than 12 
square inches. This paragraph is inapplicable to any packaged cosmetic 
product enclosed in an outer container, e.g., a folding carton. In 
addition, this paragraph is applicable only to cosmetic products meeting 
one of the following requirements:
    (1) The cosmetic products are held and displayed for sale in tightly 
compartmented trays or racks of a display unit. The holder of the 
labeling bearing the declaration of ingredients shall be attached to the 
display unit; or
    (2) The cosmetic products are ``shaded'' products, i.e., those 
falling within the product categories identified in Sec.  720.4 (c)(3), 
(7) and (8)(v) of this chapter, and are held for sale in tightly 
compartmented trays or racks. The holder of the labeling bearing the 
declaration of ingredients shall be attached to a display chart bearing 
samples of the product shades, which is displayed to purchasers. Such a 
display chart shall be of such construction and design as to permit its 
continuous use as a display, such as on a counter, and shall be designed 
for the primary purpose of displaying samples of the shades of the 
products.
    (j) The holder of labeling bearing a declaration of ingredients and 
used in accordance with paragraph (i) of this section shall be attached 
to the display unit or chart and shall meet one of the following 
conditions:
    (1) The labeling is on the front of the display unit or chart and 
can be read in full by a purchaser facing the display unit or chart 
under customary conditions of retail sale; or
    (2) The labeling is on the front of the display unit or chart, is 
partially visible, and is accompanied by a conspicuous notice on the 
front of the display unit or chart describing the location of such 
labeling in letters not less than \3/16\ of an inch in height, e.g., 
``Ingredient lists above'', that can be read by a purchaser facing the 
display unit or chart under customary conditions of retail sale, or by 
the notice required by provisions in paragraph (k)(3) of this section, 
if conspicuous at all times; or
    (3) The labeling is on a side of the display unit or chart, but not 
on the top, back, or bottom, and is accompanied by a conspicuous notice 
on the front of the display unit or chart describing the location of 
such labeling in letters not less than \3/16\ of an inch in height, 
e.g., ``Ingredient lists located on right side of display'', that can be 
read by a purchaser facing the display unit or chart under customary 
conditions of retail sale.
    (k) Any use of a display unit or chart bearing labeling under the 
provisions of paragraph (i) of this section shall meet the following 
requirements:
    (1) All articles of labeling bearing ingredient declarations and 
used in conjunction with any one display unit or chart shall be 
identical and shall declare the ingredients of all products sold in 
conjunction with the display unit or chart for which the ingredient 
declaration is made pursuant to paragraph (i) of this section.
    (2) Any display unit or chart intended for such use shall be shipped 
together with the labeling intended to be attached to it.
    (3) Every display unit or chart and/or labeling system shall be 
designed so that the words ``Federal law requires ingredient lists to be 
displayed here'' in letters not less than \3/16\ of an inch in height 
(i) become conspicuous when no ingredient declarations are displayed and 
when the last list has been taken, or (ii) are conspicuous at all times 
adjacent to the place where ingredient declarations are to be attached.
    (4) Any labeling containing a declaration of ingredients which 
reflects a formulation change and not shipped accompanying a display 
unit or chart shall be dated. Whenever any formulation change is made, 
and the labeling containing the declaration of ingredients is thereby 
required to be used in conjunction with products of both the old and new 
formulations, the labeling shall declare the ingredients of both the old 
and new formulations separately in a way that is not misleading

[[Page 149]]

and in a way that permits the purchaser to identify the ingredient 
declaration applicable to each package, or which clearly advises the 
purchaser that the formulation has been changed and that either 
declaration may be applicable.
    (5) Sufficient copies of the declaration of ingredients shall be 
provided with each shipment of a cosmetic so that a purchaser may obtain 
a copy of the declaration with each purchase. Display units and 
replacement labeling for display units shall be accompanied by 
instructions to the retailer, which when followed will result in 
compliance with the requirements of this section. Copies of the 
declaration accompanying refills shall be attached to the specific 
refill items to which they pertain, or shall be packed with the specific 
refill items to which they pertain, in a container that does not contain 
other cosmetic products.
    (6) The firm whose name appears on a product pursuant to Sec.  
701.12 shall promptly mail a copy of the declaration of ingredients to 
any person requesting it.
    (7) The display unit or chart shall be designed and located such 
that the labeling is easily accessible to a purchaser facing the display 
unit or chart under customary conditions of retail sale.
    (l) The provisions of this section do not require the declaration of 
incidental ingredients that are present in a cosmetic at insignificant 
levels and that have no technical or functional effect in the cosmetic. 
For the purpose of this paragraph, incidental ingredients are:
    (1) Substances that have no technical or functional effect in the 
cosmetic but are present by reason of having been incorporated into the 
cosmetic as an ingredient of another cosmetic ingredient.
    (2) Processing aids, which are as follows:
    (i) Substances that are added to a cosmetic during the processing of 
such cosmetic but are removed from the cosmetic in accordance with good 
manufacturing practices before it is packaged in its finished form.
    (ii) Substances that are added to a cosmetic during processing for 
their technical or functional effect in the processing, are converted to 
substances the same as constituents of declared ingredients, and do not 
significantly increase the concentration of those constituents.
    (iii) Substances that are added to a cosmetic during the processing 
of such cosmetic for their technical and functional effect in the 
processing but are present in the finished cosmetic at insignificant 
levels and do not have any technical or functional effect in that 
cosmetic.
    (m) In the event that there is a current or anticipated shortage of 
a cosmetic ingredient, the declaration required by this section may 
specify alternatives to any ingredients that may be affected. An 
alternative ingredient shall be declared either (1) immediately 
following the normally used ingredient for which it substitutes, in 
which case it shall be identified as an alternative ingredient by the 
word ``or'' following the name of the normally used ingredient and any 
other alternative ingredient, or (2) following the declaration of all 
normally used ingredients, in which case the alternative ingredients in 
the group so listed shall be listed in expected descending order of 
predominance or in accordance with the provisions of paragraph (f) of 
this section and shall be identified as alternative ingredients by the 
phrase ``may also contain''. This paragraph is inapplicable to any 
ingredient mentioned in advertising, or in labeling other than in the 
declaration of ingredients required by this section.
    (n) In the event that the shortage of a cosmetic ingredient 
necessitates a formulation change, packages bearing labels declaring the 
ingredients of the old formulation may be used if the revised ingredient 
declaration appears (1) on a firmly affixed tag, tape, card, or sticker 
or similar overlabeling attached to the package and bearing the 
conspicuous words ``new ingredient list'' in letters not less than \1/
16\ of an inch in height, or (2) on labeling inside an unsealed package 
and the package bears the conspicuous words, on a sticker or similar 
overlabeling, ``new ingredient list inside'' in letters not less than 
\1/16\ of an inch in height.

[[Page 150]]

    (o) The ingredients of products that are similar in composition and 
intended for the same use may be declared as follows:
    (1) The declaration of ingredients for an assortment of such 
products that are sold together in the same package, e.g., eyeshadows of 
different colors, may declare the ingredients that are common to all the 
products, in a single list in their cumulative order of predominance or 
in accordance with the provisions of paragraph (f) of this section, 
together with a statement, in terms that are as informative as 
practicable and that are not misleading, declaring the other ingredients 
and identifying the products in which they are present. The color 
additive ingredients of all the products in such an assortment, whether 
or not common to all the products, may be declared in a single composite 
list following the declaration of the other ingredients without 
identifying the products in which they are present.
    (2) The ingredients of an assortment of such products that are sold 
together in the same package, e.g., eyeshadows of different colors, may 
be declared in a single list in their cumulative order of predominance 
or in accordance with the provisions of paragraph (f) of this section, 
if the package is designed such that it has a total surface area 
available to bear labeling of less than 12 square inches. For the 
purpose of this paragraph, surface area is not available for labeling if 
physical characteristics of the package surface, e.g., decorative 
relief, make application of a label impractical.
    (3) The declaration of ingredients for such a product that is 
individually packaged and bears a label that is shared with other 
products pursuant to the provisions of paragraph (g)(2) of this section, 
e.g., one lipstick in a line of lipsticks, may declare the ingredients 
that are common to all such products, in a single list in their 
cumulative order of predominance or in accordance with the provisions of 
paragraph (f) of this section, together with a statement, in terms that 
are as informative as practicable and that are not misleading, declaring 
the other ingredients in such products, and identifying the products in 
which they are present. The color additive ingredients shall be declared 
in accordance with the provisions of paragraph (g) of this section.
    (4) The declaration of ingredients for an assortment of such 
cosmetic products that bears a label that is shared with other products 
pursuant to the provisions of paragraph (g)(2) of this section, e.g., 
one of several compacts in a line of compacts, may declare the 
ingredients that are common to all such products, in a single list in 
their cumulative order of predominance or in accordance with the 
provisions of paragraph (f) of this section, together with a statement, 
in terms that are as informative as practicable and that are not 
misleading, declaring the other ingredients in such products and 
identifying the products in which they are present. The color additive 
ingredients shall be declared in accordance with the provisions of 
paragraph (g) of this section.
    (p) As an alternative to the declaration of ingredients in letters 
not less than \1/16\ of an inch in height, letters may be not less than 
\1/32\ of an inch in height if the package is designed such that it has 
a total surface area available to bear labeling of less than 12 square 
inches. For the purpose of this paragraph, surface area is not available 
for labeling if physical characteristics of the package surface, e.g., 
decorative relief, make application of a label impractical.
    (q) The inside containers in a multiunit or multicomponent retail 
cosmetic package are not required to bear a declaration of ingredients 
when the labeling of the multiunit or multicomponent retail cosmetic 
package meets all the requirements of this section and the inside 
containers are not intended to be, and are not customarily, separated 
from the retail package for retail sale.
    (r) In the case of cosmetics distributed to the consumers by direct 
mail, as an alternative to the declaration of ingredients on an 
information panel, the declaration of ingredients may appear in letters 
not less than \1/16\ of an inch in height in labeling that accompanies 
and specifically relates to the

[[Page 151]]

cosmetic(s) mailed, or in labeling furnished to each consumer for his 
personal use and from which he orders cosmetics through the mail, e.g., 
a direct mail sales catalog or brochure, provided all of the following 
additional requirements are met:
    (1) The declarations of ingredients are conspicuous and presented in 
a way that permits the consumer to identify the declaration of 
ingredients applicable to each cosmetic.
    (2) The package mailed to the consumer is accompanied by a notice 
located on, or affixed to, the top of the package or on top of the 
contents inside the package, or on the face of the package platform 
surrounding and holding the product(s), readily visible to the consumer 
on opening of the package, and provides the following information in 
letters not less than \3/16\ of an inch in height:
    (i) The location of the declarations of ingredients, e.g., in an 
accompanying brochure, or in a sales catalog used for ordering;
    (ii) A statement that a copy of the declaration of ingredients will 
be mailed promptly to any person requesting it; and
    (iii) The name and place of business of the mail order distributor,
    (3) The mail order distributor promptly mails a copy of the 
declaration of ingredients to any person requesting it.

[39 FR 10056, Mar. 15, 1974, as amended at 40 FR 8922, Mar. 3, 1975; 40 
FR 18426, Apr. 28, 1975; 42 FR 4718, Jan. 25, 1977; 42 FR 15676, Mar. 
22, 1977; 42 FR 24255, May 31, 1977; 42 FR 46516, Sept. 16, 1977; 42 FR 
61257, Dec. 2, 1977; 45 FR 3577, Jan. 18, 1980; 47 FR 9397, Mar. 5, 
1982; 54 FR 24900, June 12, 1989; 64 FR 13297, Mar. 17, 1999; 69 FR 
18803, Apr. 9, 2004; 81 FR 49897, July 29, 2016]



Sec.  701.9  Exemptions from labeling requirements.

    (a) Except as provided by paragraphs (b) and (c) of this section, a 
shipment or other delivery of a cosmetic 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 
requirements of sections 601(a) and 602(b) of the act if:
    (1) The person who introduced such shipment or delivery into 
interstate commerce is the operator of the establishment where such 
cosmetic 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 cosmetic in such 
establishment as will insure, if such specifications are followed, that 
such cosmetic 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 cosmetic from 
such establishment, and shall 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 cosmetic 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 cosmetic 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 cosmetic 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 clause.
    (d) An exemption of a shipment or other delivery of a cosmetic under 
paragraph (a)(2) of this section shall expire:
    (1) At the beginning of the act of removing such shipment or 
delivery, or

[[Page 152]]

any part thereof, from such establishment if the cosmetic 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 
cosmetic is to be processed, labeled, or repacked, to make available for 
inspection a copy of the agreement, as required by such clause.



                         Subpart B_Package Form



Sec.  701.10  Principal display panel.

    The term principal display panel as it applies to cosmetics 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 of 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.  701.11  Identity labeling.

    (a) The principal display panel of a cosmetic 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:
    (1) The common or usual name of the cosmetic; or
    (2) An appropriately descriptive name or, when the nature of the 
cosmetic is obvious, a fanciful name understood by the public to 
identify such cosmetic; or
    (3) An appropriate illustration or vignette representing the 
intended cosmetic use.
    (c) The statement of identity shall be presented in bold 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.  701.12  Name and place of business of manufacturer, packer,
or distributor.

    (a) The label of a cosmetic in package form shall specify 
conspicuously the name and place of business of the manufacturer, 
packer, or distributor.
    (b) The requirement for declaration of the name of the manufacturer, 
packer, or distributor shall be deemed to be satisfied in the case of a 
corporation only by the actual corporate name, which may be preceded or 
followed by the name of the particular division of the corporation. 
Abbreviations for ``Company,'' ``Incorporated,'' etc., may be used 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.

[[Page 153]]

    (c) Where the cosmetic is not manufactured by the person whose name 
appears on the label, the name shall be qualified by a phrase that 
reveals the connection such person has with such cosmetic; such as, 
``Manufactured for _______'', ``Distributed by ________'', or any other 
wording that expresses the facts.
    (d) The statement of the place of business shall include the street 
address, city, State, and ZIP Code; however, 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 
only to consumer commodity labels developed or revised after the 
effective date of this section. In the case of nonconsumer packages, the 
ZIP Code shall appear either on the label or the labeling (including the 
invoice).
    (e) If a person manufactures, packs, or distributes a cosmetic at a 
place other than his principal place of business, the label may state 
the principal place of business in lieu of the actual place where such 
cosmetic was manufactured or packed or is to be distributed, unless such 
statement would be misleading.



Sec.  701.13  Declaration of net quantity of contents.

    (a) The label of a cosmetic in package form shall bear a declaration 
of the net quantity of contents. This shall be expressed in terms of 
weight, measure, numerical count, or a combination of numerical count 
and weight or measure. The statement shall be in terms of fluid measure 
if the cosmetic is liquid or in terms of weight if the cosmetic is 
solid, semisolid, or viscous, or a mixture of solid and liquid. If there 
is a firmly established, general consumer usage and trade custom of 
declaring the net quantity of a cosmetic by numerical count, linear 
measure, or measure of area, such respective term may be used. If there 
is a firmly established, general consumer usage and trade custom of 
declaring the contents of a liquid cosmetic by weight, or a solid, 
semisolid, or viscous cosmetic by fluid measure, it may be used. 
Whenever the Commissioner determines for a specific packaged cosmetic 
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 cosmetic.
    (b) Statements of weight shall be in terms of avoirdupois pound and 
ounce. Statements of fluid measure shall be 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.).
    (c) When the declaration of quantity of contents by numerical count, 
linear measure, or measure of area does not give accurate information as 
to the quantity of cosmetic in the package, it shall be augmented by 
such statement of weight, measure, or size of the individual units or 
the total weight or measure of the cosmetic as will give such 
information.
    (d) The declaration may contain common or decimal fractions. A 
common fraction shall be in terms of halves, quarters, eighths, 
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.
    (e) The declaration shall be located on the principal display panel 
of the label; with respect to packages bearing alternate principal 
display panels, it shall be duplicated on each principal display panel: 
Provided, That:
    (1) The principal display panel of a cosmetic marketed in a 
``boudoir-type'' container including decorative cosmetic containers of 
the ``cartridge,'' ``pill box,'' ``compact,'' or ``pencil'' variety, and 
those with a capacity of one-fourth ounce or less, may be considered to 
be a tear-away tag or tape affixed to the decorative container and 
bearing the mandatory label information as required by this part, but 
the type size of

[[Page 154]]

the net quantity of contents statement shall be governed by the 
dimensions of the decorative container; and
    (2) The principal display panel of a cosmetic 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 
content statement is governed by the dimensions of the display card.
    (f) 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 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 cosmetic 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 line 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 cosmetic 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 containers is waived.
    (g) The declaration shall accurately reveal the quantity of cosmetic 
in the package exclusive of wrappers and other material packed 
therewith: Provided, That:
    (1) In the case of cosmetics packed in containers designed to 
deliver the cosmetic 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; and
    (2) In the case of a package which contains the integral components 
making up a complete kit, and which is designed to deliver the 
components in the manner of an application (for example, a home 
permanent wave kit), the declaration may state the net quantity of the 
contents in nondeceptive terms of the number of applications available 
in the kit when the instructions for use as shown on the container are 
followed.
    (h) 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 (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.
    (i) 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

[[Page 155]]

than 5 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 (i)(1) through (4) of this 
section shall be increased by one-sixteenth of an inch.
    (j) 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 (as set forth in paragraphs (m)(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 (as set forth in paragraphs (m)(3) and (4) of this 
section). Net weight or fluid measure of less than 1 ounce shall be 
expressed in common or decimal fractions of the respective ounce and not 
in 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 ``Net 
contents 6 fl. oz.'' or ``6 fl. oz.''
    (k) 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 (as 
set forth in paragraph (m)(5) of this section).
    (l) [Reserved]
    (m) Examples: (1) A declaration of 1\1/2\ pounds weight shall be 
expressed as ``Net wt. 24 oz. (1 lb. 8 oz.)'', ``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.)''.
    (4) A declaration of 1\3/4\ quarts liquid measure shall be expressed 
as ``Net contents 56 fl. oz. (1 qt. 1\1/2\ pt.)'' or ``Net contents 56 
fl. oz. (1 qt. 1 pt. 8 oz.)'' but not in terms of quart and ounce such 
as ``Net content 56 fl. oz. (1 qt. 24 oz.)''.
    (5) A declaration of 2\1/2\ gallons liquid measure shall be 
expressed in the alternative as ``Net contents 2 gal. 2 qt.'' and not as 
``2 gal. 4 pt.''
    (n) For quantities, the following abbreviations and none other may 
be employed (periods and plural forms are optional):

weight wt.
square sq.
fluid fl.
yard yd.
feet or foot ft.
inch in.
gallon gal.
quart qt.
pint pt.
ounce oz.
pound lb.

    (o) 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. 
Examples are ``86 inches (2 yd. 1

[[Page 156]]

ft. 2 inches)'', ``90 inches (2\1/2\ yd.)'', ``30 inches (2.5 ft.)'', 
etc.
    (p) On packages labeled in terms of area measure, the declaration 
shall be expressed in terms of square inches and, if applicable (1 
square foot or more), the largest whole square unit (square yards, 
square yards and square 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. 
inches)'', etc.
    (q) 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 cosmetic 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), (c), and (j) of this section (for example, a combination of net 
weight plus numerical count) are not regarded as supplemental net 
quantity statements and shall be located on the principal display panel.
    (r) A separate statement of the net quantity of contents in terms of 
the metric system 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.
    (s) 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.



               Subpart C_Labeling of Specific Ingredients



Sec.  701.20  Detergent substances, other than soap, intended for use
in cleansing the body.

    (a) In its definition of the term cosmetic, the Federal Food, Drug, 
and Cosmetic Act specifically excludes soap. The term soap is nowhere 
defined in the act. In administering the act, the Food and Drug 
Administration interprets the term ``soap'' to apply only to articles 
that meet the following conditions:
    (1) The bulk of the nonvolatile matter in the product consists of an 
alkali salt of fatty acids and the detergent properties of the article 
are due to the alkali-fatty acid compounds; and
    (2) The product is labeled, sold, and represented only as soap.
    (b) Products intended for cleansing the human body and which are not 
``soap'' as set out in paragraph (a) of this section are ``cosmetics,'' 
and accordingly they are subject to the requirements of the act and the 
regulations thereunder. For example, such a product in bar form is 
subject to the requirement, among others, that it shall bear a label 
containing an accurate statement of the weight of the bar in avoirdupois 
pounds and ounces, this statement to be prominently and conspicuously 
displayed so as to be likely to be read under the customary conditions 
of purchase and use.



Sec.  701.30  Ingredient names established for cosmetic ingredient labeling.

    The Commissioner establishes the following names for the purpose of 
cosmetic ingredient labeling pursuant to paragraph (e) of Sec.  701.3:

------------------------------------------------------------------------
                                                     Established label
 Chemical name or description    Chemical formula           name
------------------------------------------------------------------------
Trichlorofluoromethane........  CCl3F............  Chlorofluorocarbon
                                                    11.
Trichlorofluoromethane and 0.3  CCl3F + CH3NO2...  Chlorofluorocarbon 11
 pct nitromethane.                                  S.
Dichlorodifluoromethane.......  CCl2F2...........  Chlorofluorocarbon
                                                    12.
Chlorodifluoromethane.........  CHClF2...........  Hydrochlorofluorocarb
                                                    on 22.
1, 2-dichloro-1, 1, 2, 2-       CClF2CClF2.......  Chlorofluorocarbon
 tetrafluoroethane.                                 114.
1-Chloro-1, 1-difluoroethane..  CH3CClF2.........  Hydrochlorofluorocarb
                                                    on 142 B.

[[Page 157]]

 
1, 1-difluoroethane...........  CH3CHF2..........  Hydrofluorocarbon 152
                                                    A.
Ethyl ester of hydrolyzed       .................  Ethyl ester of
 animal protein is the ester                        hydrolyzed animal
 of ethyl alcohol and the                           protein.
 hydrolysate of collagen or
 other animal protein, derived
 by acid, enzyme, or other
 form of hydrolysis.
------------------------------------------------------------------------


[42 FR 24255, May 13, 1977, as amended at 45 FR 3577, Jan. 18, 1980]



PART 710_VOLUNTARY REGISTRATION OF COSMETIC PRODUCT ESTABLISHMENTS-
-Table of Contents



Sec.
710.1 Who should register.
710.2 Time for registration.
710.3 How and where to register.
710.4 Information requested.
710.5 Amendments to registration.
710.6 Notification of registrant; cosmetic product establishment 
          registration number.
710.7 Inspection of registrations.
710.8 Misbranding by reference to registration or to registration 
          number.
710.9 Exemptions.

    Authority: 21 U.S.C. 321, 331, 361, 362, 371, 374.

    Source: 39 FR 10059, Mar. 15, 1974, unless otherwise noted.



Sec.  710.1  Who should register.

    The owner or operator of a cosmetic product establishment which is 
not exempt under Sec.  710.9 and engages in the manufacture or packaging 
of a cosmetic product is requested to register for each such 
establishment, whether or not the product enters interstate commerce. 
This request extends to any foreign cosmetic product establishment whose 
products are exported for sale in any State as defined in section 
201(a)(1) of the act. No registration fee is required.



Sec.  710.2  Time for registration.

    The owner or operator of an establishment entering into the 
manufacture or packaging of a cosmetic product should register his 
establishment within 30 days after the operation begins.



Sec.  710.3  How and where to register.

    Form FD-2511 (``Registration of Cosmetic Product Establishment'') is 
obtainable on request from the Food and Drug Administration, 5001 Campus 
Dr., College Park, MD 20740, or at any Food and Drug Administration 
district office. The completed form should be mailed to Cosmetic Product 
Establishment Registration, Food and Drug Administration, 5001 Campus 
Dr., College Park, MD 20740.

[39 FR 10059, Mar. 15, 1974, as amended at 68 FR 15355, Mar. 31, 2003; 
81 FR 49897, July 29, 2016]



Sec.  710.4  Information requested.

    Form FD-2511 requests information on the name and address of the 
cosmetic product establishment, including post office ZIP code; all 
business trading names used by the establishment; and the type of 
business (manufacturer and/or packer). The information requested should 
be given separately for each establishment as defined in Sec.  700.3(j) 
of this chapter.

[39 FR 10059, Mar. 15, 1974, as amended at 46 FR 38073, July 24, 1981; 
54 FR 39640, Sept. 27, 1989]



Sec.  710.5  Amendments to registration.

    Within 30 days after a change in any of the information contained on 
a submitted Form FD-2511, a new Form FD-2511 should be submitted to 
amend the registration. This amendment is also necessary when a 
registration is to be canceled because an establishment has changed its 
name and no longer conducts business under the original name.



Sec.  710.6  Notification of registrant; cosmetic product establishment
registration number.

    The Commissioner of Food and Drugs will provide the registrant with 
a validated copy of Form FD-2511 as evidence of registration. This 
validated copy will be sent only to the location shown for the 
registering establishment. A permanent registration number will be 
assigned to each cosmetic

[[Page 158]]

product establishment registered in accordance with the regulations in 
this part.



Sec.  710.7  Inspection of registrations.

    A copy of the Form FD-2511 filed by the registrant will be available 
for inspection at the Food and Drug Administration, 5001 Campus Dr., 
College Park, MD 20740.

[39 FR 10059, Mar. 15, 1974, as amended at 68 FR 15355, Mar. 31, 2003; 
81 FR 49897, July 29, 2016]



Sec.  710.8  Misbranding by reference to registration or to registration
number.

    Registration of a cosmetic product establishment or assignment of a 
registration number does not in any way denote approval of the firm or 
its products by the Food and Drug Administration. Any representation in 
labeling or advertising that creates an impression of official approval 
because of registration or possession of a registration number will be 
considered misleading.



Sec.  710.9  Exemptions.

    The following classes of persons are not requested to register in 
accordance with this part 710 because the Commissioner has found that 
such registration is not justified:
    (a) Beauty shops, cosmetologists, retailers, pharmacies, and other 
persons and organizations that compound cosmetic products at a single 
location and administer, dispense, or distribute them at retail from 
that location and who do not otherwise manufacture or package cosmetic 
products at that location.
    (b) Physicians, hospitals, clinics, and public health agencies.
    (c) Persons who manufacture, prepare, compound, or process cosmetic 
products solely for use in research, pilot plant production, teaching, 
or chemical analysis, and who do not sell these products.



PART 720_VOLUNTARY FILING OF COSMETIC PRODUCT INGREDIENT COMPOSITION
STATEMENTS--Table of Contents



Sec.
720.1 Who should file.
720.2 Times for filing.
720.3 How and where to file.
720.4 Information requested about cosmetic products.
720.5 [Reserved]
720.6 Amendments to statement.
720.7 Notification of person submitting cosmetic product ingredient 
          statement.
720.8 Confidentiality of statements.
720.9 Misbranding by reference to filing or to statement number.

    Authority: 21 U.S.C. 321, 331, 361, 362, 371, 374.

    Source: 39 FR 10060, Mar. 15, 1974, unless otherwise noted.



Sec.  720.1  Who should file.

    Either the manufacturer, packer, or distributor of a cosmetic 
product is requested to file Form FDA 2512 (``Cosmetic Product 
Ingredient Statement''), whether or not the cosmetic product enters 
interstate commerce. This request extends to any foreign manufacturer, 
packer, or distributor of a cosmetic product exported for sale in any 
State as defined in section 201(a)(1) of the Federal Food, Drug, and 
Cosmetic Act. No filing fee is required.

[57 FR 3129, Jan. 28, 1992]



Sec.  720.2  Times for filing.

    Within 180 days after forms are made available to the industry, Form 
FDA 2512 should be filed for each cosmetic product being commercially 
distributed as of the effective date of this part. Form FDA 2512 should 
be filed within 60 days after the beginning of commercial distribution 
of any product not covered within the 180-day period.

[57 FR 3129, Jan. 28, 1992]



Sec.  720.3  How and where to file.

    Forms FDA 2512 and FDA 2514 (``Discontinuance of Commercial 
Distribution of Cosmetic Product Formulation'') are obtainable on 
request from the Food and Drug Administration, 5001 Campus Dr., College 
Park, MD

[[Page 159]]

20740, or at any Food and Drug Administration district office. The 
completed form should be mailed or delivered to: Cosmetic Product 
Statement, Food and Drug Administration, 5001 Campus Dr., College Park, 
MD 20740, according to the instructions provided with the forms.

[57 FR 3129, Jan. 28, 1992, as amended at 68 FR 15355, Mar. 31, 2003; 81 
FR 49897, July 29, 2016]



Sec.  720.4  Information requested about cosmetic products.

    (a) Form FDA-2512 requests information on:
    (1) The name and address, including post office ZIP code of the 
person (manufacturer, packer, or distributor) designated on the label of 
the product.
    (2) The name and address, including post office ZIP code, of the 
manufacturer or packer of the product if different from the person 
designated on the label of the product, when the manufacturer or packer 
submits the information requested under this paragraph.
    (3) The brand name or names of the cosmetic product.
    (4) The cosmetic product category or categories.
    (5) The ingredients in the product.
    (b) The person filing Form FDA-2512 should:
    (1) Provide the information requested in paragraph (a) of this 
section.
    (2) Have the form signed by an authorized individual.
    (3) Provide poison control centers with ingredient information and/
or adequate diagnostic and therapeutic procedures to permit rapid 
evaluation and treatment of accidental ingestion or other accidental use 
of the cosmetic product.
    (4) Provide ingredient information (and, when requested, ingredient 
samples) to a licensed physician who, in connection with the treatment 
of a patient, requests assistance in determining whether an ingredient 
in the cosmetic product is the cause of the problem for which the 
patient is being treated.
    (c) One or more of the following cosmetic product categories should 
be cited to indicate the product's intended use.
    (1) Baby products. (i) Baby shampoos.
    (ii) Lotions, oils, powders, and creams.
    (iii) Other baby products.
    (2) Bath preparations. (i) Bath oils, tablets, and salts.
    (ii) Bubble baths.
    (iii) Bath capsules.
    (iv) Other bath preparations.
    (3) Eye makeup preparations. (i) Eyebrow pencil.
    (ii) Eyeliner.
    (iii) Eye shadow.
    (iv) Eye lotion.
    (v) Eye makeup remover.
    (vi) Mascara.
    (vii) Other eye makeup preparations.
    (4) Fragrance preparations. (i) Colognes and toilet waters.
    (ii) Perfumes.
    (iii) Powders (dusting and talcum) (excluding aftershave talc).
    (iv) Sachets.
    (v) Other fragrance preparations.
    (5) Hair preparations (noncoloring). (i) Hair conditioners.
    (ii) Hair sprays (aerosol fixatives).
    (iii) Hair straighteners.
    (iv) Permanent waves.
    (v) Rinses (noncoloring).
    (vi) Shampoos (noncoloring).
    (vii) Tonics, dressings, and other hair grooming aids.
    (viii) Wave sets.
    (ix) Other hair preparations.
    (6) Hair coloring preparations. (i) Hair dyes and colors (all types 
requiring caution statement and patch test).
    (ii) Hair tints.
    (iii) Hair rinses (coloring).
    (iv) Hair shampoos (coloring).
    (v) Hair color sprays (aerosol).
    (vi) Hair lighteners with color.
    (vii) Hair bleaches.
    (viii) Other hair coloring preparations.
    (7) Makeup preparations (not eye). (i) Blushers (all types).
    (ii) Face powders.
    (iii) Foundations.
    (iv) Leg and body paints.
    (v) Lipstick.
    (vi) Makeup bases.
    (vii) Rouges.
    (viii) Makeup fixatives.
    (ix) Other makeup preparations.
    (8) Manicuring preparations. (i) Basecoats and undercoats.
    (ii) Cuticle softeners.
    (iii) Nail creams and lotions.

[[Page 160]]

    (iv) Nail extenders.
    (v) Nail polish and enamel.
    (vi) Nail polish and enamel removers.
    (vii) Other manicuring preparations.
    (9) Oral hygiene products. (i) Dentifrices (aerosol, liquid, pastes, 
and powders).
    (ii) Mouthwashes and breath fresheners (liquids and sprays).
    (iii) Other oral hygiene products.
    (10) Personal cleanliness. (i) Bath soaps and detergents.
    (ii) Deodorants (underarm).
    (iii) Douches.
    (iv) Feminine hygiene deodorants.
    (v) Other personal cleanliness products.
    (11) Shaving preparations. (i) Aftershave lotions.
    (ii) Beard softeners.
    (iii) Men's talcum.
    (iv) Preshave lotions (all types).
    (v) Shaving cream (aerosol, brushless, and lather).
    (vi) Shaving soap (cakes, sticks, etc.).
    (vii) Other shaving preparation products.
    (12) Skin care preparations, (creams, lotions, powder, and sprays). 
(i) Cleansing (cold creams, cleansing lotions, liquids, and pads).
    (ii) Depilatories.
    (iii) Face and neck (excluding shaving preparations).
    (iv) Body and hand (excluding shaving preparations).
    (v) Foot powders and sprays.
    (vi) Moisturizing.
    (vii) Night.
    (viii) Paste masks (mud packs).
    (ix) Skin fresheners.
    (x) Other skin care preparations.
    (13) Suntan preparations. (i) Suntan gels, creams, and liquids.
    (ii) Indoor tanning preparations.
    (iii) Other suntan preparations.
    (d) Ingredients in the product should be listed as follows:
    (1) A list of each ingredient of the cosmetic product in descending 
order of predominance by weight (except that the fragrance and/or flavor 
may be designated as such without naming each individual ingredient when 
the manufacturer or supplier of the fragrance and/or flavor refuses to 
disclose ingredient data).
    (2) An ingredient should be listed by the name adopted by the Food 
and Drug Administration (FDA) for the ingredient pursuant to Sec.  
701.3(c) of this chapter.
    (3) In the absence of a name adopted by FDA pursuant to Sec.  
701.3(c) of this chapter, its common or usual name, if it has one, or 
its chemical or technical name should be listed.
    (4) If an ingredient is a mixture, each ingredient of the mixture 
should be listed in accordance with paragraphs (d)(2) and (d)(3) of this 
section, unless such mixture is a formulation voluntarily registered on 
Form FDA 2512, in which case such mixture should be identified as 
``fragrance,'' ``flavor,'' ``fragrance and flavor'' or ``base 
formulation,'' as appropriate, and by stating its FDA-assigned cosmetic 
product ingredient statement number.
    (5) When the manufacturer or supplier of a fragrance and/or flavor 
refuses to disclose ingredient data, the fragrance and/or flavor should 
be listed as such. The nonconfidential listing of the product name and/
or trade name or name of the manufacturer or supplier of each 
proprietary fragrance and/or flavor mixture is optional.
    (e) A separate Form FDA-2512 should be filed for each different 
formulation of a cosmetic product. However, except for the hair coloring 
preparations listed in paragraph (c)(6) of this section for which a 
statement for each shade of such product is required, a single Form FDA-
2512 may be filed for two or more shades of a cosmetic product where 
only the amounts of the color additive ingredient used are varied or in 
the case of flavors and fragrances where only the amounts of the flavors 
and fragrances used are varied.

(Information collection requirements in this section were approved by 
the Office of Management and Budget (OMB) and assigned OMB control 
number 0910-0030)

[39 FR 10060, Mar. 15, 1974, as amended at 46 FR 38073, July 24, 1981; 
57 FR 3129, Jan. 28, 1992]



Sec.  720.5  [Reserved]



Sec.  720.6  Amendments to statement.

    Changes in the information requested under Sec. Sec.  720.4 (a)(3) 
and (a)(5) on the ingredients or brand name of a cosmetic product should 
be submitted by filing an amended Form FDA 2512 within 60

[[Page 161]]

days after the product is entered into commercial distribution. Other 
changes do not justify immediate amendment, but should be shown by 
filing an amended Form FDA 2512 within a year after such changes. Notice 
of discontinuance of commercial distribution of a cosmetic product 
formulation should be submitted by Form FDA 2514 within 180 days after 
discontinuance of commercial distribution becomes known to the person 
filing.

[57 FR 3130, Jan. 28, 1992, as amended at 67 FR 9587, Mar. 4, 2002]



Sec.  720.7  Notification of person submitting cosmetic product 
ingredient statement.

    When Form FDA 2512 is received, FDA will either assign a permanent 
cosmetic product ingredient statement number or a Food and Drug 
Administration (FDA) reference number in those cases where a permanent 
number cannot be assigned. Receipt of the form will be acknowledged by 
sending the individual signing the statement an appropriate notice 
bearing either the FDA reference number or the permanent cosmetic 
product ingredient statement number. If the person submitting Form FDA 
2512 has not complied with Sec. Sec.  720.4 (b)(1) and (b)(2), the 
person will be notified as to the manner in which the statement is 
incomplete.

[57 FR 3130, Jan. 28, 1992]



Sec.  720.8  Confidentiality of statements.

    (a) Data and information contained in, attached to, or included with 
Forms FDA 2512 and FDA 2514, and amendments thereto are submitted 
voluntarily to the Food and Drug Administration (FDA). Any request for 
confidentiality of a cosmetic ingredient submitted with such forms or 
separately will be handled in accordance with the procedure set forth in 
this section. The request for confidentiality will also be subject to 
the provisions of Sec.  20.111 of this chapter, as well as to the 
exemptions in subpart D of part 20 of this chapter and to the 
limitations on exemption in subpart E of part 20 of this chapter.
    (b) Any request for confidentiality of the identity of a cosmetic 
ingredient should contain a full statement, in a well-organized format, 
of the factual and legal grounds for that request, including all data 
and other information on which the petitioner relies, as well as 
representative information known to the petitioner that is unfavorable 
to the petitioner's position. The statement of the factual grounds 
should include, but should not be limited to, scientific or technical 
data, reports, tests, and other relevant information addressing the 
following factors that FDA will consider in determining whether the 
identity of an ingredient qualifies as a trade secret:
    (1) The extent to which the identity of the ingredient is known 
outside petitioner's business;
    (2) The extent to which the identity of the ingredient is known by 
employees and others involved in petitioner's business;
    (3) The extent of measures taken by the petitioner to guard the 
secrecy of the information;
    (4) The value of the information about the identity of the claimed 
trade secret ingredient to the petitioner and to its competitors;
    (5) The amount of effort or money expended by petitioner in 
developing the ingredient; and
    (6) The ease or difficulty with which the identity of the ingredient 
could be properly acquired or duplicated by others.
    (c) The request for confidentiality should also be accompanied by a 
statement that the identity of the ingredient for which confidentiality 
is requested has not previously been published or disclosed to anyone 
other than as provided in Sec.  20.81(a) of this chapter.
    (d) FDA will return to the petitioner any request for 
confidentiality that contains insufficient data to permit a review of 
the merits of the request. FDA will also advise the petitioner about the 
additional information that is necessary to enable the agency to proceed 
with its review of the request.
    (e) If, after receiving all of the data that are necessary to make a 
determination about whether the identity of an ingredient is a trade 
secret, FDA

[[Page 162]]

tentatively decides to deny the request, the Agency will inform the 
person requesting trade secrecy of its tentative determination in 
writing. FDA will set forth the grounds upon which it relied in making 
this tentative determination. The petitioner may submit, within 60 days 
from the date of receipt of the written notice of the tentative denial, 
additional relevant information and arguments and request that the 
Agency reconsider its decision in light of both the additional material 
and the information that it originally submitted.
    (f) If the petitioner submits new data in response to FDA's 
tentative denial of trade secret status, the agency will consider that 
material together with the information that was submitted initially 
before making its final determination.
    (g) A final determination that an ingredient is not a trade secret 
within the meaning of Sec.  20.61 of this chapter constitutes final 
Agency action that is subject to judicial review under 5 U.S.C. Chapter 
7. If suit is brought within 30 calendar days after such a 
determination, FDA will not disclose the records involved or require 
that the disputed ingredient or ingredients be disclosed in labeling 
until the matter is finally determined in the courts. If suit is not 
brought within 30 calendar days after a final determination that an 
ingredient is not a trade secret within the meaning of Sec.  20.61 of 
this chapter, the records involved will be available for public 
disclosure in accordance with part 20 of this chapter.

[51 FR 11444, Apr. 3, 1986, as amended at 57 FR 3130, Jan. 28, 1992; 68 
FR 25288, May 12, 2003; 87 FR 55914, Sept. 13, 2022]



Sec.  720.9  Misbranding by reference to filing or to statement number.

    The filing of Form FDA 2512 or assignment of a number to the 
statement does not in any way denote approval by the Food and Drug 
Administration of the firm or the product. Any representation in 
labeling or advertising that creates an impression of official approval 
because of such filing or such number will be considered misleading.

[57 FR 3130, Jan. 28, 1992]



PART 740_COSMETIC PRODUCT WARNING STATEMENTS--Table of Contents



                            Subpart A_General

Sec.
740.1 Establishment of warning statements.
740.2 Conspicuousness of warning statements.

                      Subpart B_Warning Statements

740.10 Labeling of cosmetic products for which adequate substantiation 
          of safety has not been obtained.
740.11 Cosmetics in self-pressurized containers.
740.12 Feminine deodorant sprays.
740.17 Foaming detergent bath products.
740.18 Coal tar hair dyes posing a risk of cancer.
740.19 Suntanning preparations.

    Authority: 21 U.S.C. 321, 331, 352, 355, 361, 362, 371, 374.



                            Subpart A_General



Sec.  740.1  Establishment of warning statements.

    (a) The label of a cosmetic product shall bear a warning statement 
whenever necessary or appropriate to prevent a health hazard that may be 
associated with the product.
    (b) The Commissioner of Food and Drugs, either on his own initiative 
or on behalf of any interested person who has submitted a petition, may 
publish a proposal to establish or amend, under subpart B of this part, 
a regulation prescribing a warning for a cosmetic. Any such petition 
shall include an adequate factual basis to support the petition, shall 
be in the form set forth in part 10 of this chapter, and will be 
published for comment if it contains reasonable grounds for the proposed 
regulation.

[40 FR 8917, Mar. 3, 1975, as amended at 42 FR 15676, Mar. 22, 1977]



Sec.  740.2  Conspicuousness of warning statements.

    (a) A warning statement shall appear on the label prominently and 
conspicuously as compared to other words, statements, designs, or 
devices and in bold type on contrasting background to render it likely 
to be read and understood by the ordinary individual under customary 
conditions of purchase and use, but in no case may the letters and/

[[Page 163]]

or numbers be less than \1/16\ inch in height, unless an exemption 
pursuant to paragraph (b) of this section is established.
    (b) If the label of any cosmetic package is too small to accommodate 
the information as required by this section, the Commissioner may 
establish by regulation an acceptable alternative method, e.g., type 
size smaller than \1/16\ inch in height. A petition requesting such a 
regulation, as an amendment to this section, shall be submitted to the 
Division of Dockets Management in the form established in part 10 of 
this chapter.

[40 FR 8917, Mar. 3, 1975, as amended at 42 FR 15676, Mar. 22, 1977; 69 
FR 13717, Mar. 24, 2004]



                      Subpart B_Warning Statements



Sec.  740.10  Labeling of cosmetic products for which adequate substantiation
of safety has not been obtained.

    (a) Each ingredient used in a cosmetic product and each finished 
cosmetic product shall be adequately substantiated for safety prior to 
marketing. Any such ingredient or product whose safety is not adequately 
substantiated prior to marketing is misbranded unless it contains the 
following conspicuous statement on the principal display panel:

    Warning--The safety of this product has not been determined.

    (b) An ingredient or product having a history of use in or as a 
cosmetic may at any time have its safety brought into question by new 
information that in itself is not conclusive. The warning required by 
paragraph (a) of this section is not required for such an ingredient or 
product if:
    (1) The safety of the ingredient or product had been adequately 
substantiated prior to development of the new information;
    (2) The new information does not demonstrate a hazard to human 
health; and
    (3) Adequate studies are being conducted to determine expeditiously 
the safety of the ingredient or product.
    (c) Paragraph (b) of this section does not constitute an exemption 
to the adulteration provisions of the Act or to any other requirement in 
the Act or this chapter.

[40 FR 8917, Mar. 3, 1975]



Sec.  740.11  Cosmetics in self-pressurized containers.

    (a)(1) The label of a cosmetic packaged in a self-pressurized 
container and intended to be expelled from the package under pressure 
shall bear the following warning:

    Warning--Avoid spraying in eyes. Contents under pressure. Do not 
puncture or incinerate. Do not store at temperature above 120 [deg]F. 
Keep out of reach of children.

    (2) In the case of products intended for use by children, the phrase 
``except under adult supervision'' may be added at the end of the last 
sentence in the warning required by paragraph (a)(1) of this section.
    (3) In the case of products packaged in glass containers, the word 
``break'' may be substituted for the word ``puncture'' in the warning 
required by paragraph (a)(1) of this section.
    (4) The words ``Avoid spraying in eyes'' may be deleted from the 
warning required by paragraph (a)(1) of this section in the case of a 
product not expelled as a spray.
    (b)(1) In addition to the warning required by paragraph (a)(1) of 
this section, the label of a cosmetic packaged in a self-pressurized 
container in which the propellant consists in whole or in part of a 
halocarbon or a hydrocarbon shall bear the following warning:

    Warning--Use only as directed. Intentional misuse by deliberately 
concentrating and inhaling the contents can be harmful or fatal.

    (2) The warning required by paragraph (b)(1) of this section is not 
required for the following products:
    (i) Products expelled in the form of a foam or cream, which contain 
less than 10 percent propellant in the container.
    (ii) Products in a container with a physical barrier that prevents 
escape of the propellant at the time of use.
    (iii) Products of a net quantity of contents of less than 2 ozs. 
that are designed to release a measured amount of product with each 
valve actuation.
    (iv) Products of a net quantity of contents of less than \1/2\ oz.
    (c) Labeling requirements for cosmetics packaged in a self- 
pressurized

[[Page 164]]

container containing or manufactured with a chlorofluorocarbon 
propellant or other ozone-depleting substance designated by the 
Environmental Protection Agency (EPA) are set forth in 40 CFR part 82.

[40 FR 8917, Mar. 3, 1975, as amended at 42 FR 22033, Apr. 29, 1977; 54 
FR 39640, Sept. 27, 1989; 61 FR 20101, May 3, 1996]



Sec.  740.12  Feminine deodorant sprays.

    (a) For the purpose of this section, the term ``feminine deodorant 
spray'' means any spray deodorant product whose labeling represents or 
suggests that the product is for use in the female genital area or for 
use all over the body.
    (b) The label of a feminine deodorant spray shall bear the following 
statement:

    Caution--For external use only. Spray at least 8 inches from skin. 
Do not apply to broken, irritated, or itching skin. Persistent, unusual 
odor or discharge may indicate conditions for which a physician should 
be consulted. Discontinue use immediately if rash, irritation, or 
discomfort develops.


The sentence ``Spray at least 8 inches from skin'' need not be included 
in the cautionary statement for products whose expelled contents do not 
contain a liquified gas propellant such as a halocarbon or hydrocarbon 
propellant.
    (c) Use of the word ``hygiene'' or ``hygienic'' or a similar word or 
words renders any such product misbranded under section 602(a) of the 
Federal Food, Drug, and Cosmetic Act. The use of any word or words which 
represent or suggest that such products have a medical usefulness 
renders such products misbranded under section 502(a) of the Act and 
illegal new drugs marketed in violation of section 505 of the Act.

[40 FR 8929, Mar. 3, 1975]



Sec.  740.17  Foaming detergent bath products.

    (a) For the purpose of this section, a foaming detergent bath 
product is any product intended to be added to a bath for the purpose of 
producing foam that contains a surface-active agent serving as a 
detergent or foaming ingredient.
    (b) The label of foaming detergent bath products within the meaning 
of paragraph (a) of this section, except for those products that are 
labeled as intended for use exclusively by adults, shall bear adequate 
directions for safe use and the following caution:

    Caution--Use only as directed. Excessive use or prolonged exposure 
may cause irritation to skin and urinary tract. Discontinue use if rash, 
redness, or itching occurs. Consult your physician if irritation 
persists. Keep out of reach of children.

    (c) In the case of products intended for use by children, the phrase 
``except under adult supervision'' may be added at the end of the last 
sentence in the caution required by paragraph (b) of this section.

[51 FR 20475, June 5, 1986]



Sec.  740.18  Coal tar hair dyes posing a risk of cancer.

    (a) The principal display panel of the label and any labeling 
accompanying a coal tar hair dye containing any ingredient listed in 
paragraph (b) of this section shall bear, in accordance with the 
requirements of Sec.  740.2, the following:

    Warning--Contains an ingredient that can penetrate your skin and has 
been determined to cause cancer in laboratory animals.

    (b) Hair dyes containing any of the following ingredients shall 
comply with the requirements of this section: (1) 4-methoxy-m-
phenylenediamine (2,4-diaminoanisole) and (2) 4-methoxy-m-
phenylenediamine sulfate (2,4-diaminoanisole sulfate).

[44 FR 59522, Oct. 16, 1979]

    Effective Date Note: At 47 FR 7829, Feb. 23, 1982, Sec.  740.18 was 
stayed until further notice, effective Sept. 18, 1980.



Sec.  740.19  Suntanning preparations.

    The labeling of suntanning preparations that do not contain a 
sunscreen ingredient must display the following warning: ``Warning--This 
product does not contain a sunscreen and does not protect against 
sunburn. Repeated exposure of unprotected skin while tanning may 
increase the risk of skin aging, skin cancer, and other harmful effects 
to the skin even if you do not burn.'' For purposes of this section, the 
term ``suntanning preparations'' includes gels, creams, liquids, and 
other topical products that are intended to provide cosmetic effects on 
the skin

[[Page 165]]

while tanning through exposure to UV radiation (e.g., moisturizing or 
conditioning products), or to give the appearance of a tan by imparting 
color to the skin through the application of approved color additives 
(e.g., dihydroxyacetone) without the need for exposure to UV radiation. 
The term ``suntanning preparations'' does not include products intended 
to provide sun protection or otherwise intended to affect the structure 
or any function of the body.

[64 FR 27693, May 21, 1999]

                        PARTS 741	799 [RESERVED]

[[Page 167]]



                              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 169]]



                    Table of CFR Titles and Chapters




                      (Revised as of April 1, 2023)

                      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 170]]

     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)

[[Page 171]]

      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 172]]

    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)
       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 173]]

      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 174]]

      XLII  Rural Business-Cooperative Service and Rural Utilities 
                Service, Department of Agriculture (Parts 4200--
                4299)
         L  Rural Business-Cooperative 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  [Reserved]
        VI  Farm Credit Administration (Parts 600--699)
       VII  National Credit Union Administration (Parts 700--799)
      VIII  Federal Financing Bank (Parts 800--899)
        IX  (Parts 900--999)[Reserved]

[[Page 175]]

         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)
       VII  Bureau of Industry and Security, Department of 
                Commerce (Parts 700--799)

[[Page 176]]

      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)
        IV  U.S. Immigration and Customs Enforcement, Department 
                of Homeland Security (Parts 400--599) [Reserved]

[[Page 177]]

                     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)
        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)

[[Page 178]]

                          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]
       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]

[[Page 179]]

        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)
      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)

[[Page 180]]

        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)

                 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

[[Page 181]]

         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)
        IV  Great Lakes St. Lawrence Seaway Development 
                Corporation, Department of Transportation (Parts 
                400--499)

[[Page 182]]

                          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)

             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)

[[Page 183]]

       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)
  103--104  [Reserved]
       105  General Services Administration (Parts 105-1--105-999)

[[Page 184]]

       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 185]]

                       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 Enforcement (Child Support 
                Enforcement Program), Administration for Children 
                and Families, 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 186]]

                      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  Department of 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 187]]

        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 188]]

        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 189]]





           Alphabetical List of Agencies Appearing in the CFR




                      (Revised as of April 1, 2023)

                                                  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 190]]

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 Enforcement, Office of              45, III
Children and Families, Administration for         45, II, III, 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 191]]

  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 192]]

Export-Import Bank of the United States           2, XXXV; 5, LII; 12, IV
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        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
  Federal Acquisition Regulation                  48, 5

[[Page 193]]

  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 Enforcement, Office of            45, III
  Children and Families, Administration for       45, II, III, IV, X, XIII
  Community Services, Office of                   45, X
  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
Indian Affairs, Office of the Assistant           25, VI
     Secretary
Indian Arts and Crafts Board                      25, II

[[Page 194]]

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
  Employment and Training Administration          20, V
  Federal Acquisition Regulation                  48, 29

[[Page 195]]

  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
  Federal Acquisition Regulation                  48, 25
National Security Council                         32, XXI; 47, II

[[Page 196]]

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 Development Administration                  7, XLII
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
State, Department of                              2, VI; 22, I; 28, XI

[[Page 197]]

  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, VII
World Agricultural Outlook Board                  7, XXXVIII

[[Page 199]]



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, 2018 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.

                                  2018

21 CFR
                                                                   83 FR
                                                                    Page
Chapter I
600.21 Amended; eff. 6-11-18........................................3589
    Regulation at 83 FR 3589 withdrawn.............................19936
600.22 Removed; eff. 6-11-18........................................3589
    Regulation at 83 FR 3589 withdrawn.............................19936

                                  2019

21 CFR
                                                                   84 FR
                                                                    Page
Chapter I
600 Authority citation revised.....................................12508
600.21 Amended.....................................................12508
600.22 Removed.....................................................12508

                                  2020

21 CFR
                                                                   85 FR
                                                                    Page
Chapter I
600.3 (h) introductory text revised; (h)(6) added..................10063
610.30 (Subpart D) Removed.........................................51639
21 CFR
                                                                   85 FR
                                                                    Page
Chapter I
610.40 (h)(2)(vii) revised.........................................49922

                                  2022

21 CFR
                                                                   87 FR
                                                                    Page
Chapter I
720.8 (e) and (g) revised..........................................55914

                                  2023

 (No regulations published from January 1, 2023, through April 1, 2023)


                                  [all]