[Title 21 CFR ]
[Code of Federal Regulations (annual edition) - April 1, 1996 Edition]
[From the U.S. Government Publishing Office]


          21



          Food and Drugs



[[Page i]]

PARTS 600 TO 799

          Revised as of April 1, 1996
          CONTAINING
          A CODIFICATION OF DOCUMENTS
          OF GENERAL APPLICABILITY
          AND FUTURE EFFECT

          AS OF APRIL 1, 1996
          With Ancillaries
          Published by
          the Office of the Federal Register
          National Archives and Records
          Administration

          as a Special Edition of
          the Federal Register



[[Page ii]]


                                      




                     U.S. GOVERNMENT PRINTING OFFICE
                            WASHINGTON : 1996



               For sale by U.S. Government Printing Office
 Superintendent of Documents, Mail Stop: SSOP, Washington, DC 20402-9328



[[Page iii]]




                            Table of Contents


                                                                    Page
  Explanation.................................................       v
  Title 21:
    Chapter I--Food and Drug Administration, Department of 
        Health and Human Services (Continued).................       3
  Finding Aids:
    Material Approved for Incorporation by Reference..........     205
    Table of CFR Titles and Chapters..........................     207
    Alphabetical List of Agencies Appearing in the CFR........     223
    List of CFR Sections Affected.............................     233

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----------------------------------------------------------
    Cite this Code:  CFR
 
    To cite the regulations in this volume use title, part
      and section number. Thus, 21 CFR 600.3 refers to
      title 21, part 600, section 3.
                                                                                                                
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[[Page v]]



                               EXPLANATION

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

Title 1 through Title 16.................................as of January 1
Title 17 through Title 27..................................as of April 1
Title 28 through Title 41...................................as of July 1
Title 42 through Title 50................................as of October 1
    The appropriate revision date is printed on the cover of each 
volume.

LEGAL STATUS

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

HOW TO USE THE CODE OF FEDERAL REGULATIONS

    The Code of Federal Regulations is kept up to date by the individual 
issues of the Federal Register. These two publications must be used 
together to determine the latest version of any given rule.
    To determine whether a Code volume has been amended since its 
revision date (in this case, April 1, 1996), consult the ``List of CFR 
Sections Affected (LSA),'' which is issued monthly, and the ``Cumulative 
List of Parts Affected,'' which appears in the Reader Aids section of 
the daily Federal Register. These two lists will identify the Federal 
Register page number of the latest amendment of any given rule.

EFFECTIVE AND EXPIRATION DATES

    Each volume of the Code contains amendments published in the Federal 
Register since the last revision of that volume of the Code. Source 
citations for the regulations are referred to by volume number and page 
number of the Federal Register and date of publication. Publication 
dates and effective dates are usually not the same and care must be 
exercised by the user in determining the actual effective date. In 
instances where the effective date is beyond the cut-off date for the 
Code a note has been inserted to reflect the future effective date. In 
those instances where a regulation published in the Federal Register 
states a date certain for expiration, an appropriate note will be 
inserted following the text.

OMB CONTROL NUMBERS

    The Paperwork Reduction Act of 1980 (Pub. L. 96-511) requires 
Federal agencies to display an OMB control number with their information 
collection request. Many agencies have begun publishing numerous OMB 
control numbers as amend

[[Page vi]]

ments to existing regulations in the CFR. These OMB numbers are placed 
as close as possible to the applicable recordkeeping or reporting 
requirements.

OBSOLETE PROVISIONS

    Provisions that become obsolete before the revision date stated on 
the cover of each volume are not carried. Code users may find the text 
of provisions in effect on a given date in the past by using the 
appropriate numerical list of sections affected. For the period before 
January 1, 1986, consult either the List of CFR Sections Affected, 1949-
1963, 1964-1972, or 1973-1985, published in seven separate volumes. For 
the period beginning January 1, 1986, a ``List of CFR Sections 
Affected'' is published at the end of each CFR volume.

INCORPORATION BY REFERENCE

    What is incorporation by reference? Incorporation by reference was 
established by statute and allows Federal agencies to meet the 
requirement to publish regulations in the Federal Register by referring 
to materials already published elsewhere. For an incorporation to be 
valid, the Director of the Federal Register must approve it. The legal 
effect of incorporation by reference is that the material is treated as 
if it were published in full in the Federal Register (5 U.S.C. 552(a)). 
This material, like any other properly issued regulation, has the force 
of law.
    What is a proper incorporation by reference? The Director of the 
Federal Register will approve an incorporation by reference only when 
the requirements of 1 CFR part 51 are met. Some of the elements on which 
approval is based are:
    (a) The incorporation will substantially reduce the volume of 
material published in the Federal Register.
    (b) The matter incorporated is in fact available to the extent 
necessary to afford fairness and uniformity in the administrative 
process.
    (c) The incorporating document is drafted and submitted for 
publication in accordance with 1 CFR part 51.
    Properly approved incorporations by reference in this volume are 
listed in the Finding Aids at the end of this volume.
    What if the material incorporated by reference cannot be found? If 
you have any problem locating or obtaining a copy of material listed in 
the Finding Aids of this volume as an approved incorporation by 
reference, please contact the agency that issued the regulation 
containing that incorporation. If, after contacting the agency, you find 
the material is not available, please notify the Director of the Federal 
Register, National Archives and Records Administration, Washington DC 
20408, or call (202) 523-4534.

CFR INDEXES AND TABULAR GUIDES

    A subject index to the Code of Federal Regulations is contained in a 
separate volume, revised annually as of January 1, entitled CFR Index 
and Finding Aids. This volume contains the Parallel Table of Statutory 
Authorities and Agency Rules (Table I), and Acts Requiring Publication 
in the Federal Register (Table II). A list of CFR titles, chapters, and 
parts and an alphabetical list of agencies publishing in the CFR are 
also included in this volume.
    An index to the text of ``Title 3--The President'' is carried within 
that volume.
    The Federal Register Index is issued monthly in cumulative form. 
This index is based on a consolidation of the ``Contents'' entries in 
the daily Federal Register.
    A List of CFR Sections Affected (LSA) is published monthly, keyed to 
the revision dates of the 50 CFR titles.


[[Page vii]]


REPUBLICATION OF MATERIAL

    There are no restrictions on the republication of material appearing 
in the Code of Federal Regulations.

INQUIRIES

    For a legal interpretation or explanation of any regulation in this 
volume, contact the issuing agency. The issuing agency's name appears at 
the top of odd-numbered pages.
    For inquiries concerning CFR reference assistance, call 202-523-5227 
or write to the Director, Office of the Federal Register, National 
Archives and Records Administration, Washington, DC 20408.
SALES

    The Government Printing Office (GPO) processes all sales and 
distribution of the CFR. For payment by credit card, call 202-512-1800, 
M-F, 8 a.m. to 4 p.m. e.s.t. or fax your order to 202-512-2233, 24 hours 
a day. For payment by check, write to the Superintendent of Documents, 
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Customer Service call 202-512-1803.

                              Richard L. Claypoole,
                                    Director,
                          Office of the Federal Register.

April 1, 1996.



[[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, 1996.

    The Table of Exempt Prescription Products to part 1308 appears in 
the volume containing part 1300-end.

    Redesignation tables for Chapter I--Food and Drug Administration 
appear in the Finding Aids section for the volumes containing parts 170-
199 and 500-599.

    For this volume, Ruth Reedy Green was Chief Editor. The Code of 
Federal Regulations publication program is under the direction of 
Frances D. McDonald, assisted by Alomha S. Morris.

[[Page x]]

[GRAPHIC] [TIFF OMITTED] TFRORDR.FRM

[[Page 1]]

                                                                     HN




                        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

Cross References: Food Safety and Inspection Service, Department of 
  Agriculture: See Meat and Poultry Inspection, 9 CFR Chapter III.
Federal Trade Commission: See Commercial Practices, 16 CFR Chapter I.
U.S. Customs Service, Department of the Treasury: See Customs Duties, 19 
  CFR Chapter I.
Internal Revenue Service, Department of the Treasury: See Internal 
  Revenue, 26 CFR Chapter I.
Bureau of Alcohol, Tobacco, and Firearms, Department of the Treasury: 
  See Alcohol, Tobacco Products and Firearms, 27 CFR Chapter I.

[[Page 3]]





                CHAPTER I--FOOD AND DRUG ADMINISTRATION,






          DEPARTMENT OF HEALTH AND HUMAN SERVICES--(Continued)




                             (Parts 600-799)

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

                         SUBCHAPTER F--BIOLOGICS
Part                                                                Page
600             Biological products: general................
601             Licensing...................................
606             Current good manufacturing practice for 
                    blood and blood components..............
607             Establishment registration and product 
                    listing for manufacturers of human blood 
                    and blood products......................
610             General biological products standards.......
620             Additional standards for bacterial products.
630             Additional standards for viral vaccines.....
640             Additional standards for human blood and 
                    blood products..........................
650             Additional standards for diagnostic 
                    substances for dermal tests.............
660             Additional standards for diagnostic 
                    substances for laboratory tests.........
680             Additional standards for miscellaneous 
                    products................................
                         SUBCHAPTER G--COSMETICS
700             General.....................................
701             Cosmetic labeling...........................
710             Voluntary registration of cosmetic product 
                    establishments..........................
720             Voluntary filing of cosmetic product 
                    ingredient and cosmetic raw material 
                    composition statements..................

[[Page 4]]

730             Voluntary filing of cosmetic product 
                    experiences.............................
740             Cosmetic product warning statements.........
741--799  
[Reserved]

[[Page 5]]




                         SUBCHAPTER F--BIOLOGICS


PART 600--BIOLOGICAL PRODUCTS: GENERAL--Table of Contents




                      Subpart A--General Provisions

Sec.
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 errors.
600.15  Temperatures during shipment.

                   Subpart C--Establishment Inspection

600.20  Inspectors.
600.21  Time of inspection.
600.22  Duties of inspector.

               Subpart D--Reporting of Adverse Experiences

600.80   Postmarketing reporting of adverse experiences.
600.81   Distribution reports.
600.90   Waivers.

    Authority: Secs. 201, 501, 502, 503, 505, 510, 519, 701, 704 of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 
360, 360i, 371, 374); secs. 215, 351, 352, 353, 361, 2125 of the Public 
Health Service Act (42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25).

    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. 600.3   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 any virus, therapeutic serum, toxin, 
antitoxin, or analogous product applicable to the prevention, treatment 
or cure of diseases or injuries of man:
    (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

[[Page 6]]

containing some organic constituent or product other than a hormone or 
an amino acid, derived from whole blood, plasma, or serum.
    (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.
    (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 and which are 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 prescribed in 
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.
    (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 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.

[[Page 7]]

    (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.

[38 FR 32048, Nov. 20, 1973, as amended at 40 FR 31313, July 25, 1975; 
55 FR 11014, Mar. 26, 1990]



                   Subpart B--Establishment Standards



Sec. 600.10   Personnel.

    (a) Responsible head. A person shall be designated as the 
responsible head who shall exercise control of the establishment in all 
matters relating to compliance with the provisions of this subchapter, 
with authority to represent the manufacturer in all pertinent matters 
with the Center for Biologics Evaluation and Research, and with 
authority to enforce or to direct the enforcement of discipline and the 
performance of assigned functions by employees engaged in the 
manufacture of products. The responsible head shall have an 
understanding of the scientific principles and the techniques involved 
in the manufacture of products. The responsible head shall have the 
responsibility for the training of employees in manufacturing methods 
and for their being informed concerning the application of the pertinent 
provisions of this subchapter to their respective functions.
    (b) Other 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-bearing organisms. Persons working 
with viruses pathogenic for man or with spore-bearing 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

[[Page 8]]

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]



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 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-bearing pathogenic microorganisms are not involved and 
provided the space is thoroughly cleaned and disinfected before the 
manufacture of products is resumed.
    (2) Spore-bearing organisms for supplemental sterilization procedure 
control test. Spore-bearing 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

[[Page 9]]

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-bearing 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-bearing organisms. Except as provided in the 
previous paragraph, all work with spore-bearing microorganisms shall be 
done in an entirely separate building: Provided, That such work may be 
done in a portion of a building used in the manufacture of products not 
containing spore-bearing microorganisms if such portion is completely 
walled-off and is constructed so as to prevent contamination of other 
areas and if entrances to such portion are independent of the remainder 
of the building. All vessels, apparatus and equipment used for spore-
bearing microorganisms shall be permanently identified and reserved 
exclusively for use with those organisms. Materials destined for further 
manufacturing may be removed from such an area only under conditions 
which will prevent the introduction of spores into other manufacturing 
areas.
    (4) Live vaccine processing. Space used for processing a live 
vaccine shall not be used for any other purpose during the processing 
period for that vaccine and such space shall be decontaminated prior to 
initiation of the processing. Live vaccine processing areas shall be 
isolated from and independent of any space used for any other purpose by 
being either in a separate building, in a separate wing of a building, 
or in quarters at the blind end of a corridor and shall include adequate 
space and equipment for all processing steps up to filling into final 
containers. Test procedures which potentially involve the presence of 
microorganisms other than the vaccine strains, or the use of tissue 
culture cell lines other than primary cultures, shall not be conducted 
in space used for processing live vaccine.
    (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 10]]

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.
    (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 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,

[[Page 11]]

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]



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, 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, 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]



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 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,

[[Page 12]]

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. 
Exceptions may be authorized by the Director, Center for Biologics 
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]



Sec. 600.14   Reporting of errors.

    (a) The Director, Office of Compliance, Center for Biologics 
Evaluation and Research (HFB-100), 8800 Rockville Pike, Bethesda, MD 
20892, shall be notified promptly of errors or accidents in the 
manufacture of products that may affect the safety, purity, or potency 
of any product.
    (b) Manufacturers of licensed in vitro diagnostic products, and 
manufacturers of unlicensed in vitro diagnostic products which are 
required to be registered under part 607 of this chapter, shall notify 
the Director in accordance with paragraph (a) of this section. 
Manufacturers of other in vitro diagnostic products which are required 
to be registered under part 807 of this chapter, shall report in 
accordance with part 803 of this chapter.

[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 49 
FR 36348, Sept. 14, 1984; 55 FR 11014, Mar. 26, 1990]



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 C or colder.            
Measles and Rubella Virus Vaccine Live....  10 C or colder.             
Measles Live and Smallpox Vaccine.........      Do.                     
Measles, Mumps, and Rubella Virus Vaccine       Do.                     
 Live.                                                                  
Measles and Mumps Virus Vaccine Live......      Do.                     
Measles Virus Vaccine Live................      Do.                     
Mumps Virus Vaccine Live..................      Do.                     
Fresh Frozen Plasma.......................  -18 C or colder.            
Liquid Plasma.............................  1 to 10C.                   
Plasma....................................  -18 C or colder.            
Platelet Rich Plasma......................  Between 1 and 10 C if the   
                                             label indicates storage    
                                             between 1 and 6 C, or all  
                                             reasonable methods to      
                                             maintain the temperature as
                                             close as possible to a     
                                             range between 20 and 24 C, 
                                             if the label indicates     
                                             storage between 20 and 24  
                                             C.                         
Platelets.................................  Between 1 and 10 C if the   
                                             label indicates storage    
                                             between 1 and 6 C, or all  
                                             reasonable methods to      
                                             maintain the temperature as
                                             close as possible to a     
                                             range between 20 to 24 C,  
                                             if the label indicates     
                                             storage between 20 and 24  
                                             C.                         
Poliovirus Vaccine Live Oral Trivalent....  0 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 C.         
Red Blood Cells Frozen....................  -65 C or colder.            
Rubella and Mumps Virus Vaccine Live......  10 C or colder.             
Rubella Virus Vaccine Live................      Do.                     
Smallpox Vaccine (Liquid Product).........  0 C or colder.              
Source Plasma.............................  -5 C or colder.             
Source Plasma Liquid......................  10 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 C, or at 
                                             a temperature as close as  
                                             possible to 20  to 24 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 C    
                                             during shipment.           
Yellow Fever Vaccine......................  0 C or colder.              
------------------------------------------------------------------------

    (b) Exemptions. Exemptions or modifications shall be made only upon 
written approval, in the form of a

[[Page 13]]

supplement of the product license, issued 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]



                   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 license is pending 
need not be made until the establishment is in operation and is 
manufacturing the complete product for which a product license is 
desired. In case the license is denied following inspection for the 
original license, no reinspection need be made until assurance has been 
received that the faulty conditions which were the basis of the denial 
have been corrected. An inspection of each licensed establishment and 
its additional location(s) shall be made at least once every 2 years. 
Inspections may be made with or without notice, and shall be made during 
regular business hours unless otherwise directed.

[38 FR 32048, Nov. 20, 1973, as amended at 48 FR 26314, June 7, 1983]



Sec. 600.22   Duties of inspector.

    The inspector shall:
    (a) Call upon the active head of the establishment, stating the 
object of his visit,
    (b) Interrogate the proprietor or other personnel of the 
establishment as he may deem necessary,
    (c) Examine the details of location, construction, equipment and 
maintenance, including stables, barns, warehouses, manufacturing 
laboratories, bleeding clinics maintained for the collection of human 
blood, shipping rooms, record rooms, and any other structure or 
appliance used in any part of the manufacture of a product,
    (d) Investigate as fully as he deems necessary the methods of 
propagation, processing, testing, storing, dispensing, recording, or 
other details of manufacture and distribution of each licensed product, 
or product for which a license has been requested, including observation 
of these procedures in actual operation,
    (e) Obtain and cause to be sent to the Director, Center for 
Biologics Evaluation and Research, adequate samples for the examination 
of any product or ingredient used in its manufacture,
    (f) Bring to the attention of the manufacturer any fault observed in 
the course of inspection in location, construction, manufacturing 
methods, or administration of a licensed establishment which might lead 
to impairment of a product,
    (g) Inspect and copy, as circumstances may require, any records 
required to be kept pursuant to Sec. 600.12,
    (h) Certify as to the condition of the establishment and of the 
manufacturing methods followed and make recommendations as to action 
deemed appropriate with respect to any application for license or any 
license previously issued.

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



               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 means 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

[[Page 14]]

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 for this purpose has the same meaning as defined in 
Sec. 606.3(c) of this chapter.
    Increased frequency means an increase in the rate of occurrence of a 
particular adverse biological product experience, e.g., an increased 
number of reports of a particular adverse biological product experience 
after appropriate adjustment for biological product exposure.
    Serious means an adverse experience associated with the use of a 
biological product that is fatal or life-threatening, is permanently 
disabling, requires inpatient hospitalization, or is a congenital 
anomaly, cancer, or overdose.
    Unexpected means an adverse biological product experience that is 
not listed in the current labeling for the product and includes an event 
that may be symptomatically and pathophysiologically related to an event 
listed in the labeling, but differs 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.
    (b) Review of adverse experiences. Any person having a product 
license under Sec. 601.20 of this chapter shall promptly review all 
adverse experience information pertaining to its product obtained or 
otherwise received by the licensed manufacturer 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.
    (c)  Reporting requirements. The licensed manufacturer shall report 
to FDA adverse experience information, as described in this section. The 
licensed manufacturer shall submit two copies of each report described 
in this section for nonvaccine biological products, to the Center for 
Biologics Evaluation and Research (HFM-210), Food and Drug 
Administration, 1401 Rockville Pike, suite 200 N., Rockville, MD 20852-
1448. Submit all vaccine adverse experience reports to: Vaccine Adverse 
Event Reporting System (VAERS), P.O. Box 1100, Rockville, MD 20849-1100. 
FDA may waive the requirement for the second copy in appropriate 
instances.
    (1)  Fifteen-day Alert reports. (i) The licensed manufacturer shall 
report each adverse experience that is both serious and unexpected, 
regardless of source, as soon as possible but in any case within 15 
working days of initial receipt of the information. These reports are 
required to be submitted, for nonvaccine biological products, on a form 
designated by FDA or a suitable format containing all of the data 
elements in the FDA designated reporting form, and, for vaccines on a 
VAERS form. The licensed manufacturer shall promptly investigate all 
adverse experiences that are the subject of these 15-day Alert reports 
and shall submit followup reports within 15 working days of receipt of 
new information or as requested by FDA. If additional information is not 
obtainable, a followup report may be required that describes briefly the 
steps taken to seek additional information and the reasons why it could 
not be obtained. These 15-day Alert reports and followups to them are 
required to be submitted under separate cover and may not be included, 
except for summary or tabular purposes, in a periodic report.
    (ii) The licensed manufacturer shall review periodically (at least 
as often as the periodic reporting cycle) the frequency of reports of 
adverse biological product experiences that are both serious and 
expected and reports of therapeutic failure (lack of effect), regardless 
of source, and report any significant increase in frequency as soon as 
possible but in any case within 15 working days of determining that a 
significant increase in frequency exists. Upon written notice, FDA may 
require that licensed manufacturers

[[Page 15]]

review the frequency of reports of serious, expected adverse biological 
product experiences at intervals different than the periodic reporting 
cycle. Reports of a significant increase in frequency are required to be 
submitted in narrative form (including the time period on which the 
increased frequency is based, the method of analysis, and the 
interpretation of the results), rather than using the form designated by 
FDA. Fifteen-day Alert reports based on increased frequency are required 
to be submitted under separate cover and may not be included, except for 
summary purposes, in a periodic report.
    (iii) The requirements of paragraphs (c)(1)(i) and (c)(1)(ii) of 
this section, concerning the submission of Fifteen-day Alert reports, 
shall also apply to any person other than the licensed manufacturer of 
the final product 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. In order to avoid unnecessary duplication in the 
initial and followup submission of reports to FDA, the obligations of a 
manufacturer other than the licensed manufacturer, may be met by 
submitting all reports to the licensed manufacturer of the final 
product. If a manufacturer other than the licensed manufacturer elects 
to submit reports to the licensed manufacturer rather than to FDA, it 
shall submit each report to the licensed manufacturer within 3 working 
days of its receipt, and the licensed manufacturer shall then comply 
with the requirements of this section. Under this circumstance, the 
manufacturer shall maintain a record of this action which shall include:
    (A) A copy of all adverse biological product experience reports 
submitted to the licensed manufacturer,
    (B) Date the report was received by the manufacturer,
    (C) Date the report was submitted to the licensed manufacturer,
    (D) Name and address of the licensed manufacturer.
    (iv) Each report submitted under this paragraph shall bear prominent 
identification as to its contents, i.e., ``15-day Alert report'' or 
``15-day Alert report--followup.''
    (2)  Periodic adverse experience reports. (i) The licensed 
manufacturer shall 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 product license, and then at annual 
intervals. The licensed manufacturer shall submit each quarterly report 
within 30 days of the close of the quarter (the first quarter beginning 
on the date of issuance of the product license) and each annual report 
within 60 days of the anniversary date of the issuance of the product 
license. Upon written notice, FDA may extend or reestablish the 
requirement that a licensed manufacturer submit quarterly reports, or 
require that the licensed manufacturer 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 shall contain:
    (A) A narrative summary and analysis of the information in the 
report and an analysis of the 15-day Alert reports submitted during the 
reporting interval (all 15-day Alert reports being appropriately 
referenced by the licensed manufacturer's patient identification number, 
adverse reaction term(s), and date of submission to FDA);
    (B) A form designated for Adverse Experience Reporting by FDA for 
each adverse experience not reported under paragraph (c)(1)(i) of this 
section (with an index consisting of a line listing of the licensed 
manufacturer's patient identification number and adverse reaction 
term(s)); and
    (C) A history of actions taken since the last report because of 
adverse experiences (for example, labeling changes or studies 
initiated).
    (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.

[[Page 16]]

    (d) Scientific literature. (1) A 15-day Alert report based on 
information from the scientific literature shall 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. The 15-day Alert reporting requirements in paragraph 
(c)(1)(ii) of this section (i.e., a significant increase in frequency of 
a serious, expected adverse experience or of a therapeutic failure) 
apply only to reports found in scientific and medical journals either as 
the result of a formal clinical trial, or from epidemiologic studies or 
analyses of experience in a monitored series of patients.
    (2) As with all reports submitted under paragraph (c)(1)(i) of this 
section, reports based on the scientific literature shall be submitted 
on the reporting form designated by FDA or comparable format as 
prescribed by paragraph (f) of this section. In cases where the licensed 
manufacturer believes that preparing the form designated by FDA 
constitutes an undue hardship, the licensed manufacturer may arrange 
with the Division of Biostatistics and Epidemiology (HFM-210) for an 
acceptable alternative reporting format.
    (e) Postmarketing studies. (1) Licensed manufacturers 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 licensed manufacturer concludes that there 
is a reasonable possibility that the product caused the adverse 
experience.
    (2) The licensed manufacturer shall separate and clearly mark 
reports of adverse experiences that occur during a postmarketing study 
as being distinct from those experiences that are being reported 
spontaneously to the licensed manufacturer.
    (f)  Reporting forms. (1) Except as provided in paragraphs 
(c)(1)(ii), and (f)(3) of this section, the licensed manufacturer shall 
complete the reporting form designated by FDA (FDA-3500A, or, for 
vaccines, a VAERS form) for each report of an adverse experience.
    (2) Each completed form should refer only to an individual patient 
or single attached publication.
    (3) Instead of using a designated reporting form, a licensed 
manufacturer may use a computer-generated form or other alternative 
format (e.g., a computer-generated tape or tabular listing) provided 
that:
    (i) The content of the alternative format is equivalent in all 
elements of information to those specified in the form designated by 
FDA; and
    (ii) the format is approved in advance by MEDWATCH: The FDA Medical 
Products Reporting Program; or, for alternatives to the VAERS Form, by 
the Division of Biostatistics and Epidemiology.
    (4) Copies of the reporting form designated by FDA (FDA-3500A) for 
nonvaccine biological products may be obtained from the Center for 
Biologics Evaluation and Research (address above). Additional supplies 
of the form may be obtained from the Consolidated Forms and Publications 
Distribution Center, 3222 Hubbard Rd., Landover, MD 20785. Supplies of 
the VAERS form may be obtained from VAERS by calling 1-800-822-7967.
    (g)  Multiple reports. A licensed manufacturer should not include in 
reports under this section any adverse experiences that occurred in 
clinical trials if they were previously submitted in the product license 
application. If a report refers to more than one biological product 
marketed by a licensed manufacturer, the licensed manufacturer should 
submit the report to the license for the product listed first in the 
report.
    (h)  Patient privacy. For nonvaccine biological products, a licensed 
manufacturer should not include in reports under this section the names 
and addresses of individual patients; instead, the licensed manufacturer 
should assign a unique code number to each report, preferably not more 
than eight characters in length. The licensed manufacturer should 
include the name of the reporter from whom the information was received. 
The names of patients, health care professionals,

[[Page 17]]

hospitals, and geographical identifiers in adverse experience reports 
are not releasable to the public under FDA's public information 
regulations in part 20 this of 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.
    (i)  Recordkeeping. The licensed manufacturer shall maintain for a 
period of 10 years records of all adverse experiences known to the 
licensed manufacturer, including raw data and any correspondence 
relating to the adverse experiences.
    (j)  Guideline. FDA has prepared a guideline for the submission of 
reports of adverse experiences and suggested followup investigation of 
reports.
    (k)  Revocation of license. If a licensed manufacturer fails to 
establish and maintain records and make reports required under this 
section with respect to a licensed biological product, FDA may revoke 
the product license for such a product in accordance with the procedures 
of Sec. 601.5 of this chapter.
    (l)  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.
    (m)  Disclaimer. A report or information submitted by a licensed 
manufacturer under this section (and any release by FDA of that report 
or information) does not necessarily reflect a conclusion by the 
licensed manufacturer or FDA that the report or information constitutes 
an admission that the biological product caused or contributed to an 
adverse effect. A licensed manufacturer 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.



Sec. 600.81  Distribution reports.

    The licensed manufacturer shall submit information about the 
quantity of the product distributed under the product license, including 
the quantity distributed to distributors. The interval between 
distribution reports shall be 6 months. Upon written notice, FDA may 
require that the licensed manufacturer submit distribution reports under 
this section at times other than every 6 months. The distribution report 
shall 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 
licensed manufacturer submit reports under this section at times other 
than those stated. Requests by a licensed manufacturer to submit reports 
at times other than those stated should be made as a request for a 
waiver under Sec. 600.90.



Sec. 600.90   Waivers.

    (a) A licensed manufacturer may ask the Food and Drug Administration 
to waive under this section any requirement that applies to the licensed 
manufacturer under Secs. 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 licensed manufacturer's compliance with 
the

[[Page 18]]

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 licensed manufacturer's compliance with the requirement is 
unnecessary or cannot be achieved,
    (2) The licensed manufacturer's alternative submission satisfies the 
requirement, or
    (3) The licensed manufacturer's submission otherwise justifies a 
waiver.



PART 601--LICENSING--Table of Contents




                      Subpart A--General Provisions

Sec.
601.1  Two forms of licenses.
601.2  Applications for establishment and product licenses; procedure 
          for filing.
601.3  License forms.
601.4  Issuance and denial of license.
601.5  Revocation of license.
601.6  Suspension of license.
601.7  Procedure for hearings.
601.8  Publication of revocation.
601.9  Licenses; reissuance.

                   Subpart B--Establishment Licensing

601.10  Establishment licenses; issuance and conditions.
601.12  Changes to be reported.

                      Subpart C--Product Licensing

601.20  Product licenses; issuance and conditions.
601.21  Products under development.
601.22  Products in short supply; initial manufacturing at other than 
          licensed establishment.
601.25  Review procedures to determine that licensed biological products 
          are safe, effective, and not misbranded under prescribed, 
          recommended, or suggested conditions of use.
601.26  Reclassification procedures to determine that licensed 
          biological products are safe, effective, and not misbranded 
          under prescribed, recommended, or suggested conditions of use.

       Subpart D--Licensing of Foreign Establishments and Products

601.30  Licenses required; products for controlled investigation only.
601.31  Procedure.
601.32  Form of license.
601.33  Samples for each importation.

 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 
          establishment and product licenses.

    Authority: Secs. 201, 501, 502, 503, 505, 510, 513-516, 518-520, 
701, 704, 721, 801 of the Federal Food, Drug, and Cosmetic Act (21 
U.S.C. 321, 351, 352, 353, 355, 360, 360c-360f, 360h-360j, 371, 374, 
379e, 381); secs. 215, 301, 351, 352 of the Public Health Service Act 
(42 U.S.C. 216, 241, 262, 263); secs. 2-12 of the Fair Packaging and 
Labeling Act (15 U.S.C. 1451-1461).

    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. 601.1   Two forms of licenses.

    There shall be two forms of licenses: establishment and product.



Sec. 601.2  Applications for establishment and product licenses; procedures for filing.

    (a) General. To obtain a license for any establishment or product, 
the manufacturer shall make application to the Director, Center for 
Biologics Evaluation and Research, on forms prescribed for such 
purposes, and in the case of an application for a product license, shall 
submit data derived from

[[Page 19]]

nonclinical laboratory and clinical studies which demonstrate that the 
manufactured product meets prescribed standards 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 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 to be sold, bartered, or exchanged or offered, sent, carried or 
brought for sale, barter, or exchange; summaries of results of tests 
performed on the lot(s) represented by the submitted sample(s); and 
specimens of the labels, enclosures, and containers proposed to be used 
for the product. An application for license shall not be considered as 
filed until all pertinent information and data have been received from 
the manufacturer by the Center for Biologics Evaluation and Research. 
The applicant shall also include either a claim for categorical 
exclusion under Sec. 25.24 of this chapter or an environmental 
assessment under Sec. 25.31 of this chapter. In lieu of the procedures 
described in this paragraph, applications for radioactive biological 
products shall be handled as set forth in paragraph (b) of this section.
    (b) Radioactive biological products. In lieu of submitting an 
establishment and product license for the manufacture of a radioactive 
biological product, as defined in Sec. 600.3(ee) of this chapter, the 
manufacturer of such a product shall submit a new drug application to 
the Director, Division of Medical Imaging, Surgical, and Dental Products 
(HFD-160), Center for Drug Evaluation and Research, Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857, consistent with 
the procedures set forth in Sec. 314.50 of this chapter. For such 
products, the approval of the new drug application will be in lieu of 
issuing a product and an establishment license. Compliance with the 
provisions of part 314 of this chapter shall be deemed to constitute 
compliance with the provisions of Subchapter F of this chapter unless 
the Commissioner makes a determination that a particular regulation from 
Subchapter F shall be applicable to radioactive drugs containing a 
biological product, e.g., Sec. 610.2 of this chapter.

[40 FR 31313, July 25, 1975, as amended at 46 FR 8955, Jan. 27, 1981; 47 
FR 6618, Feb. 16, 1982; 49 FR 23833, June 8, 1984; 50 FR 7518, Feb. 22, 
1985; 50 FR 16669, Apr. 26, 1985; 55 FR 11013 and 11014, Mar. 26, 1990]



Sec. 601.3   License forms.

    (a) Establishment license. The establishment license form shall be 
prescribed by the Director, Center for Biologics Evaluation and Research 
and shall include:
    (1) The name and address of the manufacturer.
    (2) The name and address of the establishment.
    (3) The names and addresses of all locations of the establishment.
    (4) The license number.
    (5) The date of issuance.
    (b) Product license. The product license form shall be prescribed by 
the Director, Center for Biologics Evaluation and Research and shall 
include:
    (1) The name and address of the manufacturer.
    (2) The name and address of the establishment.
    (3) The name and address of each location at which the product is 
manufactured.
    (4) The license number of the establishment.
    (5) The proper name of the product, with additional specifications, 
if any, which may be approved or required for additional labeling 
purposes.

[38 FR 32052, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]

[[Page 20]]



Sec. 601.4   Issuance and denial of license.

    (a) An establishment or product license shall be issued upon a 
determination by the Director, Center for Biologics Evaluation and 
Research that the establishment or the product, as the case may be, 
meets the applicable standards established in this chapter. Licenses 
shall be valid until suspended or revoked.
    (b) If the Commissioner determines that the establishment or product 
does not meet the standards established in this chapter, he shall deny 
the application and inform the applicant of the grounds for, and of an 
opportunity for a hearing on, his 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; 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 
26, 1990]



Sec. 601.5   Revocation of license.

    (a) An establishment or product license shall be revoked upon 
application of the manufacturer giving notice of intention to 
discontinue the manufacture of all products 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) If the Commissioner finds that (1) 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, 
(2) manufacturing of products or of a product has been discontinued to 
an extent that a meaningful inspection or evaluation cannot be made, (3) 
the manufacturer has failed to report a change as required by 
Sec. 601.12, (4) 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, (5) the establishment or the manufacturing methods 
have been so changed as to require a new showing that the establishment 
or product meets the standards established in this chapter in order to 
protect the public health, or (6) the licensed product is not safe and 
effective for all of its intended uses or is misbranded with respect to 
any such use, he shall notify the licensee of his intention to revoke 
the license, setting forth the grounds for, and offering an opportunity 
for a hearing on, the proposed revocation. Except as provided in 
Sec. 601.6 or in cases involving willfulness, the notification required 
in this paragraph shall provide a reasonable period for the licensee 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 licensee does not 
waive the opportunity for a hearing, 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 19143, Apr. 12, 1977; 49 FR 23833, June 8, 1984]



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, he may notify the licensee that his 
license for the establishment or the product is suspended and require 
that the licensee (1) notify the selling agents and distributors to whom 
such product or products have been delivered of such suspension, and (2) 
furnish to the Director, Center for Biologics Evaluation and Research, 
complete records of such deliveries and notice of suspension.
    (b) Upon suspension of a license, the Commissioner shall either (1) 
proceed pursuant to the provisions of Sec. 601.5(b) to revoke the 
license, or (2) if the licensee agrees, hold revocation in abeyance 
pending resolution of the matters involved.

[42 FR 4718, Jan. 25, 1977 as amended at 49 FR 23833, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]



Sec. 601.7   Procedure for hearings.

    (a) A notice of opportunity for hearing, notice of appearance and 
request

[[Page 21]]

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 Secs. 601.4 through 601.6 shall be governed 
by part 12 of this chapter.
    (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.

    Notice of revocation of a license, with statement of the cause 
therefor, shall be issued by the Commissioner and published in the 
Federal Register.

[42 FR 4718, Jan. 25, 1977]



Sec. 601.9   Licenses; reissuance.

    (a) Compliance with standards. An establishment or product license, 
previously suspended or revoked, may be reissued or reinstated upon a 
showing of compliance with required standards and upon such inspection 
and examination as may be considered necessary by the Director, Center 
for Biologics Evaluation and Research.
    (b) Exclusion of noncomplying location. An establishment or product 
license, excluding a location or locations that fail to comply with 
required standards, may be issued without further application and 
concurrently with the suspension or revocation of the license for 
noncompliance at the excluded location or locations.

[42 FR 4718, Jan. 25, 1977, as amemded at 49 FR 23833, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]



                   Subpart B--Establishment Licensing



Sec. 601.10   Establishment licenses; issuance and conditions.

    (a) Inspection--compliance with standards. An establishment license 
shall be issued only after inspection of the establishment and upon a 
determination that the establishment complies with the applicable 
standards prescribed in the regulations in this subchapter.
    (b) Availability of product; simultaneous request for and issuance 
of product license. No establishment license shall be issued unless (1) 
a product intended for sale, barter or exchange or intended to be 
offered, sent, carried or brought for sale, barter or exchange is 
available for examination, (2) such product is available for inspection 
during all phases of manufacture and (3) a product license is requested 
and issued simultaneously with the establishment license.
    (c) One establishment license to cover all locations. One 
establishment license shall be issued to cover all locations meeting the 
establishment standards.



Sec. 601.12   Changes to be reported.

    (a) General. Important proposed changes in location, equipment, 
management and responsible personnel, or in manufacturing methods and 
labeling, of any product for which a license is in effect or for which 
an application for license is pending, shall be reported to the 
Director, Center for Biologics Evaluation and Research, by the 
manufacturer, and unless in case of an emergency, not less than 30 days 
in advance of the time such changes are intended to be made.
    (b) Manufacturing methods and labeling. Proposed changes in 
manufacturing methods and labeling may not become effective until 
notification of acceptance is received from the Director, Center for 
Biologics Evaluation and Research.

[38 FR 32052, Nov. 20, 1973. Redesignated and amended at 42 FR 4718, 
Jan. 25, 1977; 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990]

[[Page 22]]



                      Subpart C--Product Licensing



Sec. 601.20   Product licenses; issuance and conditions.

    (a) Examination--compliance with standards. A product license shall 
be issued only upon examination of the product and upon a determination 
that the product complies with the standards prescribed in the 
regulations in this subchapter: Provided, That no product license shall 
be issued except upon a determination that the establishment complies 
with the establishment standards prescribed in the regulations contained 
in this subchapter, applicable to the manufacture of such product.
    (b) 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 Commissioner of Food 
and Drugs, would impair the assurances of continued safety, purity and 
potency as provided by the regulations contained in this subchapter.



Sec. 601.21  Products under development.

    A biological product undergoing development, but not yet ready for a 
product 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 sale, barter, or exchange, except as provided in 
section 505(i) of the Federal Food, Drug, and Cosmetic Act, as amended, 
and the regulations thereunder (21 CFR part 312).

[45 FR 73923, Nov. 7, 1980, as amended at 55 FR 11014, Mar. 26, 1990]



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

    Licenses issued to a manufacturer for an establishment shall 
authorize persons other than such manufacturer to conduct at places 
other than such establishment 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 he finds upon application of such 
manufacturer, that (a) 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 (b) such 
manufacturer has established with respect to such persons and places 
such procedures, inspections, tests or other arrangements as will assure 
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 
Secs. 601.1 to 601.6, 601.9, 601.10, 601.20, 601.21, 601.30 to 601.33, 
and Secs. 610.60 to 610.65 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 Secs. 601.6 to 601.8 with respect to the 
suspension and the revocation of licenses.

[42 FR 4718, Jan. 25, 1977]



Sec. 601.25  Review procedures to determine that licensed biological products are safe, effective, and not misbranded under prescribed, recommended, or 
          suggested conditions of use.

    For purposes of reviewing biological products that have been 
licensed prior to July 1, 1972, to determine that they are safe and 
effective and not misbranded, the following regulations shall apply. 
Prior administrative action exempting biological products from the 
provisions of the Federal Food, Drug, and Cosmetic Act is superseded to 
the extent that these regulations result in imposing requirements 
pursuant to provisions therein for a designated biological product or 
category of products.
    (a) Advisory review panels. The Commissioner of Food and Drugs shall 
appoint advisory review panels (1) to evaluate the safety and 
effectiveness of biological products for which a license has been issued 
pursuant to section 351 of the Public Health Service Act, (2) to review 
the labeling of such biological products, and (3) to advise him on

[[Page 23]]

which of the biological products under review are safe, effective, and 
not misbranded. An advisory review panel shall be established for each 
designated category of biological product. The members of a panel shall 
be qualified experts, appointed by the Commissioner, and shall include 
persons from lists submitted by organizations representing professional, 
consumer, and industry interests. Such persons shall represent a wide 
divergence of responsible medical and scientific opinion. The 
Commissioner shall designate the chairman of each panel, and summary 
minutes of all meetings shall be made.
    (b) Request for data and views. (1) The Commissioner of Food and 
Drugs will publish a notice in the Federal Register requesting 
interested persons to submit, for review and evaluation by an advisory 
review panel, published and unpublished data and information pertinent 
to a designated category of biological products.
    (2) Data and information submitted pursuant to a published notice, 
and falling within the confidentiality provisions of 18 U.S.C. 1905, 5 
U.S.C. 552(b), or 21 U.S.C. 331(j), shall be handled by the advisory 
review panel and the Food and Drug Administration as confidential until 
publication of a proposed evaluation of the biologics under review and 
the full report or reports of the panel. Thirty days thereafter such 
data and information shall be made publicly available and may be viewed 
at the Dockets Management Branch of the Food and Drug Administration, 
except to the extent that the person submitting it demonstrates that it 
still falls within the confidentiality provisions of one or more of 
those statutes.
    (3) To be considered, 12 copies of the submission on any marketed 
biological product within the class shall be submitted, preferably 
bound, indexed, and on standard sized paper, approximately 8\1/2\  x  11 
inches. The time allotted for submissions will be 60 days, unless 
otherwise indicated in the specific notice requesting data and views for 
a particular category of biological products. When requested, 
abbreviated submissions should be sent. All submissions shall be in the 
following format, indicating ``none'' or ``not applicable'' where 
appropriate, unless changed in the Federal Register notice:

                 Biological Products Review Information

    I. Label or labels and all other labeling (preferably mounted. 
Facsimile labeling is acceptable in lieu of actual container labeling), 
including labeling for export.
    II. Representative advertising used during the past 5 years.
    III. The complete quantitative composition of the biological 
product.
    IV. Animal safety data.
    A. Individual active components.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    B. Combinations of the individual active components.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    C. Finished biological product.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    V. Human safety data.
    A. Individual active components.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    3. Documented case reports.
    4. Pertinent marketing experiences that may influence a 
determination as to the safety of each individual active component.
    5. Pertinent medical and scientific literature.
    B. Combinations of the individual active components.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    3. Documented case reports.
    4. Pertinent marketing experiences that may influence a 
determination as to the safety of combinations of the individual active 
components.
    5. Pertinent medical and scientific literature.
    C. Finished biological product.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    3. Documented case reports.
    4. Pertinent marketing experiences that may influence a 
determination as to the safety of the finished biological product.
    5. Pertinent medical and scientific literature.
    VI. Efficacy data.
    A. Individual active components.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    3. Documented case reports.

[[Page 24]]

    4. Pertinent marketing experiences that may influence a 
determination on the efficacy of each individual active component.
    5. Pertinent medical and scientific literature.
    B. Combinations of the individual active components.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    3. Documented case reports.
    4. Pertinent marketing experiences that may influence a 
determination as to the effectiveness of combinations of the individual 
active components.
    5. Pertinent medical and scientific literature.
    C. Finished biological product.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    3. Documented case reports.
    4. Pertinent marketing experiences that may influence a 
determination as to the effectiveness of the finished biological 
product.
    5. Pertinent medical and scientific literature.
    VII. A summary of the data and views setting forth the medical 
rational and purpose (or lack thereof) for the biological product and 
its components and the scientific basis (or lack thereof) for the 
conclusion that the biological product, including its components, has 
been proven safe and effective and is properly labeled for the intended 
use or uses. If there is an absence of controlled studies in the 
materials submitted, an explanation as to why such studies are not 
considered necessary or feasible shall be included.
    VIII. If the submission is by a licensee, a statement signed by the 
responsible head (as defined in Sec. 600.10 of this chapter) of the 
licensee shall be included, stating that to the best of his knowledge 
and belief, it includes all information, favorable and unfavorable, 
pertinent to an evaluation of the safety, effectiveness, and labeling of 
the product, including information derived from investigation, 
commercial marketing, or published literature. If the submission is by 
an interested person other than a licensee, a statement signed by the 
person responsible for such submission shall be included, stating that 
to the best of his knowledge and belief, it fairly reflects a balance of 
all the information, favorable and unfavorable, available to him 
pertinent to an evaluation of the safety, effectiveness, and labeling of 
the product.

    (c) Deliberations of an advisory review panel. An advisory review 
panel will meet as often and for as long as is appropriate to review the 
data submitted to it and to prepare a report containing its conclusions 
and recommendations to the Commissioner of Food and Drugs with respect 
to the safety, effectiveness, and labeling of the biological products in 
the designated category under review.
    (1) A panel may also consult any individual or group.
    (2) Any interested person may request in writing an opportunity to 
present oral views to the panel. Such written requests for oral 
presentations should include a summarization of the data to be presented 
to the panel. Such request may be granted or denied by the panel.
    (3) Any interested person may present written data and views which 
shall be considered by the panel. This information shall be presented to 
the panel in the format set forth in paragraph (b)(3) of this section 
and within the time period established for the biological product 
category in the notice for review by a panel.
    (d) Standards for safety, effectiveness, and labeling. The advisory 
review panel, in reviewing the submitted data and preparing the panel's 
conclusions and recommendations, and the Commissioner of Food and Drugs, 
in reviewing and implementing the conclusions and recommendations of the 
panel, shall apply the following standards to determine that a 
biological product is safe and effective and not misbranded.
    (1) 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. Proof of safety 
shall consist of adequate tests by methods reasonably applicable to show 
the biological product is safe under the prescribed conditions of use, 
including results of significant human experience during use.
    (2) Effectiveness means a reasonable expectation that, in a 
significant proportion of the target population, the pharmacological or 
other effect of the biological product, when used under adequate 
directions, for use and warnings against unsafe use, will serve a 
clinically significant function in the diagnosis, cure, mitigation, 
treatment, or prevention of disease in man. Proof of effectiveness shall 
consist of controlled clinical investigations as

[[Page 25]]

defined in Sec. 314.126 of this chapter, unless this requirement is 
waived on the basis of a showing that it is not reasonably applicable to 
the biological product or essential to the validity of the 
investigation, and that an alternative method of investigation is 
adequate to substantiate effectiveness. Alternate methods, such as 
serological response evaluation in clinical studies and appropriate 
animal and other laboratory assay evaluations may be adequate to 
substantiate effectiveness where a previously accepted correlation 
between data generated in this way and clinical effectiveness already 
exists. Investigations may be corroborated by partially controlled or 
uncontrolled studies, documented clinical studies by qualified experts, 
and reports of significant human experience during marketing. Isolated 
case reports, random experience, and reports lacking the details which 
permit scientific evaluation will not be considered.
    (3) The benefit-to-risk ratio of a biological product shall be 
considered in determining safety and effectiveness.
    (4) A biological product may combine two or more safe and effective 
active components: (i) When each active component makes a contribution 
to the claimed effect or effects; (ii) when combining of the active 
ingredients does not decrease the purity, potency, safety, or 
effectiveness of any of the individual active components; and (iii) if 
the combination, when used under adequate directions for use and 
warnings against unsafe use, provides rational concurrent preventive 
therapy or treatment for a significant proportion of the target 
population.
    (5) Labeling shall be clear and truthful in all respects and may not 
be false or misleading in any particular. It shall comply with section 
351 of the Public Health Service Act and sections 502 and 503 of the 
Federal Food, Drug, and Cosmetic Act, and in particular with the 
applicable requirements of Secs. 610.60 through 610.65 and subpart D of 
part 201 of this chapter.
    (e) Advisory review panel report to the Commissioner. An advisory 
review panel shall submit to the Commissioner of Food and Drugs a report 
containing the panel's conclusions and recommendations with respect to 
the biological products falling within the category covered by the 
panel. Included within this report shall be:
    (1) A statement which designates those biological products 
determined by the panel to be safe and effective and not misbranded. 
This statement may include any condition relating to active components, 
labeling, tests required prior to release of lots, product standards, or 
other conditions necessary or appropriate for their safety and 
effectiveness.
    (2) A statement which designates those biological products 
determined by the panel to be unsafe or ineffective, or to be 
misbranded. The statement shall include the panel's reasons for each 
such determination.
    (3) A statement which designates those biological products 
determined by the panel not to fall within either paragraph (e) (1) or 
(2) of this section on the basis of the panel's conclusion that the 
available data are insufficient to classify such biological products, 
and for which further testing is therefore required. The report shall 
recommend with as must specificity as possible the type of further 
testing required and the time period within which it might reasonably be 
concluded. The report shall also recommend whether the product license 
should or should not be revoked, thus permitting or denying continued 
manufacturing and marketing of the biological product pending completion 
of the testing. This recommendation will be based on an assessment of 
the present evidence of the safety and effectiveness of the product and 
the potential benefits and risks likely to result from the continued use 
of the product for a limited period of time while the questions raised 
concerning the product are being resolved by further study.\2\
---------------------------------------------------------------------------

    \2\ As of November 4, 1982, the provisions under paragraphs (e)(3) 
and (f)(3) of this section for the interim marketing of certain 
biological products pending completion of additional studies have been 
superseded by the review and reclassification procedures under 
Sec. 601.26 of this chapter. The superseded text is included for the 
convenience of the user only.
---------------------------------------------------------------------------

    (f) Proposed order. After reviewing the conclusions and 
recommendations of the advisory review panel, the

[[Page 26]]

Commissioner of Food and Drugs shall publish in the Federal Register a 
proposed order containing:
    (1) A statement designating the biological products in the category 
under review that are determined by the Commissioner of Food and Drugs 
to be safe and effective and not misbranded. This statement may include 
any condition relating to active components, labeling, tests required 
prior to release of lots, product standards, or other conditions 
necessary or appropriate for their safety and effectiveness, and may 
propose corresponding amendments in other regulations under this 
subchapter F.
    (2) A statement designating the biological products in the category 
under review that are determined by the Commissioner of Food and Drugs 
to be unsafe or ineffective, or to be misbranded, together with the 
reasons therefor. All licenses for such products shall be proposed to be 
revoked.
    (3) A statement designating the biological products not included in 
either of the above two statements on the basis of the Commissioner of 
Food and Drugs determination that the available data are insufficient to 
classify such biological products under either paragraph (f) (1) or (2) 
of this section. Licenses for such products may be proposed to be 
revoked or to remain in effect on an interim basis. Where the 
Commissioner determines that the potential benefits outweigh the 
potential risks, the proposed order shall provide that the product 
license for any biological product, falling within this paragraph will 
not be revoked but will remain in effect on an interim basis while the 
data necessary to support its continued marketing are being obtained for 
evaluation by the Food and Drug Administration. The tests necessary to 
resolve whatever safety or effectiveness questions exist shall be 
described.\2\
---------------------------------------------------------------------------

    \2\ As of November 4, 1982, the provisions under paragraphs (e)(3) 
and (f)(3) of this section for the interim marketing of certain 
biological products pending completion of additional studies have been 
superseded by the review and reclassification procedures under 
Sec. 601.26 of this chapter. The superseded text is included for the 
convenience of the user only.
---------------------------------------------------------------------------

    (4) The full report or reports of the panel to the Commissioner of 
Food and Drugs.

    The summary minutes of the panel meeting or meetings shall be made 
available to interested persons upon request. Any interested person may 
within 90 days after publication of the proposed order in the Federal 
Register, file with the Hearing Clerk of the Food and Drug 
Administration written comments in quintuplicate. Comments may be 
accompanied by a memorandum or brief in support thereof. All comments 
may be reviewed at the office of the Dockets Management Branch during 
regular working hours, Monday through Friday.

    (g) Final order. After reviewing the comments, the Commissioner of 
Food and Drugs shall publish in the Federal Register a final order on 
the matters covered in the proposed order. The final order shall become 
effective as specified in the order.
    (h) [Reserved]
    (i) Court Appeal. The final order(s) published pursuant to paragraph 
(g) of this section, and any notice published pursuant to paragraph (h) 
of this section, constitute final agency action from which appeal lies 
to the courts. The Food and Drug Administration will request 
consolidation of all appeals in a single court. Upon court appeal, the 
Commissioner of Food and Drugs may, at his discretion, stay the 
effective date for part or all of the final order or notice, pending 
appeal and final court adjudication.

[38 FR 32052, Nov. 20, 1973, as amended at 39 FR 11535, Mar. 29, 1974; 
40 FR 13498, Mar. 27, 1975; 43 FR 44838, Sept. 29, 1978; 47 FR 44071, 
Oct. 5, 1982; 47 FR 50211, Nov. 5, 1982; 51 FR 15607, Apr. 25, 1986; 55 
FR 11014, Mar. 26, 1990]



Sec. 601.26  Reclassification procedures to determine that licensed biological products are safe, effective, and not misbranded under prescribed, recommended, 
          or suggested conditions of use.

    This regulation establishes procedures for the reclassification of 
all biological products that have been classified into Category IIIA. A 
Category IIIA biological product is one for which an advisory review 
panel has recommended under Sec. 601.25(e)(3), the Commissioner of Food 
and Drugs (Commissioner) has proposed under Sec. 601.25(f)(3), or the 
Commissioner has finally

[[Page 27]]

decided under Sec. 601.25(g) that available data are insufficient to 
determine whether the product license should be revoked or affirmed and 
which may be marketed pending the completion of further testing. All of 
these Category IIIA products will either be reclassified into Category I 
(safe, effective, and not misbranded) or Category II (unsafe, 
ineffective, or misbranded) in accordance with the procedures set forth 
below.
    (a) Advisory review panels. The Commissioner will appoint advisory 
review panels and use existing advisory review panels to (1) evaluate 
the safety and effectiveness of all Category IIIA biological products; 
(2) review the labeling of such products; and (3) advise the 
Commissioner on which Category IIIA biological products are safe, 
effective, and not misbranded. These advisory review panels will be 
established in accordance with procedures set forth in Sec. 601.25(a).
    (b) Deliberations of advisory review panels. The deliberations of 
advisory review panels will be conducted in accordance with 
Sec. 601.25(d).
    (c) Advisory review panel report to the Commissioner. An advisory 
review panel shall submit to the Commissioner a report containing the 
panel's conclusions and recommendations with respect to the biological 
products falling within the category of products reviewed by the panel. 
The panel report shall include:
    (1) A statement designating the biological products in the category 
under review in accordance with either Sec. 601.25(e)(1) or 
Sec. 601.25(e)(2).
    (2) A statement identifying those biological products designated 
under Sec. 601.25(e)(2) that the panel recommends should be designated 
as safe and presumptively effective and should remain on the market 
pending completion of further testing because there is a compelling 
medical need and no suitable alternative therapeutic, prophylactic, or 
diagnostic agent that is available in sufficient quantities to meet 
current medical needs. For the products or categories of products so 
recommended, the report shall include: (i) A description and evaluation 
of the available evidence concerning effectiveness and an explanation 
why the evidence shows that the product has any benefit; and (ii) a 
description of the alternative therapeutic, prophylactic, or diagnostic 
agents considered and a statement of why such alternatives are not 
suitable. In making this recommendation the panel shall also take into 
account the seriousness of the condition intended to be treated, 
prevented, or diagnosed by the product, the risks involved in the 
continued use of the product, and the likelihood that, based upon 
existing data, the effectiveness of the product can eventually be 
established by further testing and new test development. The report 
shall also recommend with as much specificity as possible the type of 
further testing required and the time period within which it might 
reasonably be concluded.
    (d) Proposed order. After reviewing the conclusions and 
recommendations of the advisory review panels, the Commissioner shall 
publish in the Federal Register a proposed order containing:
    (1) A statement designating the biological products in the category 
under review in accordance with either Sec. 601.25(e)(1) or 
601.25(e)(2);
    (2) A notice of availability of the full panel report or reports. 
The full panel report or reports shall be made publicly available at the 
time of publication of the proposed order.
    (3) A proposal to accept or reject the findings of the advisory 
review panel required by Sec. 601.26(c)(2)(i) and (ii).
    (4) A statement identifying those biological products that the 
Commissioner proposes should be designated as safe and presumptively 
effective under Sec. 601.26(c)(2) and should be permitted to remain on 
the market pending completion of further testing because there is a 
compelling medical need and no suitable alternative therapeutic, 
prophylactic, or diagnostic agent for the product that is available in 
sufficient quantities to meet current medical needs. In making this 
proposal, the Commissioner shall take into account the seriousness of 
the condition to be treated, prevented, or diagnosed by the product, the 
risks involved in the continued use of the product, and the likelihood 
that, based upon existing data, the effectiveness of the product can 
eventually be established by further testing.

[[Page 28]]

    (e) Final order. After reviewing the comments on the proposed order, 
the Commissioner shall publish in the Federal Register a final order on 
the matters covered in the proposed order. Where the Commissioner 
determines that there is a compelling medical need and no suitable 
alternative therapeutic, prophylactic, or diagnostic agent for any 
biological product that is available in sufficient quantities to meet 
current medical needs, the final order shall provide that the product 
license for that biological product will not be revoked, but will remain 
in effect on an interim basis while the data necessary to support its 
continued marketing are being obtained for evaluation by the Food and 
Drug Administration. The final order shall describe the tests necessary 
to resolve whatever effectiveness questions exist.
    (f) Additional studies and labeling. (1) Within 60 days following 
publication of the final order, each licensee for a biological product 
designated as requiring further study to justify continued marketing on 
an interim basis, pursuant to paragraph (e) of this section, shall 
submit to the Commissioner a written statement intended to show that 
studies adequate and appropriate to resolve the questions raised about 
the product have been undertaken. The Federal Government may undertake 
the studies. Any study involving a clinical investigation that involves 
human subjects shall be conducted in compliance with the requirements 
for informed consent under part 50 of this chapter. Such a study is also 
subject to the requirements for institutional review under part 56 of 
this chapter unless exempt under Sec. 56.104 or Sec. 56.105. The 
Commissioner may extend this 60-day period if necessary, either to 
review and act on proposed protocols or upon indication from the 
licensee that the studies will commence at a specified reasonable time. 
If no such commitment is made, or adequate and appropriate studies are 
not undertaken, the product license or licenses shall be revoked.
    (2) A progress report shall be filed on the studies by January 1 and 
July 1 until completion. If the progress report is inadequate or if the 
Commissioner concludes that the studies are not being pursued promptly 
and diligently, or if interim results indicate the product is not a 
medical necessity, the product license or licenses shall be revoked.
    (3) Promptly upon completion of the studies undertaken on the 
product, the Commissioner will review all available data and will either 
retain or revoke the product license or licenses involved. In making 
this review the Commissioner may again consult the advisory review panel 
which prepared the report on the product, or other advisory committees, 
professional organizations, or experts. The Commissioner shall take such 
action by notice published in the Federal Register.
    (4) Labeling and promotional material for those biological products 
requiring additional studies shall bear a box statement in the following 
format:

    Based on a review by the (insert name of appropriate advisory review 
panel) and other information, the Food and Drug Administration has 
directed that further investigation be conducted before this product is 
conclusively determined to be effective for labeled indication(s).

    (5) A written informed consent shall be obtained from participants 
in any additional studies required under paragraph (f)(1) of this 
section, explaining the nature of the product and the investigation. The 
explanation shall consist of such disclosure and be made so that 
intelligent and informed consent be given and that a clear opportunity 
to refuse is presented.
    (g) Court appeal. The final order(s) published pursuant to paragraph 
(e) of this section constitute final agency action from which appeal 
lies to the courts. The Food and Drug Administration will request 
consolidation of all appeals in a single court. Upon court appeal, the 
Commissioner of Food and Drugs may, at the Commissioner's discretion, 
stay the effective date for part or all of the final order or notice, 
pending appeal and final court adjudication.
    (h) [Reserved]
    (i) Institutional review and informed consent. Information and data 
submitted under this section after July 27, 1981, shall include 
statements regarding each clinical investigation involving human 
subjects, that it was conducted in compliance with the requirements for 
informed consent under part

[[Page 29]]

50 of this chapter. Such a study is also subject to the requirements for 
institutional review under part 56 of this chapter, unless exempt under 
Sec. 56.104 or Sec. 56.105.

[47 FR 44071, Oct. 5, 1982]



       Subpart D--Licensing of Foreign Establishments and Products



Sec. 601.30   Licenses required; products for controlled investigation only.

    Any biological or trivalent organic arsenical manufactured in any 
foreign country and intended for sale, barter, or exchange shall be 
refused entry by collectors of customs unless manufactured in an 
establishment holding an unsuspended and unrevoked establishment license 
and license for the product. Unlicensed products that are not imported 
for sale, barter, or exchange and that are intended solely for purposes 
of controlled investigation are admissible only if the investigation is 
conducted in accordance with section 505 of the Federal Food, Drug, and 
Cosmetic Act and the requirements set forth in parts 50, 56 unless 
exempted under Sec. 56.104 as granted a waiver under Sec. 56.105, parts 
58 and 312 of this chapter.

[46 FR 8956, Jan. 27, 1981]



Sec. 601.31   Procedure.

    Except as otherwise provided in this subchapter, licenses for 
foreign establishments and products shall be issued, suspended, and 
revoked in the same manner as licenses for domestic establishments and 
products. Each foreign establishment holding a license and sending, 
carrying, or bringing any licensed product into any State or possession 
for sale, barter, or exchange shall file with the Director, Center for 
Biologics Evaluation and Research, the name and address of each person 
to whom such a product is thus sent, carried, or brought. Foreign 
licensees shall notify each person in the United States to whom such a 
product is thus sent, carried, or brought, to keep such records of 
distribution as are required of domestic licensed establishments. 
Failure to give such notice to maintain records shall constitute ground 
for revocation of license.

[38 FR 32052, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]



Sec. 601.32   Form of license.

    Licenses for establishments located in foreign countries shall be in 
form similar to that for domestic establishments except that they shall 
authorize manufacture for sending, carrying, or bringing for sale, 
barter or exchange from the foreign country designated in the license 
into any State or possession of the United States and shall specify that 
it is issued upon the condition that the licensee will permit the 
inspection during all reasonable hours of the establishment by any 
officer, agent, or employee of the Department of Health and Human 
Services authorized by the Secretary for such purpose.



Sec. 601.33   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, shall be at least two final containers of each 
lot of product. A copy of the associated documents which describe and 
identify the shipment shall accompany the shipment for forwarding with 
the samples to the Director, Center for Biologics Evaluation and 
Research. 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 accompanies each shipment.

[38 FR 32052, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]



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

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



Sec. 601.40  Scope.

    This subpart applies to certain biological products that have been 
studied for their safety and effectiveness in

[[Page 30]]

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 Secs. 601.40 and 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 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. 601.40 or Sec. 601.41. 
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 Secs. 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

[[Page 31]]

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.



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 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 establishment and product licenses.

    (a) For purposes of this section the biological product file 
includes all data and information submitted with or incorporated by 
reference in any

[[Page 32]]

application for an establishment or product 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 product license has been 
sent to the applicant, unless it has previously been publicly disclosed 
or acknowledged. The Director of the Center for Biologics Evaluation and 
Research will maintain a list available for public disclosure of 
biological products for which a license has been issued.
    (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) 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.
    (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 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

[[Page 33]]

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]



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--Finished Product Control

606.120  Labeling, general requirements.
606.121  Container label.
606.122  Instruction circular.

                     Subpart H--Laboratory Controls

606.140  Laboratory controls.
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.

    Authority: Secs. 201, 301, 501, 502, 505, 510, 520, 701, 704 of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 355, 
360, 360j, 371, 374); secs. 215, 351, 353, 361 of the Public Health 
Service Act (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 whole blood collected from a single donor and 
processed either for transfusion or further manufacturing.
    (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) Component means that part of a single-donor unit of 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. This process may be 
immediately repeated, once.
    (f) Plateletpheresis means the procedure in which blood is removed 
from the donor, a platelet concentrate is separated, and the remaining 
formed elements and residual plasma are returned to the donor.
    (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 compatibility testing of blood 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 in vitro serological tests 
performed on donor and recipient blood samples to establish the 
serological matching of a

[[Page 34]]

donor's blood or blood components with that of a potential recipient.



                  Subpart B--Organization and Personnel



Sec. 606.20   Personnel.

    (a) A blood establishment shall be under the direction of a 
designated, qualified person who shall exercise control of the 
establishment in all matters relating to compliance with the provisions 
of this subchapter. This person shall also have the authority to 
represent the establishment in all pertinent matters with the Center for 
Biologics Evaluation and Research and to enforce, or direct the 
enforcement of, discipline and the performance of assigned functions by 
employees engaged in the collection, processing, compatibility testing, 
storage and distribution of blood and blood components. The designated 
director shall have an understanding of the scientific principles and 
techniques involved in the manufacture of blood products and shall have 
the responsibility for ensuring that employees are adequately trained in 
standard operating procedures and that they are aware of the application 
of the pertinent provisions of this chapter to their respective 
functions.
    (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]



                     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 suitability 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.
    (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

[[Page 35]]

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.



                          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.
    (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.

[[Page 36]]

    (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) Written standard operating procedures shall be maintained and 
shall include all steps to be followed in the collection, processing, 
compatibility testing, storage and distribution of blood and blood 
components for homologous transfusion, autologous transfusion and 
further manufacturing purposes. Such procedures shall be available to 
the personnel for use in the areas where the procedures are performed, 
unless this is impractical. The written standard operating procedures 
shall include, but are not limited to, descriptions of the following, 
when applicable:
    (1) Criteria used to determine donor suitability, 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.
    (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 processing, including testing for hepatitis B surface 
antigen as prescribed in Sec. 610.40 of this chapter.
    (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 
Secs. 600.15 and 610.53 of this chapter.

[[Page 37]]

    (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) Procedure for preparing recovered (salvaged) plasma, if 
performed, including details of separation, pooling, labeling, storage 
and distribution.
    (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.
    (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 following 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]



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 qualified 
licensed physician who is aware of the health status of the donor, and 
the physician has certified in writing that the donor's health permits 
plateletpheresis or leukapheresis.
    (b) Plasmapheresis of donors who do not meet the donor requirements 
of Secs. 640.63, 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]



                   Subpart G--Finished Product Control



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]

[[Page 38]]



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 (except 
Source Plasma) by all blood establishments. Single copies of an FDA 
guideline entitled ``Guideline for the Uniform Labeling of Blood and 
Blood Components'' are available upon request (under Docket No. 80N-
0120) from the Dockets Management Branch (HFA-305), Food and Drug 
Administration, Rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857 
(copies of the guideline are available also from the American Blood 
Commission, 1901 North Ft. Myer Drive, Suite 300, Arlington, VA 22209).
    (b) The label provided by the collecting facility and the initial 
processing facility shall not be removed, altered, or obscured, except 
that the label may be altered to indicate the proper name and other 
information required to identify accurately the contents of a container 
after blood components have been prepared.
    (c) The container label shall 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, and 
modifier(s), if appropriate.
    (2) The name, address, registration number, and, if a licensed 
product, the license number of each manufacturer.
    (3) The donor, pool, or lot number relating the unit to the donor.
    (4) The expiration date, including the day, month, and year, and, if 
the dating period for the product is 72 hours or less, the hour of 
expiration.
    (5) If the product is intended for transfusion, the appropriate 
donor classification statement, i.e., ``paid donor'' or ``volunteer 
donor'', in no less prominence than the proper name of the product.
    (i) A paid donor is a person who receives monetary payment for a 
blood donation.
    (ii) A volunteer donor is a person who does not receive monetary 
payment for a blood donation.
    (iii) 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.
    (6) 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 range 
within reasonable limits.
    (7) The recommended storage temperature (in degrees Celsius).
    (8) If the product is intended for transfusion, the statements:
    (i) ``Caution: Federal law prohibits dispensing without 
prescription.''
    (ii) ``See circular of information for indications, 
contraindications, cautions, and methods of infusion.''
    (iii) ``Properly identify intended recipient.''
    (9) The statement: ``This product may transmit infectious agents.''
    (10) Where applicable, the name and volume of source material.
    (11) The statement: ``Caution: For Manufacturing Use Only'', when 
applicable.
    (12) If the product is intended for transfusion, the ABO and Rh 
groups of the donor shall be designated conspicuously. For 
Cryoprecipitated AHF, the Rh group may be omitted. The Rh group shall be 
designated as follows:
    (i) If the test using Anti-D Blood Grouping Reagent is positive, the 
product shall be labeled: ``Rh positive.''
    (ii) If the test using Anti-D Blood Grouping Reagent is negative but 
the test for Du is positive, the product shall be labeled: ``Rh 
positive.''
    (iii) If the test using Anti-D Blood Grouping Reagent is negative 
and the test for Du is negative, the product shall be labeled: ``Rh 
negative.''
    (13) The container label may bear encoded information in the form of 
machine-readable symbols approved for use by the Director, Center for 
Biologics Evaluation and Research (HFB-1).
    (d) Except for recovered plasma intended for manufacturing use or as 
otherwise approved by the Director, Center for Biologics Evaluation and 
Research (HFB-1), the paper of the container label shall be white and 
print shall be solid black, with the following additional exceptions:

[[Page 39]]

    (1) The Rh blood group shall be printed as follows:
    (i) Rh positive: Use black print on white background.
    (ii) Rh negative: Use white print on black background.
    (2) The proper name of the product, any appropriate modifier(s), the 
donor classification statement, and the statement ``properly identify 
intended recipient'' shall be printed in solid red.
    (3) The following color scheme may be used optionally for 
differentiating ABO Blood groups:

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

    (4) Ink colors used for the optional color coding system described 
in paragraph (d)(3) of this section shall be a visual match to specific 
color samples designated by the Director, Center for Biologics 
Evaluation and Research (HFB-1).
    (5) Special labels, such as those described in paragraphs (h) and 
(i) of this section, may be color coded using the colors recommended in 
the guideline (see paragraph (a) of this section), or colors otherwise 
approved for use by the Director, Center for Biologics Evaluation and 
Research (HFB-1).
    (e) Container label requirements for particular products or groups 
of products.
    (1) Whole Blood labels shall include:
    (i) The volume of anticoagulant.
    (ii) The name of the applicable anticoagulant immediately preceding 
and of no less prominence than the proper name and expressd as follows: 
(a) ACD, (b) CPD, (c) Heparin, (d) CPDA-1, (e) CP2D, or by other 
nomenclature approved for use by the Director, Office of Biologics 
Research and Review (HFN-800), Center for Drugs and Biologics.
    (iii) If tests for unexpected antibodies are positive, blood 
intended for transfusion shall be labeled: ``Contains (name of 
antibody).''
    (2) Except for frozen, deglycerolized, or washed Red Blood Cell 
products, red blood cell labels shall include:
    (i) The volume and kind of Whole Blood, including the type of 
anticoagulant, from 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) Labels for products with a dating period of 72 hours or less, 
including any product prepared in a system that may compromise 
sterility, shall bear the hour of expiration.
    (4) If tests for unexpected antibodies are positive, Plasma intended 
for transfusion shall be labeled: ``Contains (name of antibody).''
    (5) Recovered plasma labels shall include:
    (i) In lieu of an expiration date, the date of collection of the 
oldest material in the container.
    (ii) The statement: ``Caution: For Manufacturing Use Only''; or 
``Caution: For Use in Manufacturing Noninjectable Products Only'', as 
applicable.
    (iii) 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.''
    (f) Blood and blood components determined to be unsuitable for 
transfusion shall be prominently labeled: ``NOT FOR TRANSFUSION'', and 
the label shall state the reason the unit is considered unsuitable. The 
provision does not apply to recovered plasma labeled according to 
paragraph (e)(5) of this section.
    (g) As required under Sec. 610.40 of this chapter, labels for blood 
and blood components that are reactive for Hepatitis B Surface Antigen, 
but that are intended for further manufacturing, shall state 
conspicuously that the material is reactive when tested for hepatitis B 
surface antigen and may transmit viral hepatitis or, as applicable, that 
blood was collected from a donor known to be reactive for hepatitis B 
surface antigen and is presumed to be infectious, although confirmatory 
hepatitis testing has not been done.
    (h) The following additional information shall appear on the label 
for blood or blood components shipped in an emergency, prior to 
completion of

[[Page 40]]

required tests, in accordance with Sec. 640.2(f) of this chapter:
    (1) The statement: ``FOR EMERGENCY USE ONLY BY ________.''
    (2) Results of any tests prescribed under Secs. 610.40, 610.45, and 
640.5 (a), (b), or (c) of this chapter completed before shipment.
    (3) Indication of any tests prescribed under Secs. 610.40, 610.45, 
and 640.5 (a), (b), or (c) of this chapter and not completed before 
shipment.
    (i) The following additional information shall appear on the label 
for Whole Blood or Red Blood Cells intended for autologous infusion:
    (1) Information adequately identifying the patient, e.g., name, 
blood group, hospital, and identification number.
    (2) Date of donation.
    (3) The statement: ``FOR AUTOLOGOUS USE ONLY.''
    (4) In place of the blood group label, each container of blood 
intended for autologous use and obtained from a donor who fails to meet 
any of the donor suitability requirements under Sec. 640.3 of this 
chapter or who is reactive in the hepatitis tests prescribed under 
Sec. 610.40 of this chapter shall be prominently and permanently 
labeled: ``FOR AUTOLOGOUS USE ONLY.''
    (5) Units of blood originally intended for autologous use, except 
those labeled as prescribed under paragraph (i)(4) of this section, may 
be issued for homologous 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 paragraph 
(i) (1), (2), and (3) of this section shall be removed or otherwise 
obscured.
    (j) A tie-tag attached to the container may be used for providing 
the information required by paragraph (e) (1)(iii), (2)(ii), and (4), 
(h), or (i)(1), (2), and (3) of this section.

[50 FR 35469, Aug. 30, 1985, as amended at 53 FR 116, Jan. 5, 1988; 55 
FR 11014, Mar. 26, 1990; 57 FR 10814, Mar. 31, 1992; 59 FR 23636, May 6, 
1994]

    Effective Date Note: The information collection requirements 
contained in Sec. 606.121 will not become effective until OMB approval 
has been obtained. FDA will publish a notice of OMB approval in the 
Federal Register.



Sec. 606.122  Instruction circular.

    An instruction circular shall be available for distribution if the 
product is intended for transfusion. The instruction circular shall 
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) Statements that the product was prepared from blood that was 
negative when tested for antibody to Human Immunodeficiency Virus (HIV) 
and nonreactive for hepatitis B surface antigen by FDA required tests 
and nonreactive when tested for syphilis by a serologic test for 
syphilis (STS).
    (f) The statements: ``Warning. The risk of transmitting hepatitis 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 instruction circular shall 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 instruction circular shall contain:

[[Page 41]]

    (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 instruction circular shall 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 between 
30 and 37  deg.C.
    (3) When applicable, instructions to begin administration of the 
product within 6 hours after thawing.
    (4) Instructions to administer to ABO-group-compatible recipients.
    (5) A statement that this product has the same hepatitis risk as 
Whole Blood; other plasma volume expanders without this risk are 
available for treating hypovolemia.
    (n) For Cryoprecipitated AHF, the instruction circular shall 
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 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 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]

    Effective Date Note: The information collection requirements 
contained in Sec. 606.122 will not become effective until OMB approval 
has been obtained. FDA will publish a notice of OMB approval in the 
Federal Register.



                     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. 606.151   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 samples less than 48 hours old 
for all pretransfusion testing.
    (c) The testing of the donor's cells with the recipient's serum 
(major crossmatch) by a method that will demonstrate agglutinating, 
coating and hemolytic antibodies, which shall include the antiglobulin 
method.
    (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.

[[Page 42]]

    (e) Procedures to expedite transfusions in life-threatening 
emergencies. Records of all such incidents shall be maintained, 
including complete documentation justifying the emergency action, which 
shall be signed by the physician requesting the procedure.



                     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.
    (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 person(s) responsible.
    (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.
    (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) Errors and accidents.
    (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.

[[Page 43]]

    (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. The 
retention period shall be no less than 5 years after the records of 
processing have been completed or 6 months after the latest expiration 
date for the individual product, whichever is a later date. When there 
is no expiration date, records shall be retained indefinitely.
    (e) A record shall be available from which unsuitable donors may be 
identified so that products from such individuals will not be 
distributed.



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 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, Center for 
Biologics Evaluation and Research, shall be notified by telephone or 
telegraph as soon as possible; a written report of the investigation 
shall be submitted to the Director, Office of Compliance, Center for 
Biologics Evaluation and Research, 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.

(Information collection requirements approved by the Office of 
Management and Budget under control number 0910-0116)

[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]



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




                      Subpart A--General Provisions

Sec.
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 and where 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.

[[Page 44]]

607.31  Additional blood product listing information.
607.35  Notification of registrant; blood product establishment 
          registration number and NDC Labeler Code.
607.37  Inspection of establishment registrations and blood product 
          listings.
607.39  Misbranding by reference to establishment registration or to 
          registration number.

     Subpart C--Procedures for Foreign Blood Product Establishments

607.40  Blood product listing requirements for foreign blood product 
          establishments.

                          Subpart D--Exemptions

607.65  Exemptions for blood product establishments.

    Authority: Secs. 201, 301, 501, 502, 505, 510, 701, 704 of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 355, 
360, 371, 374); secs. 215, 351 of the Public Health Service Act (42 
U.S.C. 216, 262).

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



                      Subpart A--General Provisions



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.''
    (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, 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 pursuant to 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 domestic 
establishments within the same parent, subsidiary, and/or affiliate 
company.
    (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.

[40 FR 52788, Nov. 12, 1975, as amended at 55 FR 11014, Mar. 26, 1990]



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

    (a) 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.

[[Page 45]]

Registration and listing of blood products shall comply with this part. 
Registration does not permit any blood bank or similar establishment to 
ship blood products in interstate commerce.
    (b) Forms for registration of an establishment are obtainable on 
request from the Center for Biologics Evaluation and Research (HFB-240), 
8800 Rockville Pike, Bethesda, MD 20892 or at any of the Food and Drug 
Administration district offices.
    (c) The completed form should be mailed to the Center for Biologics 
Evaluation and Research (HFB-240), 8800 Rockville Pike, Bethesda, MD 
20892.

[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 55 
FR 11014, Mar. 26, 1990]



     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 607, that engage in 
the manufacture of blood products are required to register and to submit 
a list of every blood product in commercial distribution (except that 
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), 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 an 
establishment license application to manufacture blood products are 
required to register before the establishment license application is 
approved.
    (c) 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.



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)) for which a license is required, registration 
shall follow within 5 days after the submission of an establishment and 
product license application in order to manufacture blood products. 
Owners or operators of all establishments so engaged shall register 
annually between November 15 and December 31 and shall update their 
blood product listing information every June and December.



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

    (a) The first registration of an establishment shall be on Form FD-
2830 (Blood Establishment Registration and Product Listing) obtainable 
on request from the Department of Health and Human Services, Food and 
Drug Administration, Center for Biologics Evaluation and Research (HFB-
240), 8800 Rockville Pike, Bethesda, MD 20892, or from Food and Drug 
Administration district offices. Subsequent annual registration shall 
also be accomplished on Form FD-2830 which will be furnished by the Food 
and Drug Administration before November 15 of each year to 
establishments whose product registration for that year was validated 
pursuant to Sec. 607.35. The completed form shall be mailed to the above 
address before December 31 of that year.
    (b) The first list of blood products and subsequent June and 
December updatings shall be on Form FD-2830, obtainable upon request as 
described in paragraph (a) of this section. In lieu of Form FD-2830, 
tapes for computer input may be submitted if equivalent

[[Page 46]]

in all elements of information as specified in Form FD-2830. All formats 
proposed for such use will require initial review and approval by the 
Office of Compliance, Center for Biologics Evaluation and Research, Food 
and Drug Administration.

[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 55 
FR 11014, Mar. 26, 1990]



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

    (a) Form FD-2830 (Blood Establishment Registration and Product 
Listing) requires furnishing or confirming registration information 
required by the act. This information includes the name and street 
address of the establishment, including post office ZIP code; 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'' shall 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 shall be given separately for 
each establishment, as defined in Sec. 607.3(c).
    (b) Form FD-2830 also requires furnishing blood product listing 
information required by the act as follows:
    (1) A list of blood products, including bulk product substances as 
well as finished dosage forms, by established name as defined in section 
502(e) of the act and by proprietary name, which are being manufactured 
for commercial distribution and which have not been included in any list 
previously submitted on Form FD-2830 (Blood Establishment Registration 
and Product Listing) or Form FD-2250 (National Drug Code Directory 
Input).
    (2) For each blood product so listed which 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 of every 
blood product establishment within the parent company at which it is 
manufactured.

[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]



Sec. 607.26   Amendments to establishment registration.

    Changes in individual ownership, corporate or partnership structure 
location or blood-product-handling activity, shall be submitted on Form 
FD-2830 (Blood Establishment Registration and Product Listing) as 
amendment to registration within 5 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.



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 
pursuant to Sec. 607.20 shall submit on Form FD-2830 (Blood 
Establishment Registration and Product Listing) during each subsequent 
June and December, or at the discretion of the registrant at the time 
the change occurs, 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) of this 
section and for which commercial distribution has been resumed, 
including for each blood product so listed

[[Page 47]]

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.



Sec. 607.31   Additional blood product listing information.

    (a) In addition to the information routinely required by 
Secs. 607.25 and 607.30, the Commissioner 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 Commissioner for good cause, a copy of all advertisements.
    (2) For a particular blood product so listed, upon a finding by the 
Commissioner 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 Commissioner that it 
is necessary to carry out the purposes of the act, a list of each listed 
blood product containing a particular ingredient.
    (b) It is requested but not required that information concerning the 
quantity of blood product distributed be submitted in conjunction with 
the annual registration in the format prescribed in a section of Form 
FD-2831 (Blood Establishment Resource Summary), for each blood product 
currently listed.



Sec. 607.35   Notification of registrant; blood product establishment registration number and NDC Labeler Code.

    (a) The Commissioner will provide to the registrant a validated copy 
of Form FD-2830 (Blood Establishment Registration and Product Listing) 
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 blood product establishment 
registered in accordance with these regulations.
    (b) If a registered blood product establishment has not previously 
participated in the National Drug Code system, or in the National Health 
Related Items Code system, the National Drug Code (NDC) numbering system 
shall be used in assigning the first five numeric characters, otherwise 
known as the Labeler Code, of the 10-character NDC Code. The Labeler 
Code identifies the manufacturer.
    (c) Although establishment registration and blood product listing 
are required as described in Sec. 607.20, validation of registration and 
the assignment of a NDC Labeler Code do not, in themselves, establish 
that the holder of the registration is legally qualified to deal in such 
products.

[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984]



Sec. 607.37   Inspection of establishment registrations and blood product listings.

    (a) A copy of the Form FD-2830 (Blood Establishment Registration and 
Product Listing) filed by the registrant will be available for 
inspection pursuant to section 510(f) of the act, at the Department of 
Health and Human Services, Food and Drug Administration, Office of 
Compliance, Center for Biologics Evaluation and Research (HFB-100), 8800 
Rockville Pike, Bethesda, MD 20892. In addition, there will be available 
for inspection at each of the Food and Drug Administration district 
offices the same information for firms within the geographical area of 
such district office. Upon request and receipt of a self-addressed 
stamped envelope, verification of registration number, or location of a 
registered establishment will be provided. The following information 
submitted pursuant to the blood product listing requirements is 
illustrative of the type of information that will be available for 
public disclosure when it is compiled:
    (1) A list of all blood products.
    (2) A list of all blood products manufactured by each establishment.
    (3) A list of blood products discontinued.
    (4) All data or information that has already become a matter of 
public knowledge.

[[Page 48]]

    (b) Requests for information regarding blood establishment 
registrations and blood product listings should be directed to the 
Department of Health and Human Services, Food and Drug Administration, 
Office of Compliance, Center for Biologics Evaluation and Research (HFB-
100), 8800 Rockville Pike, Bethesda, MD 20892.

[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 55 
FR 11014, Mar. 26, 1990]



Sec. 607.39   Misbranding by reference to establishment registration or to registration number.

    Registration of an establishment or assignment of a registration 
number or assignment of a NDC number does not in any way denote approval 
of the firm or its products. Any representation that creates an 
impression of official approval because of establishment registration or 
possession of registration number or NDC number is misleading and 
constitutes misbranding.



     Subpart C--Procedures for Foreign Blood Product Establishments



Sec. 607.40   Blood product listing requirements for foreign blood product establishments.

    (a) Every foreign establishment shall comply with the blood product 
listing requirements contained in Subpart B of this part, unless exempt 
under Subpart D of this part, whether or not it is also registered.
    (b) No blood product may be imported from a foreign establishment 
into the United States except a blood product imported or offered for 
import pursuant to the investigational use provisions of part 312 of 
this chapter, unless it is first the subject of a blood product listing 
as required in Subpart B of this part. The blood product listing 
information shall be in the English language.
    (c) Foreign establishments shall submit, as part of the blood 
product listing, the name and address of the establishment and the name 
of the individual responsible for submitting blood product listing 
information. Any changes in this information shall be reported to the 
Food and Drug Administration at the intervals specified for updating 
blood product listing information in Sec. 607.30(a).

[40 FR 52788, Nov. 12, 1975, as amended at 55 FR 11014, Mar. 26, 1990]



                          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), (2), and (3) of the act, or because 
the Commissioner has found, under section 510(g)(4), that such 
registration is not necessary for the protection of the public health.
    (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 approved for 
Medicare

[[Page 49]]

reimbursement and 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) Clinical laboratories that are approved for Medicare 
reimbursement and are engaged in the testing of blood products in 
support of other registered blood establishments.

[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]



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  General safety.
610.11a  Inactivated influenza vaccine, general safety test.
610.12  Sterility.
610.13  Purity.
610.14  Identity.
610.15  Constituent materials
610.16  Total solids in serums.
610.17  Permissible combinations.
610.18  Cultures.
610.19  Status of specific products; Group A streptococcus.

         Subpart C--Standard Preparations and Limits of Potency

610.20  Standard preparations.
610.21  Limits of potency.

                          Subpart D--Mycoplasma

610.30  Test for Mycoplasma.

                    Subpart E--Hepatitis Requirements

610.40  Test for hepatitis B surface antigen.
610.41  History of hepatitis B surface antigen.
610.45  Human Immunodeficiency Virus (HIV) requirements.

                  Subpart F--Dating Period Limitations

610.50  Date of manufacture.
610.53  Dating periods for licensed biological products .

                      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 of selling agent or distributor.
610.65  Products for export.

    Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360, 
371); secs. 215, 351, 352, 353, 361 of the Public Health Service Act (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.

[[Page 50]]



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

    (a) General. Samples of any lot of any licensed product, except for 
radioactive biological products, 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. 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) Radioactive biological products. Samples of any lot of a 
radioactive biological product, as defined in Sec. 600.3(ee) of this 
chapter, together with the protocols showing results of applicable 
tests, may at any time be required to be sent to the Food and Drug 
Administration for official release. Upon notification by the Director, 
Center for Drug Evaluation and Research, a manufacturer shall not 
distribute a lot of a radioactive 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.

(Information collection requirements approved by the Office of 
Management and Budget under control number 0910-0206)

[40 FR 31313, July 25, 1975, as amended by 49 FR 23834, June 8, 1984; 50 
FR 10941, Mar. 19, 1985; 55 FR 11013 and 11014, Mar. 26, 1990]



                      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 manufacturer presents evidence, in the form of a product 
license supplement, 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 (HFB-1), 8800 
Rockville Pike, Bethesda, MD 20892.

[49 FR 15187, Apr. 18, 1984; 49 FR 21317, May 21, 1984, as amended at 51 
FR 15607, Apr. 25, 1986; 55 FR 11014, Mar. 26, 1990; 59 FR 49351, Sept. 
28, 1994]



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   General safety.

    A general safety test for the detection of extraneous toxic 
contaminants shall be performed on biological products intended for 
administration to humans. The general safety test is required in 
addition to other specific tests prescribed in the additional standards 
for individual products in this subchapter, except that, the test need 
not be performed on those products listed in paragraph (g) of this 
section. The general safety test shall be performed as specified in this 
section, unless: Modification is prescribed in the additional standards 
for specific products, or variation is approved as a supplement to the 
product license under Sec. 610.9.
    (a) Product to be tested. The general safety test shall be conducted 
upon a representative sample of the product in the final container from 
every final filling of each lot of the product. If any product is 
processed further after filling, such as by freeze-drying, 
sterilization, or heat treatment, the test shall be conducted upon a 
sample from each

[[Page 51]]

filling of each drying chamber run, sterilization chamber, or heat 
treatment bath.
    (b) Test animals. Only overtly healthy guinea pigs weighing less 
than 400 grams each and mice weighing less than 22 grams each shall be 
used. The animals shall not have been used previously for any test 
purpose.
    (c) Procedure. The duration of the general safety test shall be 7 
days for both species, except that a longer period may be established 
for specific products in accordance with Sec. 610.9. Once the 
manufacturer has established a specific duration of the test period for 
a specific product, it cannot be varied subsequently, except, in 
accordance with Sec. 610.9. Each test animal shall be weighed and the 
individual weights recorded immediately prior to injection and on the 
last day of the test. Each animal shall be observed every working day. 
Any animal response including any which is not specific for or expected 
from the product and which may indicate a difference in its quality 
shall be recorded on the day such response is observed. The test product 
shall be administered as follows:
    (1) Liquid product or freeze-dried product which has been 
reconstituted as directed on the label. Inject intraperitoneally 0.5 
milliliter of the liquid product or the reconstituted product into each 
of at least two mice, and 5.0 milliliters of the liquid product or the 
reconstituted product into each of at least two guinea pigs.
    (2) Freeze-dried product for which the volume of reconstitution is 
not indicated on the label. The route of administration, test dose, and 
diluent shall be as approved by the Director, Center for Biologics 
Evaluation and Research, in accordance with Sec. 610.9. Administer the 
test product as approved on at least two mice and at least two guinea 
pigs.
    (3) Nonliquid products other than freeze-dried product. The route of 
administration, test dose, and diluent shall be as approved by the 
Director, Center for Biologics Evaluation and Research, in accordance 
with Sec. 610.9. Dissolve or grind and suspend the product in the 
approved diluent. Administer the test product as approved on at least 
two mice and at least two guinea pigs.
    (d) Test requirements. A safety test is satisfactory if all animals 
meet all of the following requirements:
    (1) They survive the test period.
    (2) They do not exhibit any response which is not specific for or 
expected from the product and which may indicate a difference in its 
quality.
    (3) They weigh no less at the end of the test period than at the 
time of injection.
    (e) Repeat tests--(1) First repeat test. If a filling fails to meet 
the requirements of paragraph (d) of this section in the initial test, a 
repeat test may be conducted on the species which failed the initial 
test, as prescribed in paragraph (c) of this section. The filling is 
satisfactory only if each retest animal meets the requirements 
prescribed in paragraph (d) of this section.
    (2) Second repeat test. If a filling fails to meet the requirements 
of the first repeat test, a second repeat test may be conducted on the 
species which failed the test: Provided, That 50 percent of the total 
number of animals in that species has survived the initial and first 
repeat tests. The second repeat test shall be conducted as prescribed in 
paragraph (c) of this section, except that the number of animals shall 
be twice that used in the first repeat test. The filling is satisfactory 
only if each second repeat test animal meets the requirements prescribed 
in paragraph (d) of this section.
    (f) [Reserved]
    (g) Exceptions. The test prescribed in this section need not be 
performed for Whole Blood, Red Blood Cells, Cryoprecipitated AHF, 
Platelets, or Plasma.

[41 FR 10891, Mar. 15, 1976, as amended at 49 FR 15187, Apr. 18, 1984; 
49 FR 23834, June 8, 1984; 50 FR 4133, Jan. 29, 1985; 51 FR 15607, Apr. 
25, 1986; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994]



Sec. 610.11a   Inactivated influenza vaccine, general safety test.

    For inactivated influenza vaccine, the general safety test shall be 
conducted in the manner indicated in Sec. 610.11 of this chapter except 
that, with reference to guinea pigs, the test shall be satisfied if the 
product provides satisfactory results using either the subcutaneous or 
intraperitoneal injection

[[Page 52]]

of 5.0 milliliters of inactivated influenza vaccine into each guinea 
pig. The requirements for general safety for inactivated influenza 
vaccine shall not be considered to be satisfied unless each lot of 
influenza vaccine is assayed for endotoxin in comparison to a reference 
preparation provided by the Food and Drug Administration, and such lot 
is found to contain no more endotoxin than the reference preparation.

[39 FR 40016, Nov. 13, 1974]



Sec. 610.12  Sterility.

    Except as provided in paragraphs (f) and (g) of this section, the 
sterility of each lot of each product shall be demonstrated by the 
performance of the tests prescribed in paragraphs (a) and (b) of this 
section for both bulk and final container material.
    (a) The test. Bulk material shall be tested separately from final 
container material and material from each final container shall be 
tested in individual test vessels as follows:
    (1) Using Fluid Thioglycollate Medium--(i) Bulk and final container 
material. The volume of product, as required by paragraph (d) of this 
section (hereinafter referred to also as the ``inoculum''), from samples 
of both bulk and final container material, shall be inoculated into test 
vessels of Fluid Thioglycollate Medium. The inoculum and medium shall be 
mixed thoroughly and incubated at a temperature of 30 to 35  deg.C for a 
test period of no less than 14 days and examined visually for evidence 
of growth on the third, fourth, or fifth day, and on the seventh or 
eighth day, and on the last day of the test period. Results of each 
examination shall be recorded. If the inoculum renders the medium turbid 
so that the absence of growth cannot be determined reliably by visual 
examination, portions of this turbid medium in amounts of no less than 
1.0 milliliter shall be transferred on the third, fourth, or fifth day 
of incubation, from each of the test vessels and inoculated into 
additional vessels of the medium. The material in the additional vessels 
shall be incubated at a temperature of 30 to 35  deg.C for no less than 
14 days. Notwithstanding such transfer of material, examination of the 
original vessels shall be continued as prescribed above. The additional 
test vessels shall be examined visually for evidence of growth on the 
third, fourth, or fifth day of incubation, and on the seventh or eighth 
day, and on the last day of the incubation period. If growth appears, 
repeat tests may be performed as prescribed in paragraph (b) of this 
section and interpreted as specified in paragraph (c) of this section.
    (ii) Final container material containing a mercurial preservative. 
In addition to the test prescribed in paragraph (a)(1)(i) of this 
section, final container material containing a mercurial preservative 
shall be tested using Fluid Thioglycollate Medium following the 
procedures prescribed in such subparagraph, except that the incubation 
shall be at a temperature of 20 deg. to 25 deg. C.
    (2) Using Soybean-Casein Digest Medium. Except for products 
containing a mercurial preservative, a test shall be made on final 
container material, following the procedures prescribed in paragraph 
(a)(1)(i) of this section, except that the medium shall be Soybean-
Casein Digest Medium and the incubation shall be at a temperature of 
20 deg. to 25 deg. C.
    (b) Repeat tests. If growth appears in any of the test media during 
testing of either bulk or final container material, the test may be 
repeated to rule out faulty test procedures as follows:
    (1) Repeat bulk test. Only one repeat bulk test may be conducted. 
The volume of inoculum to be used for the repeat bulk test shall be as 
prescribed in paragraph (d)(1) of this section. The repeat test shall be 
performed using the procedure prescribed in paragraph (a)(1)(i) of this 
section.
    (2) First repeat final container test. The number of test samples 
and the volumes of product used for the first repeat test shall be as 
prescribed in paragraph (d)(2) of this section. For products that do not 
contain a mercurial preservative, the repeat test shall be performed, 
using both Fluid Thioglycollate Medium and Soybean-Casein Digest Medium, 
following the procedures prescribed in paragraphs (a)(1)(i) and (a)(2), 
respectively, of this section. If the product contains a mercurial 
preservative, the repeat test shall be performed using Fluid

[[Page 53]]

Thioglycollate Medium and the procedures prescribed in paragraphs (a)(1) 
(i) and (ii) of this section.
    (3) Second repeat final container test. If growth appears in any of 
the first repeat final container tests, all tests of the first repeat 
final container test shall be repeated, provided there was no evidence 
of growth in any test of the bulk material. The test samples used for 
the second repeat final container test shall be twice the number used 
for the first repeat final container test.
    (c) Interpretation of test results. The results of all tests 
performed on a lot shall be considered in determining whether or not the 
lot meets the requirements for sterility, except that tests may be 
excluded when demonstrated by adequate controls to be invalid. The lot 
meets the test requirements if no growth appears in the tests prescribed 
in paragraph (a) of this section. If repeat tests are performed, the lot 
meets the test requirements if no growth appears in the tests prescribed 
in paragraph (b)(2) or (3) of this section, whichever is applicable.
    (d) Test samples and volumes--(1) Bulk. Each sample for the bulk 
sterility test shall be representative of the bulk material and the 
volume tested shall be no less than 10 ml. (Note exceptions in paragraph 
(g) of this section.)
    (2) Final containers. The sample used for each test medium or each 
incubation temperature of a test medium for the final container and 
first repeat final container test shall be no less than 20 final 
containers from each filling of each lot, selected to represent all 
stages of filling from the bulk vessel. If the amount of material in the 
final container is 1.0 milliliter or less, the entire contents shall be 
tested. If the amount of material in the final container is more than 
1.0 milliliter, the volume tested shall be the largest single dose 
recommended by the manufacturer or 1.0 milliliter, whichever is larger, 
but no more than 10 milliliters of material or the entire contents from 
a single final container need be tested. If more than 2 filling 
machines, each with either single or multiple filling stations, are used 
for filling one lot, no less than 10 filled containers shall be tested 
from each filling machine for each test medium or each incubation 
temperature condition, but no more than 100 containers of each lot need 
be tested. The items tested shall be representative of each filling 
assembly and shall be selected to represent all stages of the filling 
operation. (Note exceptions in paragraph (g) of this section.)
    (e) Culture medium--(1) Formulae. (i) The formula for Fluid 
Thioglycollate Medium is as follows:

                       Fluid Thioglycollate Medium                      
1-cystine................................  0.5 Gm.                      
Sodium chloride..........................  2.5 Gm.                      
Dextrose (C6H12O6H2O)..........  5.5 Gm.                      
Granular agar (less than 15% moisture by   0.75 Gm.                     
 weight).                                                               
Yeast extract (water-soluble)............  5.0 Gm.                      
Pancreatic digest of casein..............  15.0 Gm.                     
Purified water...........................  1,000.0 ml.                  
Sodium thioglycollate (or thioglycolic     0.5 Gm.                      
 acid--0.3 ml).                                                         
Resazurin (0.10% solution, 1.0 ml.                                      
 freshly prepared).                                                     
pH after sterilization 7.1plus-minus0.2.                                
                                                                        

    (ii) The formula for Soybean-Casein Digest Medium is as follows:

                      Soybean-Casein Digest Medium                      
Pancreatic Digest of Casein..............  17.0 Gm.                     
Papaic Digest of Soybean Meal............  3.0 Gm.                      
Sodium Chloride..........................  5.0 Gm.                      
Dibasic Potassium Phosphate..............  2.5 Gm.                      
Dextrose (C6H12O6H2O)..........  2.5 Gm.                      
Purified water...........................  1,000.0 ml.                  
pH after sterilization 7.3plus-minus0.2.                                
                                                                        

    (2) Culture media requirements--(i) Definition of a lot of culture 
medium and test requirements. A lot of culture medium is that quantity 
of uniform material identified as having been thoroughly mixed in a 
single vessel, dispensed into a group of vessels of the same composition 
and design, sterilized in a single autoclave run, and identified in a 
manner to distinguish one lot from another. Each lot of culture medium 
shall be tested for its growth-promoting qualities unless it meets the 
exception for dehydrated culture medium described in this subpart. The 
growth-promoting quality test shall be performed on the smallest sized 
vessel used in an autoclave run. When using a single batch of dehydrated 
culture medium, a manufacturer need not perform growth-promoting tests 
on each lot of prepared liquid medium, provided that a validation 
program exists for autoclaves used to sterilize the culture

[[Page 54]]

medium, and the manufacturer has received approval for this practice 
from the Director, Center for Biologics Evaluation and Research.
    (ii) Test organisms, strains, characteristics, identity, and 
verification. Two or more strains of microorganisms that are exacting in 
their nutritive and aerobic/anaerobic requirements shall be used to test 
the growth-promoting qualities of each lot of test medium. When using 
Fluid Thioglycollate medium, both an aerobic and an anaerobic test 
microorganism shall be chosen. When using Soybean Casein Digest Medium, 
the yeast, Candida albicans, shall be one of the two test microorganisms 
chosen. Manufacturers shall choose the strains of microorganisms from 
the chart in this paragraph.

------------------------------------------------------------------------
                                                            Incubation  
             Medium                Test microorganisms     temperature  
------------------------------------------------------------------------
                                 Spore-formers                          
                                                                        
Fluid Thioglycollate...........  1. Bacillus subtilis    30 to 35       
                                  (ATCC No. 6633).        deg.C.        
                                 2. Clostridium              Do.        
                                  sporogenes (ATCC No.                  
                                  11437).                               
                                                                        
                                 Non-spore-formers                      
                                                                        
                                 3. Candida albicans         Do.        
                                  (ATCC No. 10231).                     
                                 4. Micrococcus luteus       Do.        
                                  (ATCC No. 9341).                      
                                 5. Bacteroides              Do.        
                                  vulgatus (ATCC No.                    
                                  8482).                                
                                                                        
                                 Spore-formers                          
                                                                        
Soybean-Casein Digest..........  1. Bacillus subtilis    20 to 25       
                                  (ATCC No. 6633).        deg.C.        
                                                                        
                                 Non-spore-formers                      
                                                                        
                                 2. Candida albicans         Do.        
                                  (ATCC No. 10231).                     
                                 3. Micrococcus luteus       Do.        
                                  (ATCC No. 9341).                      
------------------------------------------------------------------------

    ATCC strains of microorganisms described in this section are 
available from the American Type Culture Collection, 12301 Parklawn Dr., 
Rockville, MD 20852. Periodic tests shall be performed to verify the 
integrity of the test organisms in accordance with Sec. 610.18 (a) and 
(b). The results of these periodic tests shall be recorded and retained 
in accordance with Sec. 600.12(b) of this chapter.
    (iii) Storage and maintenance of cultures of test organisms. 
Cultures of the test organisms used to determine the growth-promoting 
qualities of the medium shall be stored in a manner that will prevent 
cross contamination or loss of identity, at a temperatre and by a method 
that will retain the initial characteristics of the organisms and ensure 
freedom from contamination and deterioration. If the test organisms are 
stored in the freeze-dried state, or frozen, they shall be reconstituted 
or thawed, whichever is applicable, and plated periodically to verify 
the colony count of the suspension. If the test suspensions are stored 
in a state other than freeze-dried or frozen, they shall be plated, and 
a colony count shall be performed at the time of each growth-promoting 
quality test to assure that not more than 100 organisms are used per 
test vessel. The results of tests for verification of the colony count 
shall be recorded and retained in accordance with Sec. 600.12(b) of this 
chapter.
    (iv) Storage and condition of media. A medium shall not be used if 
the extent of evaporation affects its fluidity, nor shall it be reused 
in a sterility test of the product. Fluid Thioglycollate Medium shall be 
stored in the dark at room temperature if the vessels are unsealed. 
Sealed vessels shall be stored at the manufacturer's specified storage 
temperature.
    Fluid Thioglycollate Medium shall not be used if more than the upper 
one-third of the medium has acquired a pink color. The medium may be 
restored once by heating on a steam bath or in free-flowing steam until 
the pink color disappears. The design of the test vessel for Fluid 
Thioglycollate Medium shall provide favorable aerobic and anaerobic 
conditions for growth of the microorganisms throughout the test period. 
Soybean-Casein Digest Medium shall be stored in the dark at 20 to 25 
deg.C. Unsealed vessels of either medium may be stored for more than 10 
days at the proper temperature, provided they

[[Page 55]]

are tested monthly for growth-promotion and found to be satisfactory. 
Sealed vessels of either medium may be stored at the proper temperature 
for a period of time not to exceed 1 year, provided they are tested for 
growth-promotion every 3 months and found to be satisfactory. The 
results of such testing shall be recorded and retained in accordance 
with Sec. 600.12(b) of this chapter.
    (v) Criteria for a satisfactory growth-promoting quality test. (a) 
One hundred or fewer organisms of each strain tested shall be used. The 
test is satisfactory if evidence of growth appears within 7 days in all 
vessels inoculated. If a lot of medium fails to support the growth of 
any test organism, or if the test results show that more than 100 
organisms of a strain were used or are necessary to promote growth in 
the lot of medium being tested, or if the growth is not a pure culture 
of the test organism, a second test may be performed. If it fails the 
second test, the lot of medium shall be rejected.
    (b) Inoculated Fluid Thioglycollate Medium shall be incubated at 30 
to 35  deg.C for 7 days. If the test medium is to be used in determining 
the sterility of a product containing a mercurial preservative, a second 
test shall be performed in accordance with paragraph (e)(2)(v)(a) of 
this section, except that the test shall be incubated at 20 to 25  deg.C 
for 7 days. Inoculated Soybean-Casein Digest Medium shall be incubated 
at 20 to 25  deg.C for 7 days. The sterility of each lot of medium shall 
be confirmed by the incubation of uninoculated control test vessels for 
7 days at the temperature(s) for that particular medium. The lot of 
medium is satisfactory if no growth is observed in the control test 
vessels within the incubation period. The tests for growth-promoting 
qualities of culture media may be performed simultaneously with 
sterility testing of biological products, provided the sterility test is 
considered invalid if the test medium shows no growth response.
    (vi) Volume of culture medium. The volume of each culture medium 
shall be determined for each bulk and final container sterility test 
required for each product. The ratio of the volume of inoculum to the 
volume of culture medium shall result in a dilution of the product that 
is not bacteriostatic or fungistatic, except for products to be tested 
by membrane filtration. The volume of inhibitors or neutralizers of 
preservatives added should be considered in determining the proper ratio 
of inoculum/medium. Vessels of the product-medium mixture(s) and control 
vessels of the medium shall be inoculated with dilutions of cultures of 
bacteria or fungi which are viable in the product being tested, and 
incubated at the appropriate temperature for no less than 7 days.
    (f) Membrane filtration. Bulk and final container material or 
products containing oil products in water-insoluble ointments may be 
tested for sterility using the membrane filtration procedure set forth 
in the United States Pharmacopeia (21st Revision, 1985), section 
entitled ``Test Procedures Using Membrane Filtration,'' p. 1159, which 
is incorporated by reference (copies are available from the United 
States Pharmacopeial Convention Inc., 12601 Twinbrook Parkway, 
Rockville, MD 20852, or available for inspection at the Office of the 
Federal Register, 800 North Capitol Street, NW., suite 700, Washington, 
DC 20408), except that (1) the test samples shall conform with paragraph 
(d) of this section; and (2) in addition, for products containing a 
mercurial preservative, the product shall be tested in a second test 
using Fluid Thioglycollate Medium incubated at 20 to 25  deg.C in lieu 
of the test in Soybean-Casein Digest Medium.
    (g) Exceptions. Bulk and final container material shall be tested 
for sterility as described above in this section, except as follows:
    (1) Different sterility tests prescribed. When different sterility 
tests are prescribed for a product in this subchapter.
    (2) Alternate incubation temperatures. Two tests may be performed as 
prescribed in paragraph (a)(1)(i) of this section, one test using an 
incubation temperature of 18 to 22  deg.C, the other test using an 
incubation temperature of 30 to 37  deg.C, in lieu of performing one 
test using an incubation temperature of 30 to 35  deg.C, provided that 
growth-promoting quality tests have been performed at these 
temperatures.

[[Page 56]]

    (3) [Reserved]
    (4) Test precluded or not required. (i) The tests prescribed in this 
section need not be performed for Whole Blood, Cryoprecipitated AHF, 
Platelets, Red Blood Cells, Plasma, Source Plasma, Smallpox Vaccine, 
Reagent Red Blood Cells, Anti-Human Globulin, or Blood Grouping Reagent.
    (ii) Where a manufacturer submits data which the Director, Center 
for Biologics Evaluation and Research, finds adequate to establish that 
the mode of administration, the method of preparation, or the special 
nature of the product precludes or does not require a sterility test or 
that the sterility of the lot is not necessary to assure the safety, 
purity, and potency of the product, the Director may exempt a product 
from the sterility requirements of this section subject to any 
conditions necessary to assure the safety, purity, and potency of the 
product.
    (5) Number of final containers more than 20, less than 200. If the 
number of final containers in the filling is more than 20 or less than 
200, the sample shall be no less than 10 percent of the containers.
    (6) Number of final containers--20 or less. If the number of final 
containers in a filling is 20 or less, the sample shall be two final 
containers, or the sample need be no more than one final container, 
provided (i) the bulk material met the sterility test requirements and 
(ii) after filling, it is demonstrated by testing a simulated sample 
that all surfaces to which the product was exposed were free of 
contaminating microorganisms. The simulated sample shall be prepared by 
rinsing the filling equipment with sterile 1.0 percent peptone solution, 
pH 7.1plus-minus0.1, which shall be discharged into a final 
container by the same method used for filling the final containers with 
the product.
    (7) Samples--large volume of product in final containers. For 
Albumin (Human) and Plasma Protein Fraction (Human), when the volume of 
product in the final container is 50 milliliters or more, the final 
containers selected as the test sample may contain less than the full 
volume of product in the final containers of the filling from which the 
sample is taken: Provided, That the containers and closures of the 
sample are identical with those used for the filling to which the test 
applies, and the sample represents all stages of that filling.
    (8) Diagnostic biological products not intended for injection. For 
diagnostic biological products not intended for injection, (i) only the 
Fluid Thioglycollate Medium test incubated at 30 to 35  deg.C is 
required, (ii) the volume of material for the bulk test shall be no less 
than 2.0 milliliters, and (iii) the sample for the final container test 
shall be no less than three final containers if the total number filled 
is 100 or less, and, if greater, one additional container for each 
additional 50 containers or fraction thereof, but the sample need be no 
more than 10 containers.
    (9) Immune globulin preparations. For immune globulin preparations, 
the test samples from the bulk material and from each final container 
need be no more than 2.0 ml.
    (h) Records. The records related to the testing requirements of this 
section shall be prepared and maintained as required by Secs. 211.167 
and 211.194 of this chapter.

(Information collection requirements approved by the Office of 
Management and Budget under control number 0910-0139)

[38 FR 32056, Nov. 20, 1973, as amended at 41 FR 4015, Jan. 28, 1976; 41 
FR 10428, Mar. 11, 1976; 44 FR 11754, Mar. 2, 1979; 49 FR 15187, Apr. 
18, 1984; 49 FR 23834, June 8, 1984; 50 FR 4133, Jan. 29, 1985; 51 FR 
44906, Dec. 15, 1986; 53 FR 12764, Apr. 19, 1988; 55 FR 11013, Mar. 26, 
1990]



Sec. 610.13   Purity.

    Products shall be free of extraneous material except that which is 
unavoidable in the manufacturing process described in the approved 
license. 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 
product license application. The test for residual moisture may be 
exempted by the Director, Center for Biologics Evaluation and Research, 
when deemed not necessary for the continued

[[Page 57]]

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 Secs. 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.

(Information collection requirements were approved by the Office of 
Management and Budget (OMB) and assigned OMB control number 0910-0139)

[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]



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

[[Page 58]]

labeled for use with the jet injector; 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.
    (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.

[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]



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 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

[[Page 59]]

the applicable provisions of Secs. 211.188 and 211.194 of this chapter.

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

[38 FR 32056, Nov. 20, 1973, as amended at 51 FR 44453, Dec. 10, 1986; 
55 FR 11013, Mar. 26, 1990]



Sec. 610.19  Status of specific products; Group A streptococcus.

    The presence of Group A streptococcus organisms and derivatives of 
Group A streptococcus in Bacterial Vaccines and Bacterial Antigens with 
``No U.S. Standard of Potency'' may induce dangerous tissue reactions in 
humans. Available data demonstrate that they are unsafe as ingredients 
in products for human use. Group A streptococcus organisms and 
derivatives of Group A streptococcus are prohibited from Bacterial 
Vaccines and Bacterial Antigens with ``No U.S. Standard of Potency.'' 
Any Bacterial Vaccine or Bacterial Antigen with ``No U.S. Standard of 
Potency'' containing Group A streptococcus organisms or derivatives of 
Group A streptococcus in interstate commerce is in violation of section 
351 of the Public Health Service Act (42 U.S.C. 262).

[44 FR 1549, Jan. 5, 1979]



         Subpart C--Standard Preparations and Limits of Potency



Sec. 610.20   Standard preparations.

    Standard preparations made available by the Center for Biologics 
Evaluation and Research shall be applied in testing, as follows:
    (a) Potency standards. Potency standards shall be applied in testing 
for potency all forms of the following:

                               Antibodies

Botulism Antitoxin, Type A.
Botulism Antitoxin, Type B.
Botulism Antitoxin, Type E.
Diphtheria Antitoxin.
Histolyticus Antitoxin.
Oedematiens Antitoxin.
Perfringens Antitoxin.
Antipertussis Serum.
Antirabies Serum.
Sordellii Antitoxin.
Staphylococcus Antitoxin.
Tetanus Antitoxin.
Vibrion Septique Antitoxin.

                                Antigens

Cholera Vaccine, Inaba serotype.
Cholera Vaccine, Ogawa serotype.
Diphtheria Toxin for Schick Test.
Pertussis Vaccine.
Tuberculin, Old.
Tuberculin, Purified Protein Derivative.
Typhoid Vaccine.

                            Blood Derivative

Thrombin.

    (b) Opacity standard. The U.S. Opacity Standard shall be applied in 
estimating the bacterial concentration of all bacterial vaccines. The 
assigned value of the standard when observed visually is 10 units. The 
assigned value of the standard when observed with a photometer is (1) 10 
units when the wavelength of the filter is 530 millimicrons, (2) 10.6 
units when the wavelength of the filter is 650 millimicrons, and (3) 9 
units when the wavelength of the filter is 420 millimicrons.

[38 FR 32056, Nov. 20, 1973, as amended at 41 FR 10429, Mar. 11, 1976; 
41 FR 18295, May 3, 1976; 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 
26, 1990]



Sec. 610.21   Limits of potency.

    The potency of the following products shall be not less than that 
set forth below and products dispensed in the dried state shall 
represent liquid products having the stated limitations.

                               Antibodies

Diphtheria Antitoxin, 500 units per milliliter.
Tetanus Antitoxin, 400 units per milliliter.
Tetanus Immune Globulin (Human), 50 units of tetanus antitoxin per 
milliliter.

                                Antigens

Cholera Vaccine, 8 units each of Inaba and Ogawa serotype antigens per 
milliliter.
Pertussis Vaccine, 12 units per total human immunizing dose.
Typhoid Vaccine, 8 units per milliliter.

[41 FR 10429, Mar. 11, 1976, as amended at 41 FR 18295, May 3, 1976]

[[Page 60]]



                          Subpart D--Mycoplasma



Sec. 610.30   Test for Mycoplasma.

    Except as provided otherwise in this subchapter, prior to 
clarification or filtration in the case of live virus vaccines produced 
from in vitro living cell cultures, and prior to inactivation in the 
case of inactivated virus vaccines produced from such living cell 
cultures, each virus harvest pool and control fluid pool shall be tested 
for the presence of Mycoplasma, as follows:

    Samples of the virus for this test shall be stored either (1) 
between 2 deg. and 8 deg. C. for no longer than 24 hours, or (2) at 
-20 deg. C. or lower if stored for longer than 24 hours. The test shall 
be performed on samples of the viral harvest pool and on control fluid 
pool obtained at the time of viral harvest, as follows: No less than 2.0 
ml. of each sample shall be inoculated in evenly distributed amounts 
over the surface of no less than 10 plates of at least two agar media. 
No less than 1.0 ml. of sample shall be inoculated into each of four 
tubes containing 10 ml. of a semisolid broth medium. The media shall be 
such as have been shown to be capable of detecting known Mycoplasma and 
each test shall include control cultures of at least two known strains 
of Mycoplasma, one of which must be M. pneumoniae. One half of the 
plates and two tubes of broth shall be incubated aerobically at 36 deg. 
C. plus-minus1 deg. C. and the remaining plates and tubes shall be 
incubated anaerobically at 36 deg. C. plus-minus1 deg. C. in an 
environment of 5-10 percent CO2 in N2. Aerobic incubation 
shall be for a period of no less than 14 days and the broth in the two 
tubes shall be tested after 3 days and 14 days, at which times 0.5 ml. 
of broth from each of the two tubes shall be combined and subinoculated 
on to no less than 4 additional plates and incubated aerobically. 
Anaerobic incubation shall be for no less than 14 days and the broth in 
the two tubes shall be tested after 3 days and 14 days, at which times 
0.5 ml. of broth from each of the two tubes shall be combined and 
subinoculated onto no less than four additional plates and incubated 
anaerobically. All inoculated plates shall be incubated for no less than 
14 days, at which time observation for growth of Mycoplasma shall be 
made at a magnification of no less than 300 x . If the Dienes Methylene 
Blue-Azure dye or an equivalent staining procedure is used, no less than 
a one square cm. plug of the agar shall be excised from the inoculated 
area and examined for the presence of Mycoplasma. The presence of the 
Mycoplasma shall be determined by comparison of the growth obtained from 
the test samples with that of the control cultures, with respect to 
typical colonial and microscopic morphology. The virus pool is 
satisfactory for vaccine manufacture if none of the tests on the samples 
show evidence of the presence of Mycoplasma.



                    Subpart E--Hepatitis Requirements



Sec. 610.40   Test for hepatitis B surface antigen.

    (a) Test sensitivity. Each donation of blood, plasma, or serum to be 
used in preparing a biological product shall be tested for the presence 
of hepatitis B surface antigen by a method of sufficient sensitivity to 
detect all sera labeled A, (A), B, (B), and C in the Reference Hepatitis 
B Surface Antigen Panel distributed by the Center for Biologics 
Evaluation and Research; except that, in emergency situations, a test 
method of sufficient sensitivity to detect all sera labeled A, (A), and 
B in the Reference Hepatitis B Surface Antigen Panel may be used and, in 
dire emergency situations, blood and blood products may be issued 
without any HB8Ag testing, provided that a test otherwise required 
by this paragraph is performed as soon as possible after issuance of the 
blood and blood product.
    (b) Procedures. Only Antibody to Hepatitis B Surface Antigen 
licensed under this subchapter shall be used in performing the test and 
the test method(s) used shall be that for which the antibody product is 
specifically designed to be effective as recommended by the manufacturer 
in the package insert. The sample of blood, plasma, or serum to be 
tested shall have been taken from the donor at the time of donation of 
that unit. The test need not be performed on the day of the withdrawal 
of the sample. If the radioimmunoassay method is used, it must be 
performed in one of the following ways:
    (1) The complete test is performed at the collection facility.
    (2) The test is performed at the collection facility up to the point 
of counting the radioactivity of the samples, which counting, 
thereafter, is performed at another facility by personnel from the 
collection facility or by personnel from the counting facility.
    (3) The complete test is performed by the personnel at an 
establishment licensed to manufacture blood or blood derivatives under 
section 351(a) of the

[[Page 61]]

Public Health Service Act (42 U.S.C. 262(a)), or by a clinical 
laboratory which meets the standards of the Clinical Laboratories 
Improvement Act of 1967 (CLIA) (42 U.S.C. 263a), provided the 
establishment or the clinical laboratory is qualified to perform 
radioimmunoassay testing for the presence of hepatitis B surface 
antigen.
    (4) Except as provided in this paragraph (b)(4), a collection 
facility shall not ship any blood product as a biological product or 
ship such a blood product where it is intended for use in manufacturing 
a biological product until the test for hepatitis B surface antigen is 
completed and the written test results are received by the collection 
facility. Notwithstanding the provisions of Sec. 610.1 of this chapter, 
in the case of an emergency, or as otherwise approved in writing by the 
Director, Center for Biologics Evaluation and Research, a collection 
facility may ship a blood product before the test for hepatitis B 
surface antigen is completed. To obtain approval for such shipments, the 
collection facility shall submit a description of the control procedures 
to be used by both the collection facility and the manufacturing 
facility to the Director, Center for Biologics Evaluation and Research 
(HFB-1), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 
20892. The control procedures to be used by the collection facility and 
the manufacturing facility shall include, but may not be limited to, a 
system of communicating the test results to the manufacturing facility, 
use of specific labeling warnings for the product to ensure that persons 
handling the shipment know that it may be infectious, procedures for 
quarantine of the untested or incompletely tested product both at the 
collection facility and at the manufacturing facility, and a procedure 
at the manufacturing facility to identify, preclude use of, and dispose 
of any blood product that is received and later found to be reactive for 
hepatitis B surface antigen.
    (c) Materials in storage. All blood, plasma, or serum in storage 
which has not been tested for the presence of the hepatitis B surface 
antigen shall be tested as required in paragraphs (a) and (b) of this 
section before use as a biological product, or before use in the 
manufacture of a biological product. All blood, plasma, or serum in 
storage which has been tested for the presence of the hepatitis B 
surface antigen by a method of second generation sensitivity may be used 
as a biological product or in manufacture of a biological product, 
provided it is used on or before March 15, 1976.
    (d) Restrictions on use. Blood, plasma, or serum that is reactive 
when tested for hepatitis B surface antigen or that was collected from a 
donor known to be reactive for hepatitis B surface antigen shall not be 
used in manufacturing biological products except as provided in 
paragraphs (d) (1) and (2) of this section.
    (1) Injectable biological products and licensed in vitro diagnostic 
biological products. Blood, plasma, or serum that is reactive when 
tested for hepatitis B surface antigen or that was collected from a 
donor known to be reactive for hepatitis B surface antigen may be used 
in manufacturing hepatitis B vaccine and licensed in vitro diagnostic 
biological products if all of the following conditions are met:
    (i) The final product cannot be prepared from blood, plasma, or 
serum that is nonreactive when tested for hepatitis B surface antigen, 
due either to the nature or to the scarcity of the final product.
    (ii) The label of the source blood, plasma, or serum conspicuously 
states either that it is reactive when tested for hepatitis B surface 
antigen and it may transmit viral hepatitis; or that the source blood, 
plasma, or serum was collected from a donor known to be reactive for 
hepatitis B surface antigen and it may transmit viral hepatitis, 
although confirmatory hepatitis testing has not been done.
    (iii) The package label of the licensed in vitro diagnostic 
biological product prepared from such blood, plasma, or serum states 
conspicuously that either the product was prepared from source material 
that was reactive when tested for hepatitis B surface antigen and it may 
transmit viral hepatitis; or that the source material was collected from 
a donor known to be reactive for hepatitis B surface antigen and it may

[[Page 62]]

transmit viral hepatitis, although confirmatory hepatitis testing has 
not been done.
    (iv) The package label of the licensed injectable biological product 
prepared from such blood, plasma, or serum states that the product has 
been inactivated.
    (v) The Director, Center for Biologics Evaluation and Research (HFB-
1), Food and Drug Administration, 8800 Rockville Pike, Bethesda MD 
20892, is notified in writing at the time of the shipment, or in the 
case of repetitive shipments, or April 1 and October 1 of each year, of 
each shipment of source blood, plasma, or serum for manufacture into 
hepatitis B vaccine or into a licensed in vitro diagnostic biological 
product. Such shipments shall not be subject to the requirements of 
paragraph (b)(3) of this section. Each notification shall identify the 
kind and amount of source material shipped, the name and address of the 
consignee, the date of shipment, and the manner in which the source 
material is labeled.
    (2) Unlicensed in vitro diagnostic biological products. Blood, 
plasma, or serum that is reactive when tested for hepatitis B surface 
antigen or that was collected from a donor known to be reactive for 
hepatitis B surface antigen may be used in manufacturing unlicensed in 
vitro diagnostic biological products including clinical chemistry 
control reagents if all of the following conditions are met:
    (i) The final product cannot be prepared from blood, plasma, or 
serum that is nonreactive when tested for hepatitis B surface antigen, 
due either to the nature or to the scarcity of the final product.
    (ii) The label of the source blood, plasma, or serum states 
conspicuously that either it is reactive when tested for hepatitis B 
surface antigen and it may transmit viral hepatitis; or that the source 
blood, plasma, or serum was collected from a donor known to be reactive 
for hepatitis B surface antigen and it may transmit viral hepatitis, 
although confirmatory hepatitis testing has not been done.
    (iii) The manufacturer of the source blood, plasma, or serum obtains 
written assurance from the manufacturer(s) of the final unlicensed 
product that package labels of all unlicensed products will 
conspicuously state, as required by Sec. 809.10(a)(4) of this chapter, 
that the product was prepared from blood, plasma, or serum that was 
reactive when tested for hepatitis B surface antigen and it may transmit 
viral hepatitis; or that the source material was collected from a donor 
known to be reactive for hepatitis B surface antigen and it may transmit 
viral hepatitis, although confirmatory hepatitis testing has not been 
done.
    (iv) At the time of shipment, the Director, Center for Biologics 
Evaluation and Research (HFB-1), Food and Drug Administration, 8800 
Rockville Pike, Bethesda, MD 20892, is notified in writing of each 
shipment of source blood, plasma, or serum signifying the kind and the 
amount of source material shipped, the name and address of the 
consignee, the date of shipment, and the manner in which such source 
material was labeled. Such shipments shall not be subject to the 
requirements of paragraph (b)(3) of this section.
    (e) Manufacturing responsibility. When the radioimmunoassay method 
for hepatitis B surface antigen testing is performed by personnel other 
than those of the facility collecting the blood, plasma, or serum, as 
provided in paragraph (b) of this section, it shall not be considered as 
divided manufacturing as described in Sec. 610.63, provided the 
following conditions are met:
    (1) The collecting facility 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.
    (2) The testing laboratory will participate in any proficiency 
testing programs undertaken by the Center for Biologics Evaluation and 
Research, Food and Drug Administration.
    (f) The information collection requirements in paragraph (d) of this 
section were approved by the Office of Management and Budget and 
assigned OMB control number 0910-0136.

(Information collection requirements contained in paragraph (b)(4) were 
approved by the Office of

[[Page 63]]

Management and Budget under control number 0910-0168)

[40 FR 29710, July 15, 1975, as amended at 48 FR 23181, May 24, 1983; 49 
FR 23834, June 8, 1984; 49 FR 26718, June 29, 1984; 51 FR 15607, Apr. 
25, 1986; 55 FR 11013 and 11014, Mar. 26, 1990]



Sec. 610.41  History of hepatitis B surface antigen.

    A person known to have previously tested positive for hepatitis B 
surface antigen, testing positive, or both, may not serve as a donor of 
human blood, plasma, or serum, except that under Sec. 640.120 of this 
chapter, such a donor may serve as a source of hepatitis B surface 
antigen for the manufacture of hepatitis B vaccine or the preparation of 
a diagnostic product for laboratory tests, or a person known to have 
previously tested positive for hepatitis B surface antigen may serve as 
a source of antibody to hepatitis B surface antigen for the preparation 
of a biological product or a diagnostic product for laboratory tests.

[48 FR 23182, May 24, 1983, as amended at 57 FR 10814, Mar. 31, 1992]



Sec. 610.45  Human Immunodeficiency Virus (HIV) requirements.

    (a) Testing requirements. (1) Each donation of human blood or blood 
components intended for use in preparing a product shall be tested for 
antibody to HIV by a test approved for such use by FDA, except as 
otherwise approved in writing by FDA. When the test for antibody to HIV 
is required, blood and blood products may be issued before the results 
of the test for antibody to HIV are available only in dire emergency 
situations or as otherwise approved in writing by FDA and, provided the 
test required by this paragraph is performed as soon as possible after 
issuance of the blood or blood product.
    (2) Tests approved by FDA for the screening of blood and blood 
components for evidence of HIV may only be used in place of a test for 
antibody to HIV to satisfy the requirements of this section and related 
sections if so specified by FDA.
    (b) Testing responsibility. The test for antibody to HIV shall be 
performed by the collection facility, by personnel of an establishment 
licensed to manufacture blood or blood derivatives under section 351(a) 
of the Public Health Service Act (42 U.S.C. 262(a)), or by a clinical 
laboratory which meets the standards of the Clinical Laboratory 
Improvement Act of 1967 (CLIA) (42 U.S.C. 263a), provided the 
establishment or clinical laboratory is qualified to perform the test.
    (c) Restrictions on use. (1) Blood, plasma, or other blood 
components that are repeatably reactive to a test for antibody to HIV or 
that were collected from a donor whose blood is known to be repeatably 
reactive to a test for antibody to HIV, shall not be shipped or used to 
prepare any product, including products not subject to licensure; except 
that such blood and blood components shall be shipped or used only for 
purposes and under conditions specifically approved in writing by FDA.
    (2) The restrictions on use contained in this paragraph shall not 
apply in the following cases:
    (i) Blood and blood components testing repeatably reactive or from a 
donor whose blood is known to be repeatably reactive that are shown to 
be negative for evidence of HIV infection by a method or process 
approved for such use by FDA;
    (ii) The distribution of blood, plasma, or serum samples, except 
when intended for use in the manufacture of a product;
    (iii) The in-house use of blood and blood components for research 
purposes; or
    (iv) The distribution of blood and blood components for research 
purposes, if not distributed by sale, barter, or exchange.

[53 FR 116, Jan. 5, 1988]



                  Subpart F--Dating Period Limitations



Sec. 610.50   Date of manufacture.

    The date of manufacture shall be determined as follows:

[[Page 64]]

    (a) For products for which an official standard of potency is 
prescribed in either Sec. 610.20 or Sec. 610.21, or which are subject to 
official potency tests, the date of initiation by the manufacturer of 
the last valid potency test.
    (b) For products that are not subject to official potency tests, (1) 
the date of removal from animals, (2) the date of extraction, (3) the 
date of solution, (4) the date of cessation of growth, or (5) the date 
of final sterile filtration of a bulk solution, whichever is applicable.

[38 FR 32056, Nov. 20, 1973, as amended at 42 FR 27582, May 31, 1977]



Sec. 610.53  Dating periods for licensed biological products.

    (a) General. The minimum dating periods in paragraph (c) of this 
section are based on data relating to usage, clinical experience, or 
laboratory tests that establish the reasonable period beyond which the 
product cannot be expected to yield its specific results and retain its 
safety, purity, and potency, provided the product is maintained at the 
recommended temperatures. The standards prescribed by the regulations in 
this subchapter are designed to ensure the continued safety, purity, and 
potency of the products and are based on the dating periods set forth in 
paragraph (c) of this section. Package labels for each product shall 
recommend storage at the stated temperatures.
    (b) When the dating period begins. The dating period for a product 
shall begin on the date of manufacture, as prescribed in Sec. 610.50. 
The dating period for a combination of two or more products shall be no 
longer than the dating period of the component with the shortest dating 
period.
    (c) Table of dating periods. In using the table in this paragraph, a 
product in column A may be stored by the manufacturer at the prescribed 
temperature and length of time in either column B or C, plus the length 
of time in column D. The dating period in column D shall be applied from 
the day the product leaves the manufacturer's storage, provided the 
product has not exceeded its maximum storage period, as prescribed in 
column B or C. If a product is held in the manufacturer's storage beyond 
the period prescribed, the dating period for the product being 
distributed shall be reduced by a corresponding period.

                                                                                                                
                                                                                                                
                                                                                          Dating period after   
                                      Manufacturer's storage  Manufacturer's storage    leaving manufacturer's  
              Product                period 1 to 5 C (unless   period 0 C or colder    storage when stored at 2 
                                        otherwise stated)        (unless otherwise     to 8 C (unless otherwise 
                                                                      stated)                   stated)         
A                                    B......................  C.....................  D                         
                                                                                                                
----------------------------------------------------------------------------------------------------------------
Adenovirus Vaccine Live Oral.......  6 months...............  Not applicable........  6 months.                 
Albumin (Human)....................  3 years................  ......do..............  (a) 5 years.              
                                     ......do...............  ......do..............  (b) 3 years, provided     
                                                                                       labeling recommends      
                                                                                       storage at room          
                                                                                       temperature, no warmer   
                                                                                       than 37 C.               
                                     Not applicable.........  ......do..............  (c) 10 years, if in a     
                                                                                       hermetically sealed metal
                                                                                       container and provided   
                                                                                       labeling recommends      
                                                                                       storage between 2 and 8  
                                                                                       C.                       
Allergenic Extracts labeled ``No                                                                                
 U.S. Standard of Potency'':                                                                                    
    1. With 50 percent or more       3 years................  ......do..............  3 years.                  
     glycerin.                                                                                                  
    2. With less than 50 percent     18 months..............  ......do..............  18 months.                
     glycerin.                                                                                                  
    3. Products for which cold       Not applicable.........  ......do..............  18 months (from date of   
     storage conditions are                                                            manufacture), provided   
     inappropriate.                                                                    labeling recommends      
                                                                                       storage at 30 C or       
                                                                                       colder.                  
    4. Powders and tablets.........  ......do...............  ......do..............  5 years (from date of     
                                                                                       manufacture), provided   
                                                                                       labeling recommends      
                                                                                       storage at 30 C or       
                                                                                       colder.                  
    5. Freeze-dried products:                                                                                   
      a. Unreconstituted...........  ......do...............  ......do..............  4 years (from date of     
                                                                                       manufacture).            
      b. Reconstituted.............  ......do...............  ......do..............  18 months (cannot exceed 4-
                                                                                       year unreconstituted     
                                                                                       dating period plus an    
                                                                                       additional 12 months).   
Allergenic Extracts, Alum            18 months..............  ......do..............  18 months.                
 Precipitated labeled ``No U.S.                                                                                 
 Standard of Potency''.                                                                                         
Anthrax Vaccine Adsorbed...........  2 years................  ......do..............  1 year.                   

[[Page 65]]

                                                                                                                
Antibody to Hepatitis B Surface                                                                                 
 Antigen:                                                                                                       
    1. Antibody to Hepatitis B       6 months...............  ......do..............  6 months.                 
     Surface Antigen.                                                                                           
    2. Lyophilized coated red blood  ......do...............  ......do..............      Do.                   
     cells.                                                                                                     
    3. Enzyme conjugated products..  ......do...............  ......do..............      Do.                   
Iodinated (\125\l) products........  Not applicable.........  ......do..............  45 days (from date of     
                                                                                       manufacture).            
Antihemophilic Factor (Human)......  ......do...............  ......do..............  1 year (from date of      
                                                                                       manufacture).            
Anti-Human Globulin Liquid.........  ......do...............  ......do..............  2 years.                  
Anti-Inhibitor Coagulant Complex...  ......do...............  ......do..............      Do.                   
Antirabies Serum...................  1 year.................  ......do..............      Do.                   
Antivenin (Crotalidae) Polyvalent..  ......do...............  ......do..............  5 years with an initial 10
                                                                                       percent excess of        
                                                                                       potency, provided        
                                                                                       labeling recommends      
                                                                                       storage at 37 C or       
                                                                                       colder.                  
Antivenin (Latrodectus Mactans)....  ......do...............  ......do..............  5 years with an initial 10
                                                                                       percent excess of        
                                                                                       potency.                 
Antivenin (Micurus fulvius)........  ......do...............  ......do..............      Do.                   
Asparaginase.......................  Not applicable.........  ......do..............  18 months from the date of
                                                                                       the last valid potency   
                                                                                       test.                    
BCG Vaccine........................  1 year.................  Not applicable........  6 months.                 
Blood Grouping Reagents                                                                                         
    1. Liquid......................  Not applicable.........  Not applicable........  2 years.                  
    2. Dried.......................  1 year.................  2 years...............  5 years.                  
Blood Group Substance AB...........  ......do...............  ......do..............  2 years.                  
Blood Group Substance A............  ......do...............  ......do..............      Do.                   
Blood Group Substance B............  ......do...............  ......do..............      Do.                   
Botulism Antitoxin.................  ......do...............  Not applicable........  5 years with an initial 20
                                                                                       percent excess of        
                                                                                       potency.                 
Cholera Vaccine....................  ......do...............  ......do..............  18 months.                
Coccidioidin.......................  ......do...............  ......do..............  3 years.                  
Collagenase........................  Not applicable.........  ......do..............  4 years (from date of     
                                                                                       manufacture), provided   
                                                                                       labeling recommends      
                                                                                       storage at 37 C or       
                                                                                       colder.                  
Cryoprecipitated AFH...............  ......do...............  ......do..............  12 months from the date of
                                                                                       collection of source     
                                                                                       blood, provided labeling 
                                                                                       recommends storage at -18
                                                                                       C or colder.             
Diphtheria Antitoxin:                                                                                           
    1. Liquid......................  1 year.................  ......do..............  5 years with an initial 20
                                                                                       percent excess of        
                                                                                       potency.                 
    2. Dried.......................  ......do...............  2 years...............  5 years with an initial 10
                                                                                       percent excess of        
                                                                                       potency.                 
Diphtheria and Tetanus Toxoids and   ......do...............  Not applicable........  18 months.                
 Pertussis Vaccine Adsorbed.                                                                                    
Diphtheria and Tetanus Toxoids,      ......do...............  ......do..............  2 years.                  
 Adsorbed.                                                                                                      
Diphtheria Toxin for Schick Test...  ......do...............  ......do..............  1 year.                   
Diphtheria Toxoid..................  ......do...............  ......do..............  2 years.                  
Diphtheria Toxoid Adsorbed.........  ......do...............  2 years...............      Do.                   
Diphtheria Toxoid-Schick Test        Not applicable.........  Not applicable........  1 year.                   
 Control.                                                                                                       
Factor IX Complex..................  ......do...............  ......do..............  1 year (from date of      
                                                                                       manufacture).            
Fibrinolysin (Human)...............  1 year.................  2 years...............  2 years.                  
Fibrinolysin and Desoxyribonuclease  ......do...............  ......do..............  3 years, provided labeling
 Combined (Bovine).                                                                    recommends storage at 30 
                                                                                       C or colder.             
Fibrinolysin and Desoxyribonuclease  ......do...............  ......do..............      Do.                   
 Combined (Bovine) with                                                                                         
 Chloramphenicol.                                                                                               
Hepatitis B Surface Antigen:                                                                                    
    1. Unlyophilized coated red      Not applicable.........  ......do..............  14 days (from date of     
     blood cells.                                                                      manufacture).            
    2. Iodinated (\125\ l) product.  ......do...............  ......do..............  45 days (from date of     
                                                                                       manufacture).            
    3. Enzyme conjugated product...  6 months...............  ......do..............  6 months.                 
Histoplasmin.......................  1 year.................  Not applicable........  2 years.                  
Immunoglobulins:                                                                                                
    1. Hepatitis B Immune Globulin   Not applicable.........  ......do..............  1 year.                   
     (Human).                                                                                                   
    2. Immune Globulin (Human).....  3 years................  ......do..............  3 years.                  
    3. Immune Globulin Intravenous   Not applicable.........  ......do..............  1 year.                   
     (Human).                                                                                                   
    4. Lymphocyte Immune Globulin,   ......do...............  Not applicable........  2 years.                  
     Anti-Thymocyte Globulin                                                                                    
     (Equine).                                                                                                  
    5. Pertussis Immune Globulin     3 years................  ......do..............  3 years from date the     
     (Human).                                                                          dried or frozen bulk     
                                                                                       product is placed in     
                                                                                       final solution.          

[[Page 66]]

                                                                                                                
    6. Rabies Immune Globulin        1 year.................  ......do..............  1 year.                   
     (Human).                                                                                                   
    7. Rho(D) Immune Globulin        6 months...............  ......do..............  6 months.                 
     (Human).                                                                                                   
    8. Tetanus Immune Globulin       1 year.................  ......do..............  3 years with an initial 10
     (Human).                                                                          percent excess of        
                                                                                       potency.                 
    9. Vaccinia Immune Globulin      3 years................  ......do..............  3 years.                  
     (Human).                                                                                                   
    10. Varicella-Zoster Immune      Not applicable.........  ......do..............  1 year.                   
     Globulin (Human).                                                                                          
Hepatitis B Vaccine................  2 years at 2 to 8 C....  Not applicable........  3 years.                  
Influenza Virus Vaccine............  1 year.................  ......do..............  18 months.                
Limulus Amebocyte Lysate...........  Not applicable.........  Not applicable........  18 months (from date of   
                                                                                       manufacture).            
Measles, Mumps, and Rubella Virus    ......do...............  1 year (-20 C or        1 year.                   
 Vaccine Live.                                                 colder).                                         
Measles and Mumps Virus Vaccine      ......do...............  ......do..............  1 year.                   
 Live.                                                                                                          
Measles and Rubella Virus Vaccine    ......do...............  ......do..............      Do.                   
 Live.                                                                                                          
Measles Live and Smallpox Vaccine..  Not applicable.........  ......do..............  1 year (from date of      
                                                                                       manufacture).            
Measles Virus Vaccine Live.........  ......do...............  ......do..............  1 year.                   
Meningococcal Polysaccharide                                                                                    
 Vaccine Group A:                                                                                               
    1. Final bulk powder...........  ......do...............  2 years (-20 C or       Not applicable.           
                                                               colder).                                         
    2. Final container.............  Not applicable.........  3 years (-20 C or       2 years.                  
                                                               colder).                                         
Meningococcal Polysaccharide                                                                                    
 Vaccine Group C:                                                                                               
    1. Final bulk powder...........  ......do...............  2 years (-20 C or       Not applicable.           
                                                               colder).                                         
    2. Final container.............  ......do...............  3 years (-20 C or       2 years.                  
                                                               colder).                                         
Meningococcal Polysaccharide                                                                                    
 Vaccine Groups A and C combined:                                                                               
    1. Final bulk powder...........  ......do...............  2 years (-20 C or       Not applicable.           
                                                               colder).                                         
    2. Final container.............  ......do...............  3 years (-20 C or       2 years.                  
                                                               colder).                                         
Meningococcal Polysaccharide                                                                                    
 Vaccine Groups A, C, Y, and W135                                                                               
 combined:                                                                                                      
    1. Final bulk power............  ......do...............  2 years (-20 C or       Not applicable.           
                                                               colder).                                         
    2. Final container.............  ......do...............  3 years (-20 C or       2 years.                  
                                                               colder).                                         
Mumps Skin Test Antigen............  6 months...............  Not applicable........  18 months.                
Mumps Virus Vaccine Live...........  Not applicable.........  1 year (-20 C or        1 year.                   
                                                               colder).                                         
Normal Horse Serum.................  1 year.................  2 years...............  5 years.                  
Pertussis Vaccine..................  ......do...............  Not applicable........  18 months.                
Pertussis Vaccine Adsorbed.........  ......do...............  ......do..............      Do.                   
Plague Vaccine.....................  ......do...............  ......do..............      Do.                   
Plasma products:                                                                                                
    1. Fresh Frozen Plasma.........  Not applicable.........  ......do..............  1 year from date of       
                                                                                       collection of source     
                                                                                       blood (-18 C or colder). 
    2. Liquid Plasma...............  ......do...............  ......do..............  (a) 26 days from date of  
                                                                                       collection of source     
                                                                                       blood (between 1 and 6   
                                                                                       C).                      
                                                                                      (b) 40 days from date of  
                                                                                       collection of source     
                                                                                       blood only when CPDA-1   
                                                                                       solution is used as the  
                                                                                       anticoagulant (between 1 
                                                                                       and 6 C).                
    3. Plasma......................  ......do...............  ......do..............  5 years from date of      
                                                                                       collection of source     
                                                                                       blood (-18 C or colder). 
    4. Platelet Rich Plasma........  ......do...............  ......do..............  72 hours from time of     
                                                                                       collection of source     
                                                                                       blood, provided labeling 
                                                                                       recommends storage (20 to
                                                                                       24 C or between 1 and 6  
                                                                                       C). 5 days if certain    
                                                                                       approved containers are  
                                                                                       used (20 to 24 C).       
    5. Source Leukocytes...........  ......do...............  ......do..............  In lieu of expiration     
                                                                                       date, the collection date
                                                                                       shall appear on the      
                                                                                       label.                   
    6. Source Plasma...............  ......do...............  ......do..............  10 years (at the          
                                                                                       recommended storage      
                                                                                       temperature stated on the
                                                                                       label).                  

[[Page 67]]

                                                                                                                
    7. Therapeutic Exchange Plasma.  ......do...............  ......do..............  10 years.                 
Plasma Protein Fraction (Human)....  1 year.................  ......do..............  (a) 5 years.              
                                                                                      (b) 3 years provided      
                                                                                       labeling recommends      
                                                                                       storage at room          
                                                                                       temperature, no warmer   
                                                                                       than 30 C).              
Platelets..........................  Not applicable.........  ......do..............  72 hours from time of     
                                                                                       collection of source     
                                                                                       blood, provided labeling 
                                                                                       recommends storage at 20 
                                                                                       to 24 C or between 1 and 
                                                                                       6 C. 5 days if certain   
                                                                                       approved containers are  
                                                                                       used (20 to 24 C).       
Pneumococcal Vaccine Polyvalent:                                                                                
    1. Final bulk powder...........  ......do...............  24 months after         Not applicable.           
                                                               potency assay (-20 C                             
                                                               or colder).                                      
    2. Final container.............  ......do...............  Not applicable........  2 years (from date of     
                                                                                       manufacture).            
Poliovirus Vaccine Inactivated.....  1 year.................  ......do..............  1 year.                   
Poliovirus Vaccine Live Oral                                                                                    
 Trivalent:                                                                                                     
    1. Frozen......................  Not applicable.........  1 year (-10 C or        1 year, provided labeling 
                                                               colder).                recommends storage at a  
                                                                                       temperature which will   
                                                                                       maintain ice continuously
                                                                                       in a solid state.        
    2. Liquid......................  ......do...............  Not applicable........  30 days, provided labeling
                                                                                       recommends storage       
                                                                                       between 2 and 8 C and    
                                                                                       container has been       
                                                                                       unopened.                
Poliovirus Vaccine Live Oral Type                                                                               
 I:                                                                                                             
    1. Frozen......................  ......do...............  1 year (-10 C or        1 year, provided labeling 
                                                               colder).                recommends storage at a  
                                                                                       temperature which will   
                                                                                       maintain ice continuously
                                                                                       in a solid state.        
    2. Liquid......................  ......do...............  Not applicable........  30 days, provided labeling
                                                                                       recommends storage       
                                                                                       between 2 and 8 C and    
                                                                                       container has been       
                                                                                       unopened.                
Poliovirus Vaccine Live Oral Type                                                                               
 II:                                                                                                            
    1. Frozen......................  ......do...............  1 year (-10 C or        1 year, provided labeling 
                                                               colder).                recommends storage at a  
                                                                                       temperature which will   
                                                                                       maintain ice continuously
                                                                                       in a solid state.        
    2. Liquid......................  ......do...............  Not applicable........  30 days, provided labeling
                                                                                       recommends storage       
                                                                                       between 2 and 8 C and    
                                                                                       container has been       
                                                                                       unopened.                
Poliovirus Vaccine Live Oral Type                                                                               
 III:                                                                                                           
    1. Frozen......................  ......do...............  1 year (-10 C or        1 year, provided labeling 
                                                               colder).                recommends storage at a  
                                                                                       temperature which will   
                                                                                       maintain ice continuously
                                                                                       in a solid state.        
    2. Liquid......................  ......do...............  Not applicable........  30 days, provided labeling
                                                                                       recommends storage       
                                                                                       between 2 and 8 C and    
                                                                                       container has been       
                                                                                       unopened.                
Polyvalent bacterial antigens with   1 year.................  ......do..............  18 months.                
 ``No U.S. Standard of Potency''                                                                                
 liquid.                                                                                                        
Polyvalent bacterial vaccines with   ......do...............  ......do..............      Do.                   
 ``No U.S. Standard of Potency''                                                                                
 liquid.                                                                                                        
Rabies Vaccine:                                                                                                 
    1. Dried.......................  ......do...............  2 years...............      Do.                   
    2. Liquid......................  3 months...............  Not applicable........  6 months.                 
Reagent red blood cells............  Not applicable.........  Not applicable........  Thirty-five days from     
                                                                                       earliest date of         
                                                                                       collection if kept in    
                                                                                       liquid form (indefinite  
                                                                                       storage of reagent red   
                                                                                       blood cell source        
                                                                                       material at -65 C or     
                                                                                       colder).                 

[[Page 68]]

                                                                                                                
ACD Red Blood Cells................  ......do...............  ......do..............  (a) 21 days from date of  
                                                                                       collection of source     
                                                                                       blood, provided labeling 
                                                                                       recommends storage       
                                                                                       between 1 and 6 C and the
                                                                                       hermetic seal is not     
                                                                                       broken during processing.
                                                                                      (b) 24 hours after plasma 
                                                                                       removal, provided        
                                                                                       labeling recommends      
                                                                                       storage between 1 and 6 C
                                                                                       and the hermetic seal is 
                                                                                       broken during processing.
CPD Red Blood Cells................  ......do...............  ......do..............  (a) 21 days from date of  
                                                                                       collection of source     
                                                                                       blood, provided labeling 
                                                                                       recommends storage       
                                                                                       between 1 and 6 C and the
                                                                                       hermetic seal is not     
                                                                                       broken during processing.
                                                                                      (b) 24 hours after plasma 
                                                                                       removal, provided        
                                                                                       labeling recommends      
                                                                                       storage between 1 and 6 C
                                                                                       and the hermetic seal is 
                                                                                       broken during processing.
CPDA-1 Red Blood Cells.............  ......do...............  ......do..............  (a) 35 days from date of  
                                                                                       collection of source     
                                                                                       blood, provided labeling 
                                                                                       recommends storage       
                                                                                       between 1 and 6 C and the
                                                                                       hermetic seal is not     
                                                                                       broken during processing.
                                                                                      (b) 24 hours after plasma 
                                                                                       removal, provided        
                                                                                       labeling recommends      
                                                                                       storage between 1 and 6 C
                                                                                       and the hermetic seal is 
                                                                                       broken during processing.
Red Blood Cells Deglycerolized.....  ......do...............  ......do..............  24 hours after removal    
                                                                                       from storage at -65 C or 
                                                                                       colder, provided labeling
                                                                                       recommends storage       
                                                                                       between 1 and 6 C.       
Red Blood Cells Frozen.............  ......do...............  ......do..............  3 years from date of      
                                                                                       collection of source     
                                                                                       blood, provided labeling 
                                                                                       recommends storage at -65
                                                                                       C or colder.             
Rubella and Mumps Virus Vaccine      ......do...............  1 year (-20 C or        1 year.                   
 Live.                                                         colder).                                         
Rubella Virus Vaccine Live.........  ......do...............  C.....................      Do.                   
Skin Test Antigens for Cellular      6 months...............  Not applicable........      Do.                   
 Hypersensitivity.                                                                                              
Smallpox Vaccine:                                                                                               
    1. Liquid......................  Not applicable.........  9 months (-10 C or      3 months, provided        
                                                               colder, if product is   labeling recommends      
                                                               maintained as           storage at 0 C or colder.
                                                               glycerinated or                                  
                                                               equivalent vaccine in                            
                                                               bulk or final                                    
                                                               containers).                                     
    2. Dried.......................  6 months...............  Not applicable........  18 months.                
Streptokinase......................  Not applicable.........  ......do..............      Do.                   
Tetanus and Diphtheria Toxoids       1 year.................  ......do..............  2 years.                  
 Adsorbed for Adult Use.                                                                                        
Tetanus Antitoxin:                                                                                              
    1. Liquid......................  ......do...............  ......do..............  5 years with an initial 20
                                                                                       percent excess or        
                                                                                       potency.                 
    2. Dried.......................  ......do...............  2 years...............  5 years with an initial 10
                                                                                       percent excess or        
                                                                                       potency.                 
Tetanus Toxoid.....................  ......do...............  Not applicable........  2 years.                  
Tetanus Toxoid Adsorbed............  ......do...............  ......do..............      Do.                   
Thrombin...........................  ......do...............  2 year................  3 years.                  
Thrombin Impregnated Pad...........  Not applicable.........  Not applicable........  1 year, or 6 months at 20 
                                                                                       to 24 C.                 
Tuberculin:                                                                                                     
    1. Purified Protein Derivative,  6 months...............  ......do..............  1 year.                   
     diluted.                                                                                                   
    2. Old or Purified Protein       1 year (not to exceed    ......do..............  2 years, provided labeling
     Derivative dried on multiple     30 C; do not                                     recommends storage at a  
     puncture device.                 refrigerate).                                    temperature not to exceed
                                                                                       30 C. Do not refrigerate.
    3. Old on multiple puncture      ......do...............  ......do..............      Do.                   
     device.                                                                                                    
Typhoid Vaccine....................  1 year.................  ......do..............  18 months.                

[[Page 69]]

                                                                                                                
ACD Whole Blood....................  Not applicable.........  ......do..............  21 days from date of      
                                                                                       collection, provided     
                                                                                       labeling recommends      
                                                                                       storage between 1 and 6  
                                                                                       C.                       
CPD Whole Blood....................  ......do...............  ......do..............      Do.                   
CPDA-1 Whole Blood.................  ......do...............  ......do..............  35 days from date of      
                                                                                       collection, provided     
                                                                                       labeling recommends      
                                                                                       storage between 1 and 6  
                                                                                       C.                       
Heparin Whole Blood................  ......do...............  ......do..............  48 hours from date of     
                                                                                       collection, provided     
                                                                                       labeling recommends      
                                                                                       storage between 1 and 6  
                                                                                       C.                       
Yellow Fever Vaccine...............  ......do...............  1 year (-20 C or        1 year, provided labeling 
                                                               colder).                recommends storage at 5 C
                                                                                       or colder.               

    (d) Exemptions. Exemptions or modifications shall be made only upon 
written approval, in the form of a supplement of the product license, 
issued by the Director, Center for Biologics Evaluation and Research 
(HFB-1).

[50 FR 4134, Jan. 29, 1985, as amended at 51 FR 15607, Apr. 25, 1986; 51 
FR 19750, June 2, 1986; 52 FR 37450, Oct. 7, 1987; 53 FR 12764, Apr. 19, 
1988; 55 FR 11014, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994]



                      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: ``Caution: Federal law prohibits dispensing 
without prescription,'' for prescription biologicals.
    (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]



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 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,

[[Page 70]]

(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: ``Caution: Federal law prohibits dispensing 
without prescription,'' for prescription biologicals.

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



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 establishments participate in the manufacture of a 
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.



Sec. 610.64   Name of selling agent or distributor.

    The name and address of the selling agent or distributor of a 
product may appear on the label under the designation of ``selling 
agent'' or ``distributor'' provided that the name and address of the 
manufacturer is given precedence in prominence.



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



PART 620--ADDITIONAL STANDARDS FOR BACTERIAL PRODUCTS--Table of Contents




                      Subpart A--Pertussis Vaccine

Sec.
620.1  Pertussis Vaccine.
620.2  Production.
620.3  U.S. Standard preparations.
620.4  Potency test.
620.5  Mouse toxicity test.

[[Page 71]]

620.6  General requirements.

                       Subpart B--Typhoid Vaccine

620.10  Typhoid Vaccine.
620.11  Production.
620.12  U.S. Standard preparations.
620.13  Potency test.
620.14  General requirements.

                   Subpart C--Anthrax Vaccine Adsorbed

620.20  Anthrax Vaccine Adsorbed.
620.21  Production.
620.22  U.S. Reference preparation.
620.23  Potency test.
620.24  General requirements.

                       Subpart D--Cholera Vaccine

620.30  Cholera Vaccine.
620.31  Production.
620.32  U.S. Standard preparations.
620.33  Potency tests.
620.34  Mouse toxicity test.
620.35  General requirements.

        Subpart E--Bacillus of Calmette and Guerin (BCG) Vaccine

620.40  BCG Vaccine.
620.41  Establishment and personnel requirements.
620.42  Production.
620.43  Reference BCG Vaccine.
620.44  Potency tests.
620.45  Test for freedom from virulent mycobacteria.
620.46  General requirements.
620.47  Labeling.
620.48  Samples; protocols; official release.

    Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360, 
371); secs. 215, 351, 352, 353, 361 of the Public Health Service Act (42 
U.S.C. 216, 262, 263, 263a, 264).

    Source: 38 FR 32064, 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--Pertussis Vaccine



Sec. 620.1  Pertussis Vaccine.

    The proper name of this product shall be ``Pertussis Vaccine'', 
which shall be an aqueous preparation of killed whole Bordetella 
pertussis bacteria. The vaccine may be precipitated or adsorbed and may 
be combined with other antigens.

[56 FR 63410, Dec. 4, 1991]



Sec. 620.2   Production.

    (a) Propagation of bacteria. Human blood shall not be used in 
culture medium for propagating bacteria either for seed or for vaccine. 
The culture medium for propagating bacteria for vaccine shall not 
contain ingredients known to be capable of producing allergenic effects 
in human subjects, except blood or blood products from lower animals 
other than the horse. When blood or a blood product is used, it shall be 
removed by washing the harvested bacteria. The bacterial concentrate 
shall be free of extraneous bacteria, fungi, and yeasts, as demonstrated 
by microscopic examination and cultural methods.
    (b) Bacterial content. (1) The opacity of the bacterial concentrate 
shall be determined in terms of the U.S. Opacity Standard not later than 
2 weeks after the harvest of the bacteria and before any treatment 
capable of altering the opacity of the bacterial concentrate.
    (2) The total immunizing dose of a vaccine prepared with whole 
bacteria shall contain (i) in the case of nonadsorbed vaccine no more 
bacteria than the equivalent of 60 opacity units and (ii) in the case of 
adsorbed vaccine no more than the equivalent of 48 opacity units.
    (c) Detoxification. After removing a sample for purity testing, the 
bacteria shall be killed and detoxified either (1) by heating, (2) by 
addition of a chemical agent and appropriate aging, or (3) by any 
combination of the stated procedures. The procedure used shall be one 
that has been shown to have no adverse effect on required safety, 
purity, and potency.
    (d) Preservative. The vaccine shall contain a preservative.



Sec. 620.3   U.S. Standard preparations.

    (a) The U.S. Standard Pertussis Vaccine shall be used for 
determining the potency of Pertussis Vaccine.
    (b) The U.S. Opacity Standard shall be used in estimating the 
bacterial content of the vaccine and of the challenge culture.

[[Page 72]]



Sec. 620.4   Potency test.

    The number of protective units of the total human immunizing dose 
shall be estimated for each lot of vaccine from the results of 
simultaneous intracerebral mouse protection tests of the vaccine under 
test and the U.S. Standard Pertussis Vaccine. The potency test shall be 
performed as follows:
    (a) Mice. Healthy mice shall be used, all from a single strain and 
of the same sex, or an equal number of each sex in each group, with 
individual weight varying no more than 4 grams in a single test. In no 
event shall any of the mice weigh less than 10 grams or more than 20 
grams. A system of randomization shall be used to distribute the mice 
into the groups, with respect to shelf position and to determine the 
order of challenge. There shall be at least 3 groups consisting of no 
less than 16 mice each, for each vaccine. In addition, there shall be at 
least 4 groups consisting of no less than 10 mice each, for control 
purposes: one group for the challenge dose and 3 groups for titrating 
the virulence of the challenge dose.
    (b) Vaccination. (1) Five-fold serial dilutions of the vaccine to be 
tested and of the standard vaccine shall be made in 0.85 percent sodium 
chloride solution. The dilutions of the vaccine under test shall have 
the same protective unitage, based on an estimate of 12 units per total 
human immunizing dose, as the unitage of the corresponding dilution of 
the standard vaccine. Each mouse in each group for vaccination shall be 
injected intraperitoneally with 0.5 ml. of the appropriate dilution.
    (2) The interval between vaccination and challenge shall be 14 to 17 
days. At least 87.5 percent of the mice in each group shall survive the 
period between vaccination and challenge and each mouse challenged shall 
appear healthy.
    (c) The challenge. (1) The challenge culture of Bordetella pertussis 
for each test shall be taken from a batch of cultures which have been 
maintained by a method, such as freeze-drying, that retains constancy of 
virulence.
    (2) The challenge and virulence titration doses shall be prepared as 
follows: The bacteria shall be harvested from a 20 to 24 hour culture 
grown on Bordet-Gengou medium seeded from a rapidly growing culture less 
than 48 hours old and uniformly suspended in a solution containing 1.0 
percent casein peptone and about 0.6 percent sodium chloride at pH 
7.1plus-minus0.1. The suspension, freed from agar particles and 
clumps of bacteria, and adjusted to an opacity of 10 units, shall be 
diluted in the solution used for suspending the bacteria, to provide in 
a volume of 0.03 ml. (i) a challenge dose of 0.0001 opacity units 
(1:3000) and (ii) virulence titration doses of \1/50\, \1/250\ and \1/
1250\ respectively of the challenge dose.
    (3) Each vaccinated mouse shall be injected intracerebrally with the 
challenge dose. The four groups of control mice shall be injected 
intracerebrally with the challenge dose and its three dilutions, 
respectively. The challenge-dose control mice shall be injected last. 
The interval between the removal of the bacteria from the culture medium 
and the injection of the last mouse shall not exceed 2\1/2\ hours.
    (d) Recording the results. The mice shall be observed for 14 days. 
Mice dying within 72 hours after challenge shall be excluded from the 
test. Records shall be maintained of the number of mice that die after 
72 hours and of the number of mice showing both paralysis and 
enlargement of the head at the end of 14 days. All mice that show both 
paralysis and enlargement of the head shall be considered as deaths for 
the purposes of determining the ED50.
    (e) Validity of the test. The test shall be valid provided (1) the 
ED50 of the vaccine under test and the standard vaccine is between 
the largest and smallest vaccinating doses; (2) the limits of one 
standard deviation of each ED50 fall within the range of 64 percent 
to 156 percent; (3) the protective response is graded in relation to the 
vaccinating doses; (4) the dose-response curves of the vaccine under 
test and the standard vaccine are parallel; (5) the challenge dose 
contains approximately 200 LD50; (6) the LD50 contains no more 
than 300 colony forming units; and (7) the \1/1250\ dilution of the 
challenge dose contains no less than 10 and no more than 50 colony 
forming units.
    (f) Estimate of the potency. The ED50 of each vaccine shall be 
calculated by a

[[Page 73]]

method that provides an estimate of the standard deviation. The 
protective unit value per total human immunizing dose of the vaccine 
under test shall be calculated in terms of the unit value of the 
standard vaccine.
    (g) Potency requirements. The vaccine shall have a potency of 12 
units per total human immunizing dose based upon either a single test 
estimate of no less than 8 units or a two-, three- or four-test 
geometric mean estimate of no less than 9.6, 10.8, or 12 units, 
respectively, except that for the vaccine in a multiple antigen product 
containing Poliovirus Vaccine Inactivated, the estimate shall be no less 
than 14 units. In no event shall the estimate be more than 36 units.
    (h) Test design variation. Variations in the design of the potency 
test may be permitted providing the results are demonstrated to be of 
equal or greater precision.

[38 FR 32064, Nov. 20, 1973, as amended at 50 FR 4137, Jan. 29, 1985]



Sec. 620.5   Mouse toxicity test.

    The final vaccine shall be demonstrated to be free from toxicity by 
the following test:
    A group of no less than 10 mice, each mouse weighing 14 to 16 grams, 
shall have free access to food and water for no less than 2 hours before 
injection. The group weight of the mice shall be determined immediately 
prior to injection. Each mouse shall be injected intraperitoneally with 
a test dose of one-half of the largest recommended single human dose of 
the final vaccine in a volume of no less than 0.5 ml. nor more than 0.75 
ml. The group weight of the mice shall be determined at the end of 72 
hours and at the end of 7 days after injection. At the end of 72 hours 
the average weight per mouse may be no less than the average weight per 
mouse immediately preceding the injection; at the end of 7 days the 
average weight gain per mouse may be no less than 3.0 grams; and at the 
end of 7 days there may be vaccine-related deaths of no more than 5 
percent of the total number of mice in all the toxicity tests performed.



Sec. 620.6   General requirements.

    (a) Safety. Each lot of product containing Pertussis Vaccine shall 
be tested for safety by the procedures prescribed in Sec. 610.11 of this 
chapter except that the test shall consist of the intraperitoneal 
injection of no less than one-half of the recommended largest individual 
human dose into each of the mice, and either the intraperitoneal 
injection of no less than three times the recommended largest individual 
human dose, or the subcutaneous injection of 5.0 milliliters into each 
of the guinea pigs.
    (b) Dose. These additional standards are based on a single injection 
of 0.5 ml., 1.0 ml., or 1.5 ml., and a total human immunizing dose of 
three single injections of a nonadsorbed vaccine, and two or three 
single injections of an adsorbed vaccine.
    (c) Product characteristics. Recommendations shall be made through 
appropriate labeling that the product after issue should not be frozen 
and should be well shaken immediately prior to use.
    (d) Labeling. In addition to the items required by other applicable 
labeling provisions of this part, the package label shall give the 
following information:

    (1) For a vaccine containing a precipitant or an adsorbent, the word 
``Adsorbed'' shall follow the proper name in the same style of type and 
prominence as the proper name.
    (2) The total immunizing dose contains 12 units of pertussis 
vaccine.

    (e) Multiple antigen products. The Pertussis Vaccine components of 
multiple antigen products shall be manufactured pursuant to these 
additional standards, except that the mouse toxicity test (Sec. 620.5) 
and the potency test (Sec. 620.4) shall be performed on the multiple 
antigen product.
    (f) Adsorbed vaccines. Only aluminum compound reagents shall be 
introduced into the product to cause precipitation or adsorption of 
either Pertussis Vaccine or other antigens incorporated with Pertussis 
Vaccine.
    (g) Freezing prohibition. Pertussis Vaccine and multiple antigen 
products of which Pertussis Vaccine is a component shall not be frozen 
at any time during storage.

[[Page 74]]

    (h) Samples and protocols. For each lot of vaccine, the following 
material shall be submitted to the Director, Center for Biologics 
Evaluation and Research, Food and Drug Administration, 8800 Rockville 
Pike, Bethesda, MD 20892.
    (1) A sample of no less than 20 milliliters of the final product for 
pertussis vaccine testing.
    (2) Protocols showing summaries of the manufacturing processes and 
the results of all mouse toxicity (Sec. 620.5) and potency (Sec. 620.4) 
tests performed.

[38 FR 32064, Nov. 20, 1973, as amended at 41 FR 35480, Aug. 23, 1976; 
48 FR 13025, Mar. 29, 1983; 49 FR 23834, June 8, 1984; 51 FR 15610, Apr. 
25, 1986; 55 FR 11013, Mar. 26, 1990]



                       Subpart B--Typhoid Vaccine



Sec. 620.10  Typhoid Vaccine.

    The proper name of this product shall be Typhoid Vaccine which shall 
be an aqueous or dried preparation of killed Salmonella typhi bacteria.

[48 FR 7167, Feb. 18, 1983]



Sec. 620.11   Production.

    (a) Strain of bacteria. (1) Strain Ty 2 of Salmonella typhi shall be 
used in the manufacture of Typhoid Vaccine.
    (2) The antigenic integrity of the Ty 2 strain shall be verified by 
an appropriate serological procedure.
    (b) Propagation of bacteria. The culture medium for propagation of 
S. typhi shall not contain ingredients known to be capable of producing 
allergenic effects in human subjects. The harvested bacteria shall be 
free of extraneous bacteria, fungi, and yeasts, as demonstrated by 
microscopic examination and cultural methods.
    (c) Bacterial content. (1) The number of bacteria in the concentrate 
of harvested bacteria shall be estimated not later than 2 weeks after 
harvest and before any treatment capable of altering the accuracy of the 
estimate.
    (2) The number of S. typhi bacteria in the vaccine shall not exceed 
10\9\ per milliliter.
    (d) Nitrogen content. The total nitrogen content of the vaccine 
shall not exceed 0.035 mg./ml. for nonextracted bacteria preparations 
and shall not exceed 0.023 mg./ml. for acetone-extracted bacteria 
preparations.
    (e) Preservative. Aqueous vaccine and the solution for 
reconstitution supplied with dried vaccine shall contain a preservative. 
Dried vaccine shall not contain a preservative.

[38 FR 32064, Nov. 20, 1973, as amended at 48 FR 7167, Feb. 18, 1983]



Sec. 620.12  U.S. Standard preparations.

    The following U.S. Standard preparations shall be obtained from the 
Center for Biologics Evaluation and Research (HFB-210), Food and Drug 
Administration, 8800 Rockville Pike, Bethesda, MD 20892, for use as 
prescribed in this part:
    (a) Vaccine standard. The U.S. Standard Typhoid Vaccine for 
determining the potency of Typhoid Vaccine.
    (b) Opacity standard. The U.S. Opacity Standard for adjusting the 
opacity of the suspension from which the challenge culture is prepared.

[48 FR 7167, Feb. 18, 1983, as amended at 49 FR 23834, June 8, 1984; 51 
FR 15610, Apr. 25, 1986; 55 FR 11015, Mar. 26, 1990]



Sec. 620.13   Potency test.

    The number of potency units per milliliter shall be estimated for 
each lot of vaccine from the results of simultaneous mouse protection 
tests of the vaccine under test and of the U.S. Standard Typhoid 
Vaccine. At least four dilutions of each lot of vaccine shall be tested. 
The test shall be performed as follows:
    (a) Mice. Healthy mice shall be used, all from a single strain and 
of the same sex, or an equal number of each sex in each group, with 
individual weights between 13 and 16 grams. A system of randomization 
shall be used to distribute the mice into the groups, with respect to 
shelf position and to determine the order of challenge. A group of at 
least 16 mice shall be used for each dilution of each vaccine. There 
shall be at least 4 groups consisting of no less than 10 mice each for 
control testing purposes, as required under paragraph (c) of this 
section.
    (b) Inoculation of vaccine. (1) Serial dilutions, no greater than 
fivefold, of the vaccine to be tested and of the standard vaccine shall 
be made in saline (0.85 percent sodium chloride solution or phosphate-
buffered saline). The mean

[[Page 75]]

effective dose (ED50) value shall be bracketed by the dilutions 
used. Each mouse in each group for inoculation shall be injected 
intraperitoneally with 0.5 milliliter of the appropriate dilution.
    (2) The interval between inoculation of the vaccine and challenge 
shall be no less than 7 days nor more than 14 days. At least 87.5 
percent of the mice in each group shall survive the period between 
vaccine inoculation and challenge and each mouse challenged shall appear 
healthy.
    (c) The challenge. (1) The challenge culture of Strain Ty 2 of S. 
typhi for each test shall be taken from a batch of cultures maintained 
by a method, such as freeze-drying, that retains constancy of virulence.
    (2) The challenge and virulence titration doses shall be prepared as 
follows: The bacteria shall be harvested from a 5- to 6-hour culture 
grown at 36 deg.1 deg. C on a suitable agar medium that 
shall have been seeded from a 16- to 20-hour culture grown at 
36 deg.1 deg. C on a suitable agar medium, and the harvested 
bacteria then shall be uniformly suspended in saline or phosphate-
buffered saline. The suspension, freed from agar particles and clumps of 
bacteria and adjusted to an opacity of 10 units, shall be diluted in 
saline or phosphate-buffered saline by tenfold increments. The 
suspensions for the challenge and virulence titration doses shall be put 
into a sterile gastric mucin preparation or other suitable virulence-
enhancing preparation. The challenge suspension shall be prepared from 
whichever bacteria dilution provides about 1,000 colony forming units 
for a 0.5 milliliter challenge dose. The virulence titration suspensions 
shall be 101, 102, 103 dilutions, respectively, of the 
challenge suspension.
    (3) Each mouse inoculated with vaccine shall be injected 
intraperitoneally with an 0.5 ml. dose of the challenge suspension. Each 
mouse in the four groups of control mice shall be injected 
intraperitoneally with an 0.5 ml. dose of the challenge suspension and 
its three dilutions, respectively. The challenge dose control mice shall 
be injected last. The interval between removal of the bacteria from the 
culture medium and the injection of the last mouse shall not exceed 2\1/
2\ hours.
    (d) Recording the results. The mice shall be observed daily for 3 
days. A record shall be maintained of the number of mice that die. A 
record of the number of mice that survive shall be made at the end of 
the observation period.
    (e) Validity of the test. The test is deemed valid if: (1) The 
ED50 of the vaccine under test and the standard vaccine is between 
the largest and smallest doses inoculated into the mice;
    (2) The homogeneity of the dose response lines for both the vaccine 
under test and the standard vaccine is acceptable;
    (3) A graded protective response is obtained in relation to the 
vaccine dilutions;
    (4) The slopes of the dose response curves for the vaccine under 
test and the standard vaccine are shown to be parallel by an appropriate 
statistical method;
    (5) The results of all dilutions are used to calculate the ED50 
value of both the standard and test vaccine by a parallel line bioassay 
method or a statistically equivalent method;
    (6) The challenge dose contains approximately 1,000 colony forming 
units; and
    (7) The LD50 of the challenge dose contains no more than 20 
colony forming units.
    (f) Repeat tests. If the test does not meet the criteria prescribed 
in paragraph (e) of this section, repeat tests may be performed. The 
results of all tests shall be combined by geometric mean. Any test 
result established as invalid under Sec. 610.1 of this chapter may be 
disregarded. The determination that the vaccine meets the potency 
requirements shall be made from the results of not more than four valid 
tests.
    (g) Estimate of the potency. The ED50 of each vaccine shall be 
calculated. The protective unit value per milliliter of the vaccine 
under test shall be calculated in terms of the unit value of the 
standard vaccine.
    (h) Potency requirements. The results of at least two separate tests 
shall be included on the release protocol, required under 
Sec. 620.14(c)(2), that is submitted to the Center for Biologics

[[Page 76]]

Evaluation and Research, Food and Drug Administration. The vaccine shall 
have a potency of 8.0 units per milliliter. This requirement shall be 
met only if the geometric mean potency for two tests is not less than 
3.9 units per milliliter; or for three tests, not less than 4.4 units 
per milliliter; or for four tests, not less than 4.8 units per 
milliliter.

[38 FR 32064, Nov. 20, 1973, as amended at 48 FR 7167, Feb. 18, 1983; 49 
FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]



Sec. 620.14   General requirements.

    (a) Dose. These standards are based on a human adult dose of 0.5 ml. 
for a single injection and a total immunizing dose of two injections of 
0.5 ml. given at appropriate intervals.
    (b) Labeling. In addition to the items required by other applicable 
labeling provisions of this subchapter, the package label shall state 
that the vaccine contains 8 units per milliliter.
    (c) Samples; protocols; official release. For each lot of vaccine, 
the following material shall be submitted to the Director, Center for 
Biologics Evaluation and Research (HFB-1), 8800 Rockville Pike, Bethesda 
MD 20892.
    (1) A sample of no less than 40 ml. of the product distributed in no 
less than four containers.
    (2) A protocol that consists of a summary of the history of 
manufacture of each lot including all results of each test for which 
test results are requested by the Director, Center for Biologics 
Evaluation and Research.
    (3) The product shall not be issued by the manufacturer until 
written notification of official release of each filling lot of dried 
vaccine and of each bulk lot of aqueous vaccine is received from the 
Director, Center for Biologics Evaluation and Research.

[38 FR 32064, Nov. 20, 1973, as amended at 42 FR 27582, May 31, 1977; 48 
FR 7168, Feb. 18, 1983; 48 FR 11430, Mar. 18, 1983; 49 FR 23834, June 8, 
1984; 51 FR 15610, Apr. 25, 1986; 55 FR 11013 and 11015, Mar. 26, 1990]



                   Subpart C--Anthrax Vaccine Adsorbed



Sec. 620.20   Anthrax Vaccine Adsorbed.

    The proper name of this product shall be Anthrax Vaccine Adsorbed, 
which shall consist of an aqueous preparation of a fraction of Bacillus 
anthracis which contains the protective antigen adsorbed on aluminum 
hydroxide.

[38 FR 32064, Nov. 20, 1973, as amended at 50 FR 4137, Jan. 29, 1985]



Sec. 620.21   Production.

    (a) Strain of bacteria. A nonencapsulated, nonproteolytic, avirulent 
strain of Bacillus anthracis shall be used in the manufacture of anthrax 
vaccine.
    (b) Medium. A chemically defined medium shall be used for the 
propagation of Bacillus anthracis which has protective-antigen promoting 
properties that are no less effective than the protective-antigen 
promoting properties of the Puziss and Wright 1095 medium as set forth 
in U.S. Patent No. 3,208,909, issued September 28, 1965, which patent is 
hereby incorporated by reference and deemed published herein. U.S. 
Patent No. 3,208,909 has been assigned to the Federal Government and 
copies will be provided to persons affected by the provisions of this 
subchapter upon request to the Director, Center for Biologics Evaluation 
and Research, or to the appropriate Information Center Officer listed in 
45 CFR, part 5. Copies also may be obtained upon request from the U.S. 
Patent Office, Washington, DC. The medium shall not contain ingredients 
known to be capable of producing allergenic effects in human subjects.
    (c) Propagation of bacteria. The medium shall be inoculated with a 
24-hour old vegetative culture seeded from a stock suspension of spores. 
The propagation culture, flushed with nitrogen, shall be incubated at 
37 deg. C.plus-minus1.0 deg. C., agitated for approximately 27 
hours, cooled to about 20 deg. C., the pH adjusted to 
8.0plus-minus0.1 and then filtered through a sterilizing filter(s) 
using nitrogen gas under pressure.

[[Page 77]]

    (d) Adsorption of the protective antigen. The sterile filtrate shall 
be adsorbed on sterile aluminum hydroxide gel and the recovered 
precipitate shall be resuspended and diluted in sterile 0.85 percent 
sodium chloride solution.

[38 FR 32064, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]



Sec. 620.22   U.S. Reference preparation.

    The U.S. Reference Anthrax Vaccine distributed by the Center for 
Biologics Evaluation and Research shall be used for determining the 
potency of anthrax vaccine.

[38 FR 32064, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]



Sec. 620.23   Potency test.

    The potency of each lot of vaccine shall be estimated from the 
results of simultaneous tests of the vaccine under test and the U.S. 
Reference Anthrax Vaccine. The test shall be performed as follows:
    (a) Guinea pigs. Healthy guinea pigs shall be used, all from a 
single strain and of the same sex, or an equal number of each sex in 
each group, with individual weights between 325 and 350 grams. The diet 
of the guinea pigs shall be supplemented with vitamin C throughout the 
test period. At least three groups of no less than eight guinea pigs 
shall be used for each vaccine and at least one group of four guinea 
pigs shall be used for the challenge control.
    (b) Vaccination. Serial dilutions, not greater than three-fold, of 
each vaccine shall be made in 0.85 percent sodium chloride solution. The 
mid-dilution of the vaccine under test shall contain that amount of 
vaccine which will afford protection to approximately 50 percent of the 
guinea pigs in the group vaccinated with that dilution. Each guinea pig 
in the test and reference vaccine groups shall be injected 
subcutaneously with 0.5 ml. of the appropriate dilution on the left side 
of the abdomen and about 2 cm. from the midline. The interval between 
vaccination and challenge shall be 14 days.
    (c) The challenge. Each vaccinated and control guinea pig shall be 
injected intracutaneously on the right side of the abdomen with 0.1 ml. 
of a spore suspension of the virulent Vollum strain of Bacillus 
anthracis diluted in sterile distilled water to contain 10,000 spores 
per milliliter.
    (d) Recording the results. The guinea pigs shall be observed daily 
for 10 days and the deaths recorded. The number of survivors shall be 
recorded at the end of the observation period.
    (e) Validity of the test. The test shall be valid provided (1) the 
protective response to each vaccine is graded in relation to the amount 
of vaccine in the respective dilutions and (2) all control animals die 
within 10 days.
    (f) Potency requirement. The potency of the product is satisfactory 
if the vaccine is no less potent than the reference. The potency of the 
product is considered to be equal to the reference when (1) the average 
time of death of the product-vaccinated guinea pigs is no less than the 
average time of death of the reference-vaccinated guinea pigs and the 
number of survivors of the product-vaccinated guinea pigs is no less 
than the number of survivors of the reference-vaccinated guinea pigs, or 
(2) the use of another statistical procedure, shown to be adequate for 
evaluating the potency of anthrax vaccine, demonstrates that the product 
is no less potent than the reference.



Sec. 620.24   General requirements.

    (a) Dose. These standards are based on a single human dose of 0.5 
ml. and a total primary immunizing doses of three single doses, each 
given at appropriate intervals.
    (b) Product characteristics. Recommendation shall be made through 
appropriate labeling that the product after issue should not be frozen.
    (c) Samples; protocols; official release. For each lot of vaccine, 
the following material shall be submitted to the Director, Center for 
Biologics Evaluation and Research, Food and Drug Administration, 8800 
Rockville Pike, Bethesda, MD 20892:
    (1) A protocol which consists of a summary of the manufacture of 
each lot including all results of all tests for which test results are 
requested by the Director, Center for Biologics Evaluation and Research.

[[Page 78]]

    (2) A sample of no less than 40 milliliters of the final product 
distributed in approximately equal amounts into four final containers.
    (3) The product shall not be issued by the manufacturer until 
written notification of official release of the lot is received from the 
Director, Center for Biologics Evaluation and Research.

[38 FR 32064, Nov. 20, 1973, as amended at 42 FR 27582, May 31, 1977; 48 
FR 13025, Mar. 29, 1983; 49 FR 23834, June 8, 1984; 51 FR 15610, Apr. 
25, 1986; 55 FR 11013, Mar. 26, 1990]



                       Subpart D--Cholera Vaccine



Sec. 620.30   Cholera Vaccine.

    The proper name of this product shall be Cholera Vaccine, which 
shall consist of an aqueous preparation of equal parts of Ogawa and 
Inaba serotypes of killed Vibrio cholerae bacteria.
[41 FR 18295, May 3, 1976]



Sec. 620.31   Production.

    (a) Strains of bacteria. (1) A strain of Ogawa and a strain of Inaba 
serotypes of V. cholerae shall be used in the manufacture of the 
vaccine. Each serotype strain shall have been shown in controlled field 
studies to yield a vaccine no less potent than vaccines prepared from 
Ogawa strain 41 and Inaba strain 35A3 obtained from the Center for 
Biologics Evaluation and Research.
    (2) Antigenic integrity of the strains shall be verified by (i) the 
agglutination of living bacteria of each serotype by cholera O Group I 
antiserum; (ii) the agglutination of the Ogawa strain in monospecific 
Ogawa antiserum and of the Inaba strain in monospecific Inaba antiserum; 
and (iii) the absence of spontaneous agglutination of living bacteria of 
either strain in 0.85 percent sodium chloride solution during incubation 
for at least 5 hours at 37 deg. C.
    (b) Propagation of bacteria. The culture medium for the propagation 
strains shall not contain ingredients known to be capable of producing 
allergenic effects in human subjects. The harvested bacteria shall be 
free of extraneous bacteria, fungi, and yeasts as demonstrated by 
microscopic examination and cultural methods. Bacteria of the two 
serotypes shall be grown separately.
    (c) Bacterial content. (1) The number of bacteria in each separate 
bacterial harvest shall be determined by use of the U.S. Opacity 
Standard not later than 2 hours after harvest and before treatment with 
a preservative or other agent capable of altering opacity of the 
bacterial suspension.
    (2) The vaccine shall contain equal numbers of bacteria of the Ogawa 
and Inaba serotypes, and the total number shall not exceed 8  x  
109 bacteria per milliliter.
    (d) Nitrogen content. The total nitrogen content of the vaccine 
shall not exceed 0.3 milligram per milliliter for bacteria grown on 
solid medium or 1.0 milligram per milliliter if grown in liquid medium. 
In no instance shall the vaccine contain more than 0.07 milligram per 
milliliter of nitrogen precipitable by the addition of an equal volume 
of 10 percent trichloracetic acid.
    (e) Preservative. The vaccine shall contain a preservative.

[41 FR 18295, May 3, 1976, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]



Sec. 620.32   U.S. Standard preparations.

    The following U.S. Standard preparations shall be obtained from the 
Center for Biologics Evaluation and Research, Food and Drug 
Administration, for use as prescribed in this subpart:
    (a) Vaccine standard. The U.S. Standard Cholera Vaccine, Ogawa 
serotype, and U.S. Standard Cholera Vaccine, Inaba serotype, shall be 
reconstituted as directed for determining the potency of Cholera 
Vaccine.
    (b) Opacity standard. The U.S. Opacity Standard for use in 
estimating the bacterial content of the vaccine and of the challenge 
culture.
    (c) Seed culture. Seed cultures of V. cholerae, Inaba serotype, 
strain 35A3 and Ogawa serotype, strain 41, for preparation of vaccine 
challenge cultures for use in the vaccine potency test.

[41 FR 18295, May 3, 1976, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]



Sec. 620.33   Potency tests.

    Each lot of vaccine shall be subjected to two potency tests. One 
test shall determine the potency of the vaccine in comparison with the 
U.S. Standard

[[Page 79]]

Cholera Vaccine, Ogawa serotype, and the other test shall determine the 
potency of the vaccine in comparison with the U.S. Standard Cholera 
Vaccine, Inaba serotype. At least four dilutions of each vaccine shall 
be tested. Each test shall be performed as follows:
    (a) Mice. Healthy mice shall be used, all from a single strain and 
of the same sex, or an equal number of each sex in each group, with 
individual weights between 10 and 14 grams. A group of at least 16 mice 
shall be used for each dilution of each vaccine. In addition, there 
shall be at least 4 groups consisting of no less than 10 mice each for 
each potency test as a control for virulence titration of the challenge 
suspension.
    (b) Injections of vaccine. Serial dilutions, no greater than 
fivefold, of the vaccine to be tested and of the appropriate serotype 
standard vaccine shall be made in 0.85 percent sodium chloride solution. 
The median effective dose (ED50), which is the dose of vaccine that 
is expected to protect 50 percent of the animals that received the 
vaccine, shall be bracketed by the dilutions used. Each mouse in each 
dilution group shall receive intraperitoneally 0.5 milliliter of the 
appropriate vaccine dilution. At least 87.5 percent of the mice in each 
dilution group shall survive, and all surviving mice shall appear 
healthy at the time of challenge.
    (c) The challenge. The challenge shall be administered 12 to 16 days 
after injection of the vaccine.
    (1) The strains of V. cholerae for challenge shall be Ogawa 41 and 
Inaba 35A3, except that V. cholerae, Inaba serotype, strain V86 may be 
used instead of Inaba serotype, strain 35A3, for preparation of vaccine 
challenge culture: Provided, That the source of the challenge culture 
shall be identified and verified by the manufacturer as equal to that 
distributed by the World Health Organization. For each test, the 
challenge culture shall be taken from a batch of cultures maintained by 
a method such as freeze-drying that retains constancy of virulence.
    (2) The challenge and virulence titration doses shall be prepared as 
follows: The bacteria for each challenge shall be harvested from a 6- to 
18-hour culture grown at 36 deg.plus-minus1 deg. C, on a suitable 
agar medium adjusted to pH 7.4. The harvested bacteria shall be 
uniformly suspended in a diluent consisting of M/15 phosphate buffered 
saline adjusted to pH 7.4 and shall contain 0.1 to 0.2 percent gelatin. 
The suspension shall be free from agar particles and clumps of bacteria. 
The suspension shall be adjusted to an opacity of 10 units, and diluted 
in tenfold increments using the same diluent. The suspensions for the 
challenge and virulence titrations shall be suspended in a 5 to 10 
percent sterile gastric mucin preparation adjusted to pH 7.4. The 
challenge suspension shall be prepared from whichever bacterial dilution 
provides the required median lethal dose (LD50) for a 0.5 
milliliter challenge dose. The LD50 is the dose of the challenge 
suspension that is expected to kill 50 percent of the animals that 
received the challenge. The virulence titration suspensions shall 
consist of the challenge suspension and at least three dilutions of the 
challenge suspension calculated to bracket the LD50 value.
    (3) At least 16 surviving mice, randomly selected from each dilution 
group that received vaccine, shall be inoculated intraperitoneally with 
a 0.5-milliliter dose of the challenge suspension. Mice in each of the 
four groups of control mice used for the virulence titration of the 
challenge suspension shall be inoculated intraperitoneally with a 0.5-
milliliter dose of the challenge suspension and its respective 
dilutions. The challenge dose control mice shall be inoculated last. The 
interval between removal of the bacteria from the culture medium and the 
inoculation of the last mouse shall not exceed 2\1/2\ hours.
    (d) Recording the results. The mice shall be observed daily for 2 
days following challenge. A daily record shall be maintained of the 
number of mice that die. A record of the number of mice that survive 
shall be made at the end of the observation period.
    (e) Validity of the test. The test is valid provided: (1) The 
ED50 value of the vaccine under test and the standard vaccine is 
between the largest and smallest doses inoculated into the mice;

[[Page 80]]

    (2) The homogeneity of the dose response lines for both the vaccine 
under test and the standard vaccine is acceptable;
    (3) The log-dose response lines for the vaccine under test and the 
standard vaccine are shown to be parallel by an appropriate statistical 
method;
    (4) The results of all dilutions shall be used to calculate the 
ED50 value of both the standard and test vaccine by a parallel line 
bioassay method or a method statistically equivalent;
    (5) The challenge dose contains between 100 and 10,000 LD50 
doses; and
    (6) The LD50 value of the challenge suspension contains no more 
than 10,000 colony-forming units determined by plate count.
    (f) Repeat tests. Repeat tests need be performed only on the 
serotype which failed to meet the potency requirements prescribed in 
paragraph (h) of this section. The results of each test on each serotype 
meeting the criteria in paragraph (e) of this section shall be combined 
by means of a geometric mean. The determination that the vaccine meets 
the potency requirements shall be made from the results of not more than 
three valid tests on each serotype.
    (g) Estimate of the potency. The ED50 value of each vaccine 
shall be calculated. The protective unit value of each serotype per 
milliliter of the vaccine under test shall be calculated in terms of the 
unit value of the corresponding standard vaccine.
    (h) Potency requirements. The vaccine shall have a potency of not 
less than 8 units per serotype per milliliter. This requirement shall be 
met only if the potency for a single test is not less than 4.4 units per 
serotype per milliliter, or for two tests not less than 5.3 units, or 
for three tests not less than 5.7 units.

[41 FR 18295, May 3, 1976, as amended at 41 FR 46587, Oct. 22, 1976]



Sec. 620.34   Mouse toxicity test.

    The final vaccine shall be demonstrated to be free from toxicity by 
the following test: A group of no less than 10 and no more than 40 mice, 
each mouse weighing 14 to 16 grams, shall have free access to food and 
water at least 2 hours before injection and throughout the test period. 
The group weight of the mice shall be determined immediately before 
injection. Each mouse shall be injected intraperitoneally with a test 
dose of 0.5 milliliter of undiluted vaccine. The group weight of the 
mice shall be determined again at the end of 72 hours. The 72-hour 
average weight per mouse shall be no less than the average weight per 
mouse immediately preceding the injection. No more than 5 percent of the 
total number of mice used may die during the test period; however, 
neither death nor significant toxic signs attributable to the vaccine 
shall result.

[41 FR 18295, May 3, 1976]



Sec. 620.35   General requirements.

    (a) Freezing prohibition. Cholera Vaccine shall not be frozen at any 
time.
    (b) Dose. These standards are based on a total immunizing dose of 
two injections of 0.5 milliliter and 1.0 milliliter, respectively, given 
at intervals specified in the manufacturer's labeling.
    (c) Date of manufacture. The date of manufacture shall be the date 
of initiation of the last valid potency test for the Ogawa serotype or 
the Inaba serotype, whichever date is earlier.
    (d) Labeling. In addition to the applicable labeling provisions of 
this chapter, the package label shall bear the following: (1) A 
statement that the vaccine contains 8 units of each serotype antigen per 
milliliter.
    (2) The statement, ``DO NOT FREEZE''.
    (3) The statement, ``SHAKE WELL''.
    (e) Samples; protocols; official release. For each lot of vaccine, 
the following material shall be submitted to the Director, Center for 
Biologics Evaluation and Research, Food and Drug Administration, 8800 
Rockville Pike, Bethesda, MD 20892.
    (1) A sample consisting of no less than 40 milliliters of the 
product. The sample may be in the final container or from the vaccine 
bulk lot.
    (2) A protocol which consists of a summary of the history of 
manufacture of each lot including all results of each test for which 
test results are requested by the Director, Center for Biologics 
Evaluation and Research,

[[Page 81]]

Food and Drug Administration. The raw data and results from each potency 
test performed shall be included.
    (3) The product shall not be issued by the manufacturer until 
written notification of official release of the lot is received from the 
Director, Center for Biologics Evaluation and Research.

[41 FR 18295, May 3, 1976, as amended at 42 FR 27582, May 31, 1977; 49 
FR 23834, June 8, 1984; 51 FR 15610, Apr. 25, 1986; 55 FR 11013, Mar. 
26, 1990]



        Subpart E--Bacillus of Calmette and Guerin (BCG) Vaccine

    Source: 44 FR 14545, Mar. 13, 1979, unless otherwise noted.



Sec. 620.40  BCG Vaccine.

    (a) Proper name and definition. The proper name of this product is 
BCG Vaccine. The product is defined as a freeze-dried preparation 
containing viable bacteria of the Bacillus of Calmette and Guerin, which 
is an attenuated strain of Mycobacterium bovis.
    (b) Criteria for an acceptable strain. The source of the BCG strain 
used in the manufacture of any lot of the final product must be 
identified by complete historical records.
    (1) Seed lot system. The BCG strain must be maintained in the form 
of a primary seed lot that is to be the basic material from which all 
secondary seed lots are prepared. Production of BCG Vaccine may be from 
either primary or secondary seed lots. Each seed lot must be stored in 
either a freeze-dried state at -20 deg. C or colder, or in a frozen 
state at -70 deg. C or colder.
    (2) Freedom from virulence. The BCG strain is demonstrated to be 
incapable of producing progressive tuberculosis in guinea pigs tested as 
prescribed in Sec. 620.45, except that no fewer than 48 guinea pigs must 
be used to test the primary seed lot and no fewer than 12 guinea pigs 
must be used to test each secondary seed lot. At least two-thirds of the 
animals must survive the observation period of no less than 6 months.
    (3) Induction of tuberculin sensitivity in guinea pigs. Each of at 
least 10 guinea pigs is to be injected with 1 human dose of BCG Vaccine 
and, within 4 to 6 weeks after vaccination, skin tested with tuberculin. 
At least 80 percent of the guinea pigs tested must develop tuberculin 
sensitivity, as prescribed in Sec. 620.44(b)(3)(ii).
    (4) Clinical information. Clinical data must establish that the BCG 
strain is safe and induces tuberculin sensitivity. After having passed 
all laboratory tests prescribed for BCG Vaccine, each primary and 
secondary seed lot of vaccine must be tested for its ability to induce 
sensitivity in tuberculin-negative persons. Only those persons tested by 
injection of 5 U.S. Tuberculin Units, Purified Protein Derivative, by 
the Mantoux technique and found negative in this test are to be selected 
for clinical trials. At least 100 tuberculin-negative persons must be 
included in the test of the primary seed lot, and at least 20 
tuberculin-negative persons must be included in the test of each 
secondary seed lot. Within 6 to 8 weeks after BCG vaccination, the 
vaccinees must be tested for tuberculin reactivity by injecting not more 
than 10 U.S. Tuberculin Units, Purified Protein Derivative, by the 
Mantoux technique. The test is considered satisfactory if a least 90 
percent of those persons from each group develop tuberculin reactivity 
as indicated by an induration reaction of at least 5 millimeters in 
diameter.



Sec. 620.41  Establishment and personnel requirements.

    In addition to the applicable requirements of Secs. 600.10 and 
600.11 of this chapter, the following practices and procedures are 
required:
    (a) Isolation of BCG unit. (1) A BCG unit is defined as the space 
used for storage of primary and secondary seed cultures and for vaccine 
preparation, including culture maintenance, media inoculation for 
propagation, harvesting, filling into final containers, sealing of final 
containers, media production, and cleaning and sterilization of 
glassware. For purposes of these additional standards, the space used 
for incubation of bulk and final container sterility tests, tests to 
determine the numbers of colony-forming units, animal tests, and 
necropsies are not part of the BCG unit.
    (2) The BCG unit must be completely isolated from other production 
and surrounding areas and must be situated

[[Page 82]]

and designed to prevent contamination of the product. It must have a 
separate facility for ventilation, designed to prevent contamination of 
the product. The facilities for water supply and sewage and trash 
disposal must be designed to prevent microbial contamination of the BCG 
unit. The equipment used in BCG Vaccine production must remain in the 
BCG unit at all times.
    (3) Microbial controlled areas must be available for handling the 
BCG cultures. No cultures of microorganisms other than the BCG 
production strain are permitted in the BCG unit. No animals are 
permitted in the BCG unit. All tests necessary for the control of the 
vaccine, in which contaminating microorganisms may be cultured, or in 
which animals are used, must be conducted in space physically separated 
from the BCG unit.
    (b) Restrictions on personnel. (1) A staff specially trained in 
maintaining the seed cultures, propagating the cultures, preparing the 
vaccine, and filling the vaccine into final containers shall be employed 
in the production of the BCG Vaccine. Such personnel shall not work with 
other infectious agents in any laboratory at any time and shall not be 
exposed to a known risk of tuberculosis. Within 30 days before 
employment in the BCG unit, each person working in the unit shall have 
had a medical examination, including a tuberculin skin test with 5 U.S. 
Tuberculin Units, Purified Protein Derivative, by the Mantoux procedure, 
and a chest X-ray. No person who has had a history of tuberculosis or 
mycobacterial disease is permitted in the BCG unit. There must be 
periodic medical examinations of BCG unit personnel, including X-ray 
examinations, of sufficient frequency to detect the appearance of early 
active tuberculosis. Repeated tuberculin skin testing of staff who are 
negative to tuberculin may be used as an additional diagnostic aid in 
isolating any potential source of tuberculosis exposure. If a person 
working in the BCG unit develops active tuberculosis, (i) the entire 
staff shall be examined for possible tuberculosis infection, (ii) all 
current vaccine preparations and all cultures with which the person may 
have come into contact since his or her last satisfactory medical 
examination, except cultures sealed before that examination, must be 
discarded, and (iii) the BCG unit and all equipment with which the 
person may have come in contact must be decontaminated.
    (2) Personnel shall wear protective clothing and use protective 
devices to the extent necessary to protect the product from 
contamination.
    (3) Any person not assigned to the BCG unit shall not be allowed 
into the BCG unit at any time unless a medical examination shows the 
person to be free from mycobacterial disease.



Sec. 620.42  Production.

    (a) BCG inoculum. The inoculum of BCG used for seed lot or 
production of final lot in seed buildup must have been removed from the 
preceding seed lot in accordance with the following passage and time 
schedule:
    (1) No more than 3 passages from primary to secondary seed lot 
within a 2-month period.
    (2) If no secondary seed lot is used, no more than 9 passages from 
primary seed lot to final lot within a 6-month period.
    (3) No more than 9 passages from secondary seed lot to final lot 
within a 6-month period.
    (b) Propagation of bacteria. The culture medium for propagation of 
BCG Vaccine must not contain ingredients known to be capable of 
producing allergenic effects in humans or of causing the bacteria to 
become virulent for guinea pigs. The growth in each container must be 
examined visually, and only those cultures that have the typical growth 
pattern characteristic of BCG are to be used in a vaccine.
    (c) Colony-forming units (CFU) before and after freeze-drying. Each 
lot of BCG Vaccine must be tested to determine the number of CFU per 
individual final container both before and after freeze-drying, by the 
method prescribed in Sec. 620.44(a). The upper and lower limits of the 
viable count are to be established by the manufacturer of the vaccine 
for the particular route of administration recommended and must be 
specified in the license application. The loss in viability after drying 
must not exceed 90 percent.

[[Page 83]]



Sec. 620.43  Reference BCG Vaccine.

    A reference BCG Vaccine, for use in determining the validity of the 
test for colony-forming units, is to be obtained from the Director, 
Center for Biologics Evaluation and Research, Food and Drug 
Administration, 8800 Rockville Pike, Bethesda, MD 20892.

[44 FR 14545, Mar. 13, 1979, as amended at 49 FR 23834, June 8, 1984; 51 
FR 15610, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990]



Sec. 620.44  Potency tests.

    (a) Colony-forming units (CFU). The number of CFU must be determined 
on the contents of each of at least 10 individual final containers of 
each lot of BCG Vaccine. Of the 10 or more individual final containers, 
the contents of at least 5 before, and an equal number after, freeze-
drying must be tested. Final containers of the freeze-dried vaccine are 
to be reconstituted as for human use with the diluent recommended by the 
manufacturer. The number of CFU to be reported for each lot of BCG 
Vaccine must be determined only from test tubes containing between 10 
and 50 CFU. Dilutions must be made as follows:
    (1) Dilutions are made from an appropriate volume of the liquid 
vaccine before freeze-drying or the reconstituted vaccine after freeze-
drying. Appropriate dilutions are made with modified Youman's medium 
specified in paragraph (a)(4) of this section, up to a point where 
subsequent serial half-log dilutions will result in at least 1 tube 
containing between 10 and 50 CFU.
    (2) Serial half-log dilutions are made in 16 x 125 millimeter screw-
capped test tubes into which 4.5 milliliter aliquots of the diluent 
prescribed in paragraph (a)(4) of this section have been dispensed. Two 
milliliters of thoroughly mixed vaccine are added to the first tube of 
the half-log series, mixed thoroughly, and 2.0 milliliters from this 
tube are transferred to the next tube in the series. The process of 
mixing and serially transferring 2.0 milliliters is repeated through 
each consecutive tube and 2.0 milliliters are discarded from the last 
tube.
    (3) After the serial half-log dilutions are completed, 0.5 
milliliter of 1.5 percent agar solution that has been cooled to 42 deg. 
C is quickly added, where necessary, to make a final concentration of 
0.15 percent agar, and the contents of the tubes are thoroughly mixed. 
After mixing, all tubes are incubated at 35 deg. to 37 deg. C for 3 to 4 
weeks.
    (4) The composition of modified Youman's medium with bovine albumin 
is as follows:

Asparagine................................  5.0 grams.                  
Monopotassium phosphate (KH2PO4)..........  Do.                         
Potassium sulfate (K2SO4).................  0.5 grams.                  
Magnesium citrate.........................  1.5 grams.                  
Monosodium glutamate......................  19.0 grams.                 
Glycerine.................................  20.0 milliliters.           
Distillled water q.s. to..................  900.0 milliliters.          
                                                                        

    One hundred milliliters of 5-percent aqueous solution of bovine 
albumin that has been sterilized by filtration are added to the Youman's 
medium to produce a final concentration of 0.5 percent of bovine 
albumin. The pH is adjusted to 7.0 with 5N sodium hydroxide.

    (b) Intradermal guinea pig test. Two or more guinea pigs, each 
weighing no less than 250 grams, must be injected intradermally in 4 
different sites with the following amounts and dilutions of each lot of 
BCG Vaccine:
    (1) Vaccine intended for intradermal injection is reconstituted as 
for human use with the diluent recommended by the manufacturer. One-
tenth milliliter of reconstituted vaccine and 0.1 milliliter each of 
three ten-fold dilutions (1:10, 1:100, and 1:1000) of the reconstituted 
vaccine are injected into the guinea pigs. The diluent for the ten-fold 
dilutions is isotonic solution for injection.
    (2) Vaccine intended for percutaneous injection into humans is 
reconstituted with the diluent recommended by the manufacturer so that 
at least one human dose (estimated to be within a range of from 1 to 
33 x 105 CFU) is contained in 0.1 milliliter. A narrower range of 
CFU is determined for each specific vaccine by the manufacturer and 
specified in the license application. One-tenth milliliter of the 
selected dose of vaccine and 0.1 milliliter each of three ten-fold 
dilutions (1:10, 1:100, and 1:1000) are injected into the guinea pigs. 
The diluent for the ten-fold dilutions is an isotonic solution for 
injection.
    (3) The lot of vaccine is satisfactory if:

[[Page 84]]

    (i) At the end of 2 to 4 weeks after BCG vaccination, nodules have 
developed that are graded in relation to the amount of the test dose, 
with the largest dose inducing a nodule of from 4 to 10 millimeters in 
diameter and the smallest dose inducing essentially no nodule, and all 
observations are read on the same day;
    (ii) By the end of 4 to 6 weeks after BCG vaccination, each guinea 
pig shows a degree of sensitivity such that an intradermal injection of 
no greater than 25 U.S. Tuberculin Units, Purified Protein Derivative, 
in 0.1 milliliter will induce an erythematous reaction at least 10 
millimeters in diameter within 18 to 24 hours; and
    (iii) At the end of the test period, each guinea pig is weighed and 
each shows a weight increase.
    (c) Induction of tuberculin sensitivity in tuberculin-negative 
humans. At least once annually, no less than one lot of BCG Vaccine that 
has satisfied all requirements and has been released by the Center for 
Biologics Evaluation and Research must be tested for its ability to 
induce sensitivity in 20 persons negative to Tuberculin, Purified 
Protein Derivative, as prescribed in Sec. 620.40(b)(4). The results of 
these tests must be sent to the Director, Center for Biologics 
Evaluation and Research, as they are completed.

[44 FR 14545, Mar. 13, 1979, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]



Sec. 620.45  Test for freedom from virulent mycobacteria.

    (a) Each lot of BCG Vaccine must be tested to determine that it does 
not contain virulent mycobacteria. The test must be performed using at 
least 6 guinea pigs, each weighing between 250 and 300 grams. Vaccine 
intended for intradermal injection in humans must be tested by injecting 
into guinea pigs the number of bacteria contained in at least 50 human 
doses. Vaccine intended for percutaneous use in humans must be tested by 
injecting into guinea pigs 50 times the number of bacteria estimated to 
be introduced parenterally into humans by the recommended procedure. The 
vaccine for all tests must be inoculated subcutaneously or 
intramuscularly into the guinea pigs. All animals that die during the 
observation period must be examined postmortem. All animals that survive 
the observation period must be sacrificed and examined post mortem. The 
lot passes the test if at least two-thirds of the animals on test 
survive an observation period of not less than 6 weeks, and if the post-
mortem examination reveals no evidence of tuberculosis in any of the 
test animals.
    (b) If any virulent mycobacteria are found in any lot of BCG 
Vaccine, whether or not the manufacturer intends to submit samples and 
protocols of this lot to the Center for Biologics Evaluation and 
Research for release, the following actions must be taken:
    (1) In addition to the requirements of Secs. 600.12 and 600.14 of 
this chapter, the manufacturer shall immediately report by telephone, 
telegraph, or cable the finding of virulent mycobacteria to the 
Director, Center for Biologics Evaluation and Research.
    (2) All production and distribution of lots of BCG Vaccine produced 
from the same secondary seed lot as the contaminated lot of BCG Vaccine 
must be discontinued. If no secondary seed lot is used the same 
requirements apply to the primary seed lot.
    (3) The manufacturer shall conduct a thorough and prompt 
investigation concerning the failure of the lot to meet the required 
safety and purity specifications, including retesting the suspect lot 
and the source secondary seed lot (or primary seed lot, if no secondary 
seed lot is used) and shall undertake a thorough review of all 
manufacturing records and procedures to determine the probable cause of 
the failure.
    (4) A written record of the investigation, including the retest 
results, must be submitted to the Director, Center for Biologics 
Evaluation and Research.
    (5) Neither production nor distribution of BCG Vaccine may be 
resumed until the manufacturer is notified in writing by the Director, 
Center for Biologics Evaluation and Research, that such activity may be 
resumed.

[44 FR 14545, Mar. 13, 1979, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]

[[Page 85]]



Sec. 620.46  General requirements.

    (a) Dose. These standards are based on (1) vaccine intended for 
intradermal injection in a single human immunizing dose of 0.1 
milliliter and (2) vaccine intended for percutaneous injection in a 
single skin application through which inoculation is made by a multiple 
puncture device.
    (b) Date of manufacture. The date of manufacture is the date of 
initiation of the last valid determination for CFU after freeze-drying.



Sec. 620.47  Labeling.

    In addition to conforming to the applicable requirements of 
Secs. 610.60, 610.61, and 610.62 of this chapter, the package label must 
bear the following information:
    (a) Specification of the route of administration.
    (b) A statement that the vaccine contains live bacteria and should 
be protected against exposure to light.
    (c) A statement that the vaccine must be administered within 8 hours 
after reconstitution, and that reconstituted vaccine not used within 8 
hours must be discarded.



Sec. 620.48  Samples; protocols; official release.

    (a) For each lot of vaccine, the following materials must be 
submitted to the Director, Center for Biologics Evaluation and Research, 
Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892.
    (1) Samples and diluent that will provide at least 20 milliliters 
when the samples are reconstituted as recommended in the package insert 
by the manufacturer of the vaccine.
    (2) A protocol that consists of a complete summary of the 
manufacture of each lot, including all results of each test required by 
all applicable regulations. If the protocol is not included in the 
shipment of the samples, it must be sent promptly to the Director, 
Center for Biologics Evaluation and Research, Food and Drug 
Administration, 8800 Rockville Pike, Bethesda, MD 20892.
    (b) The BCG Vaccine must not be issued by the manufacturer until 
written notification of official release is received from the Director, 
Center for Biologics Evaluation and Research, Food and Drug 
Administration.

[44 FR 14545, Mar. 13, 1979, as amended at 49 FR 23834, June 8, 1984; 51 
FR 15610, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990]



PART 630--ADDITIONAL STANDARDS FOR VIRAL VACCINES--Table of Contents




                Subpart A--Poliovirus Vaccine Inactivated

Sec.
630.1  Poliovirus Vaccine Inactivated.
630.2  Poliovirus Vaccine Inactivated.
630.3  Potency test.
630.4  Tests for safety.
630.5  General requirements.

            Subpart B--Poliovirus Vaccine Live Oral Trivalent

630.10  Poliovirus Vaccine Live Oral Trivalent.
630.11  Clinical trails to qualify for license.
630.12  Animal source and quarantine; personnel.
630.13  Manufacture of Poliovirus Vaccine Live Oral Trivalent.
630.14  Reference virus preparations.
630.15  Potency test.
630.16  Test for neurovirulence.
630.17  Alternative test for neurovirulence.
630.18  Additional tests for safety.
630.19  General requirements.

                          Subpart C--[Reserved]

                  Subpart D--Measles Virus Vaccine Live

630.30  Measles Virus Vaccine Live.
630.31  Clinical trials to qualify for license.
630.32  Manufacture of live, attenuated Measles Virus Vaccine.
630.33  Reference virus.
630.34  Potency test.
630.35  Test for safety.
630.36  General requirements.

                          Subpart E--[Reserved]

                   Subpart F--Mumps Virus Vaccine Live

630.50  Mumps Virus Vaccine Live.
630.51  Clinical trials to qualify for license.
630.52  Manufacture of Mumps Virus Vaccine Live.
630.53  Reference virus.
630.54  Potency test.
630.55  Test for safety.
630.56  General requirements.

                  Subpart G--Rubella Virus Vaccine Live

630.60  Rubella Virus Vaccine Live.
630.61  Clinical trials to qualify for license.
630.62  Production.

[[Page 86]]

630.63  Reference virus.
630.64  Potency test.
630.65  Test for safety.
630.66  General requirements.

                       Subpart H--Smallpox Vaccine

630.70  Smallpox Vaccine.
630.71  Production.
630.72  Reference vaccine.
630.73  Potency test.
630.74  Tests for safety.
630.75  General requirements.

    Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360, 
371); secs. 215, 351, 352, 353, 361 of the Public Health Service Act (42 
U.S.C. 216, 262, 263, 263a, 264).

    Source: 38 FR 32068, 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--Poliovirus Vaccine Inactivated



Sec. 630.1  Poliovirus Vaccine Inactivated.

    (a) Proper name and definition. The proper name of this product 
shall be ``Poliovirus Vaccine Inactivated'' which shall consist of an 
aqueous preparation of poliovirus types 1, 2, and 3, grown in monkey 
kidney tissue cultures, inactivated by a suitable method.
    (b) Strains of virus. Strains of poliovirus used in the manufacture 
of vaccine shall be identified by historical records, infectivity tests 
and immunological methods. Any strain of virus may be used that produces 
a vaccine meeting the requirements of Secs. 630.2, 630.3, and 630.4, but 
the Director, Center for Biologics Evaluation and Research may from time 
to time prohibit the use of any specific strain whenever he finds that 
it is practicable to use another strain of the same type that is 
potentially less pathogenic to man and that will produce a vaccine of at 
least equivalent safety and potency.
    (c) Monkeys; species permissible as source of kidney tissue. Only 
Macaca or Cercopithecus monkeys, or a species found by the Director, 
Center for Biologics Evaluation and Research, to be equally suitable, 
which have met all requirements of Secs. 600.11(f)(2) and 600.11(f)(8) 
of this chapter shall be used as a source of kidney tissue for the 
manufacture of Poliovirus Vaccine Inactivated.

[38 FR 32068, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50 
FR 4137, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990]



Sec. 630.2  Poliovirus Vaccine Inactivated.

    (a) Cultivation of virus. Virus for manufacturing vaccine shall be 
grown with aseptic techniques in monkey kidney cell cultures. Suitable 
antibiotics in the minimum concentration required may be used 
(Sec. 610.15(c) of this chapter).
    (b) Filtration. Within 72 hours preceding the beginning of 
inactivation, the virus suspensions shall be filtered or clarified by a 
method having an efficiency equivalent to that of filtration through an 
S1 Seitz type filter pad.
    (c) Virus titer. The 50 percent endpoint (TCID50) of the virus 
fluids after filtration shall be 106.5 or greater as confirmed by 
comparison in a simultaneous test (using groups of 10 tubes at 1 log 
steps or groups of 5 tubes at 0.5 log steps) with a reference virus 
distributed by the Center for Biologics Evaluation and Research. 
Acceptable titrations of the reference virus shall not vary more than 
plus-minus0.5 log10 from its labeled titer using 0.5 
milliliter inoculum in tissue culture.
    (d) Inactivation of virus. The virus shall be inactivated, as 
evidenced by the tests described in Sec. 630.4, through the use of an 
agent or method which has been demonstrated to be consistently effective 
in the hands of the manufacturer in inactivating a series of lots of 
poliovirus. If formaldehyde is used for inactivation, it shall be added 
to the virus suspension to a final concentration of U.S.P. solution of 
formaldehyde of 1:4000, and the inactivation conducted under controlled 
conditions of pH and time, at a temperature of 36 deg. to 38 deg. C. 
Three or more virus titers, suitably spaced to indicate rate of 
inactivation, shall be determined during the inactivation process. 
Filtration equivalent to that described in paragraph (b) of this section 
shall be performed after the estimated baseline time (time at which the 
50 percent end-

[[Page 87]]

point reaches one tissue culture infective dose per milliliter), but 
prior to sampling for the first single strain tissue culture test 
required in Sec. 630.4(b), except that this filtration may be omitted 
for strains of a virulence for monkeys equal to or less than that of the 
MEF-1 Type 2 strain of poliovirus.
    (e) Additional processing. Single strain or trivalent pools that 
have failed to pass safety tests prescribed in Sec. 630.4 (b), (c), or 
(e) may be treated as follows:
    (1) Filtration or clarification by a method having an efficiency 
equivalent to that of filtration through an S1 Seitz type filter pad.
    (2) Negative tests performed as described in Sec. 630.4 (b) and (c) 
must be obtained on each of two successive samples taken so as to be 
separated by an interval of at least 3 days while the material is being 
subjected to treatment with 1:4000 U.S.P. formaldehyde solution and heat 
at 36 deg. to 38 deg. C. The first sample may be taken before incubation 
is begun and the second sample shall be taken after the incubation of at 
least 3 days is completed. For both single strain and trivalent pools 
the volume tested for each tissue culture safety test shall be 
equivalent to at least 1,500 human doses.
    (3) Pools which are positive following such additional processing 
shall not be used for the manufacture of Poliovirus Vaccine Inactivated
    (f) Supplemental inactivation. Supplemental inactivation employing a 
method capable of reducing the titer of a similarly produced virus 
suspension by a factor of 10-6 may be applied at any point after 
the filtration step described in paragraph (d) or (e)(1) of this 
section.

[38 FR 32068, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50 
FR 4137, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990]



Sec. 630.3   Potency test.

    Each lot of vaccine shall be subjected to a potency test which 
permits an estimation of the antigenic capacity of the vaccine. This is 
done by means of a simultaneous comparison of the serum antibody levels 
produced in monkeys by the vaccine under test with the antibody level of 
the reference serum distributed by the Center for Biologics Evaluation 
and Research. The potency test shall be performed on samples taken after 
all final processing of the product has been completed, including 
addition of preservative, except that when the final product contains 
material having an adjuvant effect an additional test shall be performed 
with a sample taken before the addition of the adjuvant material. The 
volume of the test sample for the additional test shall be adjusted to 
the equivalent volume of Poliovirus Vaccine Inactivated in the final 
product. The test shall be conducted as follows:
    (a) Inoculation of monkeys. A group of 12 or more Macaca monkeys, or 
a species found by the Director, Center for Biologics Evaluation and 
Research, to be equally suitable for the purpose, shall be used. Animals 
shall weigh between 4 and 8 pounds and shall be in overt good health. 
Animals that become ill and remain ill during the course of immunization 
shall be excluded from the group. The test shall not be valid unless at 
least 10 animals survive the test period and their preinoculation serum 
antibody levels are as prescribed in paragraph (d) of this section. The 
test vaccine shall be given intramuscularly to each monkey in 3 doses at 
7-day intervals, each dose to be the recommended individual human dose. 
Only undiluted vaccine shall be used.
    (b) Serum samples. A blood sample shall be taken from each monkey 
prior to vaccination and then again 7 days after the last injection. 
Serum shall be separated aseptically, and stored under refrigeration.
    (c) Serum-virus neutralization test. The titers of individual monkey 
serums shall be determined in comparison with the reference serum in 
tests designed to include controls for all the variables of significance 
including the following:
    (1) Serum toxicity control;
    (2) Cell control and cell titration;
    (3) Virus titration control (at least 4 tubes for each dilution at 
0.5 log steps); and
    (4) Serum controls using type-specific serums to identify the type 
of virus used in the neutralization test.
    (d) Interpretation of the test. Animals showing preinoculation 
titers of 1:4 or over when tested against not more

[[Page 88]]

than 1,000 TCID50 of virus, shall be excluded from the test. The 
geometric mean titer of antibody induced in the monkeys surviving the 
course of immunization and bleeding, shall be calculated. A comparison 
of the value so obtained shall be made with the value for the reference 
serum that was tested simultaneously and expressed as the ratio between 
the geometric mean titer value of the serums under test and the mean 
titer value of the reference serum.
    (e) Potency requirements. A lot of vaccine tested against the 
reference serum shall be satisfactory if the geometric mean value of the 
group of individual monkey serums representing the lot of vaccine tested 
is at least 1.29 times the mean value of the reference serum for Type 1, 
at least 1.13 times for Type 2, and at least 0.72 times for Type 3.

[38 FR 32068, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50 
FR 4137, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990]



Sec. 630.4   Tests for safety.

    In the manufacture of the product, the following tests relating to 
safety shall be conducted by the manufacturer.
    (a) The virus pool--tests prior to inactivation--(1) B virus and 
Mycobacterium tuberculosis. Prior to inactivation, each individual virus 
harvest or virus pool shall be tested for the presence of B virus and 
Mycobacterium tuberculosis.
    (2) SV-40. Prior to inactivation, the material shall be tested for 
the presence of SV-40 as follows (or by any other test producing equally 
reliable results): A sample of at least 5 ml. from the virus harvest or 
virus pool shall be neutralized by high titer specific antiserum of 
other than primate origin. A similar sample from the pool of tissue 
culture fluids from control vessels representing the tissue from which 
the virus was prepared may be tested in place of the virus sample. The 
sample shall be tested in primary cercopithecus tissue cultures or in a 
cell line demonstrated as at least equally susceptible to SV-40. Each 
tissue culture system shall be observed for at least 14 days and at the 
end of the observation period at least one subculture of fluid shall be 
made in the same tissue culture system and the subculture shall be 
observed for at least 14 days.
    (3) Test results. The virus harvest or virus pool is satisfactory 
for poliovirus vaccine only if the tests produce no evidence of the 
presence of B virus, Mycobacterium tuberculosis or SV-40.
    (b) Single strain pool tissue culture tests for poliovirus. (1) 
Before pooling to make the final poliovirus vaccine, during inactivation 
at 36 deg. to 38 deg. C., two samples of each monovalent bulk strain 
pool shall be tested for the presence of virus by tissue culture 
methods, the second sample to be taken at least 3 days after taking the 
first sample.
    (2) Each sample shall be no smaller than the equivalent of 1,500 
human doses and shall be subjected to the complete testing process and 
each test shall be performed on a different monkey kidney tissue culture 
cell preparation. The test sample for one of these tests may be used 
also for the test prescribed in paragraph (f) of this section provided 
the cell cultures used have been demonstrated as fully susceptible to 
SV-40 and poliovirus. Each sample shall be inoculated into five or more 
tissue culture bottles of a suitable capacity, the ratio of the vaccine 
to the nutrient fluid being approximately 1:1 to 1:3, and the area of 
the surface growth of cells being at least 3 square centimeters per 
milliliter of sample. The tissue culture bottles shall be observed for 
at least 14 days.
    (3) A first subculture shall be made at the end of 7 days from date 
of inoculation by planting at least 2 percent of the volume from each 
original bottle into suitable tissue culture vessels, followed by 
refeeding.
    (4) A second subculture shall be made from each original bottle in 
the same manner at the end of 14 days from date of inoculation.
    (5) Each of the first and second subcultures shall be observed for 
at least 7 days.
    (6) If cytopathogenic effects occur either in the original bottles 
of the two tests or in the subcultures from them, or if cellular 
degeneration appears in the original bottles or in the subcultures 
before degeneration occurs in uninoculated cultures, the pool shall be

[[Page 89]]

held until the matter is resolved. If active poliovirus is indicated, 
the strain pool shall not be used for inclusion in a final vaccine 
unless effectively reprocessed as described in Sec. 630.2(e). If other 
viruses are present, the pool shall not be used unless it can be 
demonstrated that such viruses have originated from other than the 
strain pool being tested.
    (c) Trivalent vaccine pool tissue culture test. No less than 1,500 
human doses of the trivalent vaccine pool, without final preservative, 
prepared by pooling the three type pools, each of which has passed all 
tests prescribed in paragraph (b) of this section, shall be subjected to 
the complete tissue culture test prescribed in such paragraph (b) in at 
least two approximately equal tests in separate monkey kidney tissue 
culture preparations. This test sample may be used also for the test 
prescribed in paragraph (f) of this section provided the cell cultures 
used have been demonstrated as fully susceptible to SV-40 and 
poliovirus.
    (d) Trivalent vaccine pool lymphocytic choriomeningitis test. The 
final vaccine shall be shown to be free of lymphocytic choriomeningitis 
virus by intracerebral inoculation of the maximum volume tolerated into 
10 or more mice which shall be observed daily for at least 21 days and a 
negative test shall not be valid unless at least eight mice survive for 
this period.
    (e) Test in monkeys for active virus. (1) Vaccine from final 
containers selected at random from each filling of each lot shall be 
pooled to provide a test sample of at least 400 milliliters representing 
the various fillings. An equal volume of bulk vaccine may be substituted 
for test samples from each filling lot provided the procedure has been 
approved by the Director, Center for Biologics Evaluation and Research.
    (2) A total of not less than 20 monkeys shall be inoculated with the 
test sample. A preinjection serum sample from each monkey must not 
contain neutralizing antibody against the three poliovirus types 
detectable in a dilution of 1:4 when tested against not more than 1,000 
TCID50 of virus. At least 80 percent of the test animals 
representing each filling or each bulk sample must survive the test 
period without significant weight loss, except that if at least 60 
percent of the test animals survive the first 48 hours after injection, 
those animals which do not survive this 48-hour test period may be 
replaced by an equal number of test animals. At least 80 percent of the 
animals used in the test must show microscopic evidence of inoculation 
trauma in the lumbar region of the spinal cord, and gross or microscopic 
evidence of inoculation trauma in the thalamic area. If less than 60 
percent of the test animals survive the first 48 hours, or if less than 
80 percent of the animals fail to meet the other criteria prescribed in 
this section, the test must be repeated.
    (3) Vaccines shall be injected by combined intracerebral, 
intraspinal, and intramuscular routes into Macaca or Cercopithecus 
monkeys or a species found by the Director, Center for Biologics 
Evaluation and Research, to be equally suitable for the purpose. The 
animals shall be in overt good health and injected under deep 
barbiturate anesthesia. The intracerebral injection shall consist of 0.5 
milliliter of test sample into the thalamic region of each hemisphere. 
The intraspinal injection shall consist of 0.5 milliliter of 
concentrated test sample into the lumbar spinal cord enlargement, the 
test sample to be concentrated 100 fold in the ultracentrifuge by a 
method demonstrated to recover at least 90 percent of the virus 
particles in the sediment after it has been resuspended in the same lot 
of unconcentrated test sample. The intramuscular injection shall consist 
of 1.0 milliliter of test sample into the right leg muscles. At the same 
time, 200 milligrams of cortisone acetate shall be injected into the 
left leg muscles, and 1.0 milliliter of procaine penicillin (300,000 
units) into the right arm muscles. The monkeys shall be observed for 17 
to 19 days and signs suggestive of poliomyelitis shall be recorded.
    (4) At the end of the observation period, samples of cerebral cortex 
and of cervical and lumbar spinal cord enlargements shall be taken for 
virus recovery and identification. Histological sections shall be 
prepared from both spinal cord enlargements and examined.

[[Page 90]]

    (5) Doubtful histopathological findings necessitate (i) examination 
of a sample of sections from several regions of the brain in question, 
and (ii) attempts at virus recovery from the nervous tissues previously 
removed from the animal. The test results must be negative. Test results 
are negative if the histological and other studies leave no doubt that 
poliovirus infection did not occur.
    (f) Tissue culture safety test for SV-40. At least 500 human doses 
of each monovalent or trivalent pool of vaccine shall be tested for the 
presence of SV-40 using primary cercopithecus monkey tissue cultures or 
using a cell line demonstrated as at least equally susceptible to SV-40. 
The test shall be conducted as described in paragraph (b) of this 
section, except for the volume of test sample and except that one 
subculture of at least 2 percent of the volume of the fluids shall be 
made no less than 14 days from the date of inoculation and examined for 
at least 14 days from the date of subinoculation. The vaccine is 
satisfactory only if there is no evidence of the presence of SV-40 in 
any of the cultures or subcultures.

[38 FR 32068, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50 
FR 4137, Jan. 29, 1985; 50 FR 16229, Apr. 25, 1985; 55 FR 11013, Mar. 
26, 1990; 57 FR 10814, Mar. 31, 1992]



Sec. 630.5   General requirements.

    (a) Consistency of manufacture. No lot of final vaccine shall be 
released unless it is one of a series of five consecutive lots produced 
by the same manufacturing process, all of which have shown negative 
results with respect to all tests for the presence of live poliovirus, 
and unless each of the monovalent pools of which a polyvalent final 
vaccine is composed similarly is one of a series of five consecutive 
monovalent pools of the same type of inactivated poliovirus, all of 
which have shown negative results in all tests for the presence of live 
poliovirus.
    (b) Dose. These additional standards are based on a human dose of 
1.0 milliliter for a single injection and a total human immunizing dose 
of three injections of 1.0 milliliter given at appropriate intervals.
    (c) Samples and protocols. For each lot of vaccine, the following 
material shall be submitted to the Director, Center for Biologics 
Evaluation and Research, Food and Drug Administration, 8800 Rockville 
Pike, Bethesda, MD 20892:
    (1) A 2,500 milliliter sample, neutralized, not dialyzed, and 
without final preservative, taken at the latest possible stage of 
manufacturing before the addition of such preservative.
    (2) A 200 milliliter bulk sample of the final vaccine containing 
final preservative.
    (3) A total of not less than a 200 milliliter sample of the final 
vaccine in final labeled containers.
    (4) A protocol which consists of a summary of the history of 
manufacture of each lot including all results of each test for which 
test results are requested by the Director, Center for Biologics 
Evaluation and Research.

[38 FR 32068, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 51 
FR 18580, May 21, 1986; 55 FR 11013, Mar. 26, 1990]



            Subpart B--Poliovirus Vaccine Live Oral Trivalent

    Source: 56 FR 21432, May 8, 1991, unless otherwise noted.



Sec. 630.10  Poliovirus Vaccine Live Oral Trivalent.

    (a) Proper name and definition. The proper name of this product 
shall be Poliovirus Vaccine Live Oral Trivalent. The vaccine shall be a 
preparation containing the three types of live, attenuated polioviruses 
grown in monkey kidney cell cultures, or in a cell line found by the 
Director, Center for Biologics Evaluation and Research, to meet the 
requirements of Sec. 610.18(c) of this chapter. The vaccine shall be 
prepared in a form suitable for oral administration.
    (b) Criteria for acceptable strains. (1) The Sabin strains of 
attenuated poliovirus, Type 1 (LS-c, 2ab/KP2), Type 2 (P712, Ch, 
2ab/KP2), and Type 3 (Leon 12a1b/KP3), or derivatives 
from them, may be used in the manufacture of vaccine.
    (2)(i) Other poliovirus strains may be used in the manufacture of 
Poliovirus Vaccine Live Oral Trivalent provided that they are identified 
by historical records including:
    (A) Origin,

[[Page 91]]

    (B) Techniques of attenuation,
    (C) Antigenic properties,
    (D) Neurovirulence for monkeys,
    (E) Pathogenicity for tissue cultures of various cell types, and
    (F) Established virus markers, including rct/40, and d.
    (ii) The data shall be submitted to the Director, Center for 
Biologics Evaluation and Research, along with other data that establish:
    (A) That each such strain is at least as safe as the Sabin strain of 
the corresponding type,
    (B) That each such strain demonstrates results comparable to the 
Sabin srain when inoculated into monkeys by the intrathalamic and 
intramuscular routes, and
    (C) That each such strain has been used to produce vaccines meeting 
the safety and potency requirements of Secs. 630.11, 630.15, 630.16 or 
630.17, and 630.18.
    (3) The Director, Center for Biologics Evaluation and Research, may 
prohibit the use of a specified strain whenever the Director finds that 
it is practicable to use another strain of the same type that will 
produce a vaccine of greater safety and of at least equivalent potency.
    (4) If vaccine lots have been produced directly from strain 
materials (e.g., Sabin Original, Sabin Original Merck, or Sabin Original 
Rederived), the strain material is not required to be tested in 
accordance with the provisions of Sec. 630.10(c).
    (c) Criteria for qualification of the seed virus. (1) Each seed 
virus used in vaccine manufacture shall be prepared from an acceptable 
strain in monkey kidney cell cultures, derived from animals which have 
met all of the requirements of Sec. 630.12(a), or in a cell culture of a 
type determined to be suitable by the Director, Center for Biologics 
Evaluation and Research. The seed virus used in vaccine manufactures 
shall be demonstrated to be free of extraneous microbial agents except 
for unavoidable bacteriophage.
    (2) Seed virus used for the manufacture of oral poliovirus vaccine 
shall meet the requirements of Secs. 630.13, 630.16 or 630.17, and 
630.18. In addition, the neurovirulence of each of the first five 
consecutive monovalent virus pools prepared from the seed virus shall 
meet the neurovirulence requirements prescribed in Secs. 630.16(b)(2) or 
630.17 (b)(3).
    (3) A new seed virus may be used for production provided data are 
submitted in the form of a product license a supplement that show the 
new seed virus and each of the first five consecutive monovalent virus 
pools prepared from it meet the safety requirements of Secs. 630.13 and 
630.16 or 630.17 and 630.18 and approval for the use of the seed virus 
is received in writing from the Director, Center for Biologics 
Evaluation and Research.
    (4) Seed virus in vaccine manufacture shall be prepared in a seed 
lot system from a master virus seed lot at a passage level consistent 
with Sec. 630.13(a).
    (5) For monovalent virus pools tested in accordance with 
Sec. 630.16(b), the use of the seed virus may continue provided that the 
frequency of monovalent virus pools produced with it which fail to meet 
the criteria of neurovirulence for monkeys prescribed in 
Sec. 630.16(b)(2) is not greater than predicted on the basis of 
comparison with the corresponding reference preparation. If the 
frequency of monovalent virus pools produced with the same seed virus 
which fail to meet the criteria of neurovirulence for monkeys prescribed 
in Secs. 630.16(b)(2) is greater than the predicted 1 percent on the 
basis of the 99-percent fiduciary one-sided upper limit, that seed virus 
shall be disqualified for further use in vaccine production.
    (6) For monovalent virus pools tested in accordance with 
Sec. 630.17, subsequent and identical neurovirulence tests of the seed 
virus shall be performed in monkeys whenever there is evidence of a 
significant increase in the neurovirulence of the seed virus, upon 
introduction of a new production seed lot, and as often as is necessary 
to otherwise establish, to the satisfaction of the Director, Center for 
Biologics Evaluation and Research, that the seed virus for vaccine 
manufacture has maintained its neurovirulence properties as set forth in 
Sec. 630.17 (b)(3).

[56 FR 21432, May 8, 1991, as amended at 59 FR 49351, Sept. 28, 1994]

[[Page 92]]



Sec. 630.11  Clinical trials to qualify for license.

    To qualify for license, the antigenicity of the vaccine shall have 
been determined by clinical trials of adequate statistical design 
conducted in compliance with part 56 of this chapter, unless exempted 
under Sec. 56.104 or granted a waiver under Sec. 56.105, and with part 
50 of this chapter. Such clinical trials shall be conducted with five 
lots of oral poliovirus vaccine that have been manufactured by the same 
methods. Type specific neutralizing antibody for each type of poliovirus 
in the vaccine shall be induced in 90 percent or more of susceptibles 
after a series of doses.



Sec. 630.12  Animal source and quarantine; personnel.

    (a) Monkeys--(1) Species permissible as source of kidney tissue. 
Only Macaca monkeys, Cercopithecus monkeys, or other species found by 
the Director, Center for Biologics Evaluation and Research, to be 
equally suitable, which meet the requirements of Sec. 600.11 (f)(2) and 
(f)(8) of this chapter, shall be used as the source of kidney tissue for 
the manufacture of Poliovirus Vaccine Live Oral Trivalent.
    (2) Experimental and test monkeys. Monkeys that have been used 
previously for experimental or test purposes shall not be used as a 
source of kidney tissue in the processing of vaccine.
    (3) Quarantine; additional requirements. Excluding deaths from 
accidents or causes not due to infectious diseases, if the death rate of 
any group of monkeys being conditioned in accordance with 
Sec. 600.11(f)(2) of this chapter exceeds 5 percent per month, the 
remaining monkeys may be used for the manufacture of Poliovirus Vaccine 
Live Oral Trivalent only if all of the monkeys survive a new quarantine 
period.
    (b) Personnel. All reasonably possible steps shall be taken to 
ensure that personnel involved in processing the vaccine are immune to 
all three types of poliovirus and do not excrete poliovirus.

[56 FR 21432, May 8, 1991; 56 FR 27787, June 17, 1991]



Sec. 630.13  Manufacture of Poliovirus Vaccine Live Oral Trivalent.

    (a) Virus passages. Virus in the final vaccine shall represent no 
more than five tissue culture passages from the original strain or no 
more than five tissue culture passages from a virus clone derived from 
one of the first five tissue culture passages of the original strain.
    (b) Virus propagated in primary monkey kidney cell cultures--(1) 
Continuous cell lines. When primary monkeys kidney cell cultures are 
used in the manufacture of poliovirus vaccine, continuous cell lines 
shall not be introduced or propagated in vaccine manufacturing areas.
    (2) Identification of processed kidneys. The kidneys from each 
monkey shall be processed separately. The resulting viral fluid shall be 
identified as a separate monovalent harvest and kept separately from 
other monovalent harvests until all samples for the tests prescribed in 
paragraphs (b)(3) and (b)(4) of this section relating to that pair of 
kidneys have been withdrawn from the harvest.
    (3) Monkey kidney tissue production vessels prior to virus 
inoculation. Prior to inoculation with the seed virus and at least 3 
days after complete formation of the tissue sheet, the tissue culture 
growth in vessels derived from each pair of kidneys shall be examined 
microscopically for evidence of cell degeneration. If such evidence is 
observed, the tissue cultures from that pair of kidneys shall not be 
used for poliovirus vaccine manufacture. To test the tissue found free 
of cell degeneration for further evidence of freedom from demonstrable 
viable microbial agents, the fluid shall be removed from the cell 
cultures immediately prior to virus inoculation and tested in each of 
four culture systems:
    (i) Macaca monkey kidney cells,
    (ii) Cercopithecus monkey kidney cells,
    (iii) Primary rabbit kidney cells, and
    (iv) Cells from one of the systems described in Sec. 630.18(a)(6).
    The fluid shall be tested in the following manner: Aliquots of fluid 
from each vessel derived from the same pair of kidneys shall be pooled 
and at least 10 milliliters of the pool inoculated into each system. The 
dilution of the

[[Page 93]]

pool with medium shall be no greater than 1:4 and the area of surface 
growth of cells shall be at least 3 square centimeters per milliliter of 
test inoculum. The cultures shall be observed for at least 14 days. At 
the end of the observation period, at least one subculture of fluid from 
the Cercopithecus monkey kidney cell cultures shall be made in the same 
tissue culture system and the subculture shall be observed for at least 
14 days. If these tests indicate the presence in the monkey kidney 
tissue culture production vessels of any viable microbial agent, the 
viral harvest from these tissue cultures so implicated shall not be used 
for poliovirus vaccine manufacture.
    (4) Control vessels. At least 25 percent of the cell suspension from 
each pair of kidneys shall be set aside and used to establish control 
cultures. The control cultures shall be examined microscopically for 
cell degeneration for an additional 14 days. The culture fluids from 
such control cells shall be tested, both at the time of virus harvest 
and at the end of the additional observation period, by the method 
prescribed for testing of fluids in paragraph (b)(3) of this section. In 
addition, the control cell sheet shall be examined for presence of 
hemadsorbing viruses by the addition of guinea pig red blood cells.
    (5) Interpretation of test results. At least 80 percent of the 
control vessels shall be free of cell degeneration at the end of the 
observation period to qualify the kidneys for poliovirus vaccine 
manufacture. If the test results of the control cells indicate the 
presence of any extraneous agent at the time of virus harvest, the virus 
harvest from that tissue culture preparation shall not be used for 
poliovirus vaccine manufacture. If any of the tests or observations 
described in paragraph (b)(3) or (b)(4) of this section demonstrate the 
presence in the tissue culture preparation of any microbial agent known 
to be capable of producing human disease, the virus grown in each tissue 
culture preparation shall not be used for poliovirus vaccine 
manufacture.
    (6) Temperature of kidney tissue production vessels after virus 
inoculation. After virus inoculation, production vessels shall be 
maintained at 33.0 to 35.0  deg.C during the course of virus 
propagation.
    (7) Kidney tissue virus harvests. Virus shall be harvested not later 
than 72 hours after virus inoculation. Virus harvested from vessels 
containing the kidney tissue from one monkey may be tested separately, 
or samples of viral harvests from more than one pair of kidneys may be 
combined, identified, and tested as a monovalent virus pool. Each pool 
shall be mixed thoroughly and samples withdrawn for testing as 
prescribed in Sec. 630.18(a). The samples shall be withdrawn immediately 
after harvesting and prior to further processing, except that samples of 
test materials frozen immediately after harvesting and maintained at -60 
 deg.C or below, may be tested upon thawing, provided no more than one 
freeze-thaw cycle is employed.
    (8) Filtration. After harvesting and removal of samples for the 
safety tests prescribed in Sec. 630.18(a), the pool shall be passed 
through sterile filters having a sufficiently small porosity to assure 
bacteriologically sterile filtrates.

[56 FR 21432, May 8, 1991, as amended at 58 FR 19609, Apr. 15, 1993]



Sec. 630.14  Reference virus preparations.

    (a) Titration test controls. The following reference viruses may be 
obtained from the Center for Biologics Evaluation and Research:
    (1) Reference Poliovirus, Live, Attenuated, Type 1, as a control for 
correlation of virus titers in tissue cultures.
    (2) Reference Poliovirus, Live, Attenuated, Type 2, as a control for 
correlation of virus titers in tissue cultures.
    (3) Reference Poliovirus, Live, Attenuated, Type 3, as a control for 
correlation of virus titers in tissue cultures.
    (4) Reference Poliovirus, Live, Attenuated, Trivalent, as a control 
for correlation of virus titers in tissue cultures.
    (b) Neurovirulence test controls. (1) Except as provided in 
paragraph (b)(2) of this section, the following reference virus may be 
obtained from the Center for Biologics Evaluation and Research:

[[Page 94]]

    (i) Reference Attenuated Poliovirus, Type 1, as a control for 
evaluation of monkey neurovirulence tests.
    (ii) Reference Attenuated Poliovirus, Type 2, as a control for 
evaluation of monkey neurovirulence tests.
    (iii) Reference Attenuated Poliovirus, Type 3, as a control for 
evaluation of monkey neurovirulence tests.
    (2) Alternatively, upon FDA approval, World Health Organization 
(WHO) reference standards of the corresponding type, WHO/I, WHO/II, and 
WHO/III, may be used as controls for evaluation of monkey neurovirulence 
tests.



Sec. 630.15  Potency test.

    (a) Test for virus titer. The concentration of living virus in each 
monovalent virus pool and in each trivalent vaccine, expressed as 
infectivity titer per milliliter for cell cultures, shall be determined 
using the Reference Poliovirus, Live, Attenuated of the same type as a 
control or using another reference preparation of the same type that has 
been calibrated against the appropriate reference preparation listed in 
Sec. 630.14(a). A titration of the monovalent virus pool or the 
trivalent vaccine shall not constitute a valid test unless the titration 
of the reference virus when tested in parallel is within 0.5 
log10 of its established titer. The titration of the parallel 
reference is intended to validate the test system and shall not be used 
to adjust the titer of the pool or lot under test.
    (b) Dose. The human dose of trivalent vaccines shall be constituted 
to have infectivity titers in the final container material of 106.0 
to 107.0 for type 1, 105.1 to 106.1 for type 2, and 
105.8 to 106.8 for type 3, when assayed in HEp-2 cells, or the 
equivalent when titrated by a different method.



Sec. 630.16  Test for neurovirulence.

    (a) Except as provided in Sec. 630.17, the following test relating 
to safety prescribed in paragraph (b) of this section shall be performed 
on each monovalent virus pool after the filtration process.
    (b) Neurovirulence in monkeys. Except as provided in paragraph 
(b)(5) of this section, each monovalent virus pool shall be tested 
concurrently with the corresponding type Reference Attenuated Poliovirus 
for neurovirulence by the intraspinal route of injection in Macaca 
monkeys. Whenever possible the monkeys should be of comparable age and 
weight and from the same quarantine group. The monkeys shall be 
distributed randomly between the two test groups. If the number of 
monkeys included in both groups precludes completion during a single 
workday, approximately equal numbers of monkeys shall be inoculated with 
the monovalent virus pool and the reference preparation during each of 
the testing days. A preinjection serum sample obtained from each monkey 
shall be shown to contain no neutralizing antibody in a dilution of 1:4 
when tested against no more than 1,000 TCID50 (mean tissue culture 
infectious doses) of each of the three types of poliovirus. The 
neurovirulence test is not valid unless the inoculation sample is shown 
to contain the equivalent of 106.5 to 107.5 TCID50 per 
milliliter when a representative sample of the monovalent virus pool is 
titrated in HEp-2 cells in comparison with the Reference Poliovirus, 
Live, Attenuated of the appropriate type. All monkeys shall be observed 
for 17 to 21 days and any evidence of physical abnormalities indicative 
of poliomyelitis or other viral infections shall be recorded.
    (1) Intraspinal inoculation. For tests with type 1 and type 2 
monovalent virus pools and the Reference Attenuated Poliovirus of the 
corresponding types, each of a group of at least 12 monkeys after being 
suitably anesthetized shall be injected intraspinally into the 
enlargement of the lumbar cord with 0.1 milliliter of the inoculation 
sample. For tests with type 3 poliovirus materials, groups of at least 
20 monkeys shall be injected as above after being suitably anesthetized. 
A test of a virus pool shall include at least one group of monkeys, and 
no more than three groups shall be inoculated, with the results from 
testing one, two, or three groups of monkeys being evaluated as 
prescribed in Sec. 630.16(b)(2). In addition, if on examination there is 
no evidence of correct inoculation, additional animals may be inoculated 
in order to reestablish the minimum number of 11 positive monkeys for 
tests of types 1 and 2 virus

[[Page 95]]

pools and the minimum number of 18 positive monkeys for tests of Type 3 
virus pools. A positive monkey is an animal which either survives for 11 
or more days or succumbs or is sacrificed due to a severe poliovirus 
infection at any time before the 11th day of the observation period and 
in which neural lesions specific for poliovirus are seen in the central 
nervous system. If at least 60 percent of the animals of a group survive 
48 hours after inoculation, those animals that did not survive may be 
replaced by additional animals. If less than 60 percent of the animals 
in a group survive 48 hours after inoculation, the test shall be 
considered invalid and shall be repeated.
    (2) Determination of neurovirulence. At the conclusion of the 
observation period, the animals are sacrificed and a comparative 
evaluation shall be made of the evidence of neurovirulence of the 
monovalent virus pool under test and the Reference Attenuated Poliovirus 
of the corresponding type with respect to the histopathology of lesions 
caused by poliovirus. Animals dying or sacrificed when severely 
paralyzed or moribund during the test period, should be included in the 
evaluation, except that these examinations of these monkeys shall be 
made immediately after death. Histopathological examinations by a 
qualified pathologist shall be made of at least the lumbar and cervical 
enlargements, the medulla, the mesencephalon, the thalamus, and motor 
cortex of each monkey in the groups injected with the monovalent virus 
pool or with the reference under test. The magnitude of the 
neuropathology exhibited in the lumbar and cervical areas, the medulla, 
and mesencephalon of all positive monkeys inoculated with the monovalent 
virus pool shall be quantified and compared to the magnitude of the 
neuropathology determined based on the same type of evaluation of 
monkeys in the current test and all previous tests of the Reference 
Attenuated Poliovirus of the corresponding type. The monovalent virus 
pool may be used for poliovirus vaccine if a comparative analysis of the 
test results demonstrates that the numerical value assigned for 
neurovirulence of the monovalent virus pool is equal to or less than 
that of the Reference Attenuated Poliovirus of the corresponding type. 
If the numerical value assigned for neurovirulence of the monovalent 
virus pool is greater than that of the Reference Atteneuated Poliovirus, 
the monovalent virus pool is acceptable if the difference is not greater 
than that calculated by a mathematical method that is expected to reject 
vaccines with neurovirulence identical to the reference at a frequency 
of not less than 1 in 100 when 1 group of monkeys is inoculated. If 2 
groups are injected with the same monovalent virus pool under test, the 
frequency of rejection shall be not less than 5 in 100 and for 3 groups, 
not less than 10 in 100. If the difference in numerical values is 
greater than that calculated, irrespective of which reference 
preparation was used in the test, the monovalent virus pool shall be 
considered unacceptable and shall not be used for vaccine manufacture.
    (3) Outlier scores. In the event that one or more monkeys inoculated 
with virus from the monovalent virus pool have individual mean lesion 
scores higher than that previously or concurrently associated with the 
Reference Attenuated Poliovirus of the corresponding type, but the 
monovalent virus pool meets the criteria for acceptable neurovirulence 
given in Sec. 630.16(b)(2), the significance of the outlier scores shall 
be evaluated by a method approved by the Director, Center for Biologics 
Evaluation and Research before the vaccine may be released for use.
    (4) Test with Reference Attenuated Poliovirus. Except as provided in 
paragraph (b)(5) of this section, the Reference Attenuated Poliovirus of 
the appropriate type shall be tested as prescribed in paragraph 
(b)(1)(i) of this section concurrently with the monovalent virus pool. 
More than one monovalent virus pool of the same type may be tested with 
the same corresponding Reference Attenuated Poliovirus. Initially, a 
minimum of four tests by the testing laboratory of each Reference 
Attenuated Poliovirus is required. These tests must be such as to 
provide sufficient experience to define the performance of the Reference 
Attenuated Poliovirus and establish the variability of the assay. Each 
test of

[[Page 96]]

the Reference Attenuated Poliovirus shall be considered acceptable and 
added to the previous testing experience only if the magnitude of its 
poliovirus neuropathology is statistically compatible with the results 
of all previous tests with the same reference preparations of the same 
type performed by the testing laboratory.
    (5) Alternative procedures in case of monkey shortage. In the event 
of a shortage of test monkeys and upon approval of the Director, Center 
for Biologics Evaluation and Research, a monovalent virus pool may be 
tested without concurrent testing of the corresponding type Reference 
Attenuated Poliovirus. In such a case, the magnitude of the 
neuropathology of the monovalent virus pool shall be compared with the 
magnitude of the neuropathology exhibited in all previous tests of the 
corresponding Reference Attenuated Poliovirus.



Sec. 630.17  Alternative test for neurovirulence.

    (a) In lieu of the neurovirulence test in Sec. 630.16, the following 
test may be performed after the filtration process, on each monovalent 
virus pool or on each multiple thereof (monovalent lot).
    (b) Neurovirulence in monkeys. Each monovalent virus pool or 
monovalent lot shall be tested in comparison with the Reference 
Attenuated Poliovirus, Type 1, for neurovirulence in Macaca monkeys by 
both the intrathalamic and intraspinal routes of injection. A 
preinjection serum sample obtained from each monkey must be shown to 
contain no neutralizing antibody in a dilution of 1:4 when tested 
against no more than 1,000 TCID50 (mean tissue culture infectious 
dose) of each of the three types of poliovirus. The neurovirulence tests 
are not valid unless the sample contains at least 107.6 TCID50 
per milliliter when titrated in HEp-2 cells in comparison with the 
Reference Poliovirus, Live, Attenuated of the appropriate type. All 
monkeys shall be observed for 17 to 21 days and any evidence of physical 
abnormalities indicative of poliomyelitis or other viral infections 
shall be recorded.
    (1) Intrathalamic inoculation. Each of at least 30 monkeys shall be 
injected intracerebrally by placing 0.5 milliliter of virus pool 
material into the thalamic region of each hemisphere. Comparative 
evaluations shall be made with the virus pool under test and the 
Reference Attenuated Poliovirus, Type 1. Only monkeys that show evidence 
of inoculation into the thalamus shall be considered as having been 
injected satisfactorily. With respect to inoculation, a test is deemed 
valid if at least 24 monkeys are considered as having been injected 
satisfactorily. If on examination there is evidence of failure to 
inoculate virus pool material into the thalamus, additional monkeys may 
be inoculated in order to reestablish the minimum number of monkeys for 
the test.
    (2) Intraspinal inoculation. Each of a group of at least five 
monkeys shall be injected intraspinally with 0.2 milliliter of virus 
pool material containing at least 107.6 TCID50 per milliliter 
when titrated in HEp-2 cells, and each monkey in additional groups of at 
least five monkeys shall be injected intraspinally with 0.2 milliliter 
of a 1:1,000 and 1:10,000 dilution, respectively, of the same virus pool 
material. Comparative evaluations shall be made with the virus pool 
under test and the reference material. Only monkeys that show 
microscopic evidence of inoculation into the gray matter of the lumbar 
cord shall be considered as having been injected satisfactorily. With 
respect to inoculation, a test is deemed valid if at least four monkeys 
per group are considered as having been injected satisfactorily. If on 
examination there is evidence of failure to inoculate intraspinally, 
additional animals may be inoculated in order to reestablish the minimum 
number of animals per group.
    (3) Determination of neurovirulence. At the conclusion of the 
observation period comparative histopathological examinations by a 
qualified pathologist shall be made of the lumbar cord, cervical cord, 
lower medulla, upper medulla, mesencephalon and motor cortex of each 
monkey in the groups injected with virus under test and those injected 
with the Reference Attenuated Poliovirus, Type 1, except that for 
animals dying during the test period, these examinations shall be made 
immediately after death. If at least 60

[[Page 97]]

percent of the animals of a group survive 48 hours after inoculation, 
those animals which did not survive may be replaced by an equal number 
of animals tested as prescribed in paragraph (b) of this section. If 
less than 60 percent of the animals of a group survive 48 hours after 
inoculation, the test must be repeated. At the conclusion of the 
observation the animals shall be examined to ascertain whether the 
distribution and histological nature of the lesions are characteristics 
of poliovirus infection. A comparative evaluation shall be made of the 
evidence of neurovirulence of the virus under test and the Reference 
Attenuated Poliovirus, Type 1, with respect to:
    (i) The number of animals showing lesions characteristic of 
poliovirus infection;
    (ii) The number of animals showing lesions other than those 
characteristic of poliovirus infection;
    (iii) The severity of the lesions;
    (iv) The degree of dissemination of the lesions; and
    (v) The rate of occurrence of paralysis not attributable to the 
mechanical injury resulting from inoculation trauma. These five factors 
may be weighted and interpreted as the Director, Center for Biologics 
Evaluation and Research, or the Director's delegatees deem appropriate. 
Among permissible interpretations, the factors may be considered in 
different ways for monkeys inoculated intraspinally and for monkeys 
inoculated intrathalamically. Other relevant factors in addition to 
those listed in paragraph (b)(3)(i) through (b)(3)(v) of this section, 
such as public health consequences, may be considered in evaluating 
neurovirulence test results. The virus pool under test is satisfactory 
for poliovirus vaccine only if at least 80 percent of the animals in 
each group survive the observation period and if a comparative analysis 
of the test results demonstrates that the neurovirulence of the test 
virus pool does not exceed that of the Reference Attenuated Poliovirus, 
Type 1.
    (4) Test with Reference Attenuated Poliovirus. The Reference 
Attenuated Poliovirus, Type 1, shall be tested as prescribed in 
paragraphs (b)(1) and (b)(2) of this section at least once for every 10 
production lots of vaccine, except that the interval between the test of 
the reference and the test of any lot of vaccine shall not be greater 
than 3 months. The test procedure shall be considered acceptable only if 
lesions of poliomyelitis are seen in monkeys inoculated with the 
reference material at a frequency statistically compatible with all 
previous tests with this preparation.



Sec. 630.18  Additional tests for safety.

    (a) Tests prior to filtration. Monovalent virus pools shall contain 
no demonstrable viable microbial agent, except for unavoidable 
bacteriophage and the intended attenuated live poliovirus. The vaccine 
shall be tested for the absence of other infectious agents, including 
polioviruses of other types or strains. Testing of each monovalent pool 
shall include the following procedures:
    (1) Inoculation of rabbits. A minimum of 100 milliliters of each 
monovalent virus pool shall be tested by inoculation into at least 10 
healthy rabbits, each weighing 1,500 to 2,500 grams. Each rabbit shall 
be injected with a total of 1.0 milliliter intradermally in multiple 
sites, and subcutaneously with 9.0 milliliters, of the monovalent virus 
pool and the animals observed for at least 3 weeks. Each rabbit that 
dies after the first 24 hours of the test, or is sacrificed because of 
illness, shall be necropsied and the brain and organs removed and 
examined. The monovalent virus pool may be used for poliovirus vaccine 
only if at least 80 percent of the rabbits remain healthy and survive 
the entire period and if all the rabbits used in the test fail to show 
lesions of any kind at the sites of inoculation and fail to show 
evidence of cercopithecid herpesvirus 1 or any other viral infection.
    (2) Inoculation of adult mice. Each of at least 20 adult mice, each 
weighing 15 to 20 grams, shall be inoculated intraperitoneally with 0.5 
milliliter and intracerebrally with 0.03 milliliter of each monovalent 
virus pool. The mice shall be observed for 21 days. Each mouse that dies 
after the first 24 hours of the test, or is sacrificed because of 
illness, shall be necropsied and

[[Page 98]]

examined for evidence of viral infection by direct observation and 
subinoculation of appropriate tissue into at least five additional mice 
which shall be observed for 21 days. The monovalent virus pool may be 
used for poliovirus vaccine only if at least 80 percent of the mice 
remain healthy and survive the entire period and if all the mice used in 
the test fail to show evidence of lymphocytic choriomeningitis virus or 
other viral infection.
    (3) Inoculation of suckling mice. Each of at least 20 suckling mice 
less than 24 hours old shall be inoculated intracerebrally with 0.01 
milliliter and intraperitonally with 0.1 milliliter of the monovalent 
virus pool. The mice shall be observed daily for at least 14 days. Each 
mouse that dies after the first 24 hours of the test, or is sacrificed 
because of illness, shall be necropsied and examined for evidence of 
viral infection. Such examination shall include subinoculation of 
appropriate tissue suspensions into an additional group of at least five 
suckling mice by the intracerebral and intraperitoneal routes and 
observed daily for 14 days. In addition, a blind passage shall be made 
of a single pool of the emulsified tissue (minus skin and viscera) of 
all mice surviving the original 14-day test. The monovalent virus pool 
may be used for poliovirus vaccine only if at least 80 percent of the 
mice remain healthy and survive the entire period and if all the mice 
used in the test fail to show evidence of Coxsackie or other viral 
infection.
    (4) Inoculation of guinea pigs. Each of at least five guinea pigs, 
each weighting 350 to 450 grams, shall be inoculated intracerebrally 
with 0.1 milliliter and intraperitoneally with 5.0 milliliters on the 
monovalent virus pool to be tested. The animals shall be observed for at 
least 42 days and rectal temperatures recorded daily for the last 3 
weeks of the test. Each animal that dies after the first 24 hours of the 
test, or is sacrificed because of illness, shall be necropsied and its 
tissues shall be examined both microscopically and culturally for 
evidence of tubercle bacilli, and by passage of tissue suspensions into 
at least three other guinea pigs by the intracerebral and 
intraperitoneal routes of inoculation for evidence of viral infection. 
If clinical signs suggest infection with lymphocytic choriomeningitis 
virus, serological tests shall be performed on blood samples of the test 
guinea pigs to confirm the clinical observations. Animals that die or 
are sacrificed during the first 3 weeks after inoculation with the 
monovalent virus pools shall be examined for infection with lymphocytic 
choriomeningitis virus. Animals that die in the final 3 weeks shall be 
examined both microscopically and culturally for Mycobacterium 
tuberculosis. The monovalent virus pool may be used for poliovirus 
vaccine only if at least 80 percent of all animals remain healthy and 
survive the observation period and if all the animals used in the test 
fail to show evidence of infection with Mycobacterium tuberculosis or 
any viral infection.
    (5) Inoculation of monkey kidney tissue cultures. At least 500 doses 
or 50 milliliters, whichever is a greater volume of virus, taken either 
from each undiluted monovalent virus pool or, in equal proportions from 
individual harvests or subpools, shall be tested for simian viruses in 
Macaca monkey kidney tissue cultures and, in the same volume, in 
Cercopithecus monkey kidney tissue cultures. A dilution of the virus 
pool in medium not to exceed 1:4 shall be used. The area of surface 
growth of the cells shall be at least 3 square centimeters per 
milliliter of test inoculum. The test poliovirus shall be neutralized by 
high-titer specific antiserum of nonprimate origin. The immunizing 
antigens used for the preparation of antisera shall be grown in a cell 
line other than the cell line used for testing the vaccine. The cultures 
shall be observed for at least 14 days. At the end of the observation 
period at least one subculture of fluid from the Cercopithecus kidney 
cell culture shall be made in the same tissue culture system and the 
subculture shall be observed for at least 14 days. The monovalent virus 
pool may be used for poliovirus vaccine only if all the tissue cultures 
fail to show evidence of the presence of simian viruses or any other 
viral infection.
    (6) Inoculation of human cell cultures. At least 500 doses or 50 
milliliters, whichever represents a greater volume of virus, taken from 
either a single monovalent

[[Page 99]]

pool or, in equal proportions from individual harvests or subpools, 
shall be tested for the presence of measles virus in either:
    (i) Primary human amnion cells,
    (ii) Primary human kidney cells, or
    (iii) Any other human or nonhuman cell system of comparable 
suspectibility to unmodified measles virus.
The virus pool shall be diluted with medium not to exceed 1:4. The area 
of surface growth of cells shall be at least 3 square centimeters per 
milliliter of test inoculum. The test material shall be neutralized with 
poliovirus antiserum of other than primate origin if the tissue culture 
cell system used is susceptible to poliovirus. The immunizing antigens 
used for the preparation of antiserum shall be grown in a cell line 
other than the cell line used for testing the vaccine. The culture shall 
be observed for at least 14 days. The monovalent virus pool may be used 
for poliovirus vaccine only if all tissue cultures fail to show evidence 
of the presence of measles virus or any other viral infection.
    (7) Inoculation of a rabbit kidney tissue culture. At least 500 
milliliters of virus pool, taken from either a single monovalent pool or 
in equal proportions from individual harvests or subpools, shall be 
tested in primary rabbit kidney tissue culure preparations for evidence 
of cercopithecid herpesvirus 1. The virus pool shall be diluted with 
medium not to exceed 1:4. The area of surface growth of cells shall be 
at least 3 square centimeters per milliliter of test inoculum. The 
culture shall be observed for at least 14 days. The monovalent virus 
pool may be used for poliovirus vaccine only if all tissue cultures fail 
to show evidence of the presence of herpesvirus.
    (b) Tests for in vitro markers. In addition to the neurovirulence 
test required by Secs. 630.16 or 630.17, the following tests relating to 
safety shall be performed on each monovalent virus pools after the 
filtration process. Tests shall be performed on each monovalent virus 
pool using the marker tests described below or other methods shown to be 
of comparable value in indentification of the attenuated strain. The 
test results shall demonstrate that the monovalent virus pool under test 
and the seed virus have substantially the same marker characteristics.
    (1) rct/40 Marker. Attenuated strains which grow readily at 40 
deg.C (0.5  deg.C) are classified as rct/40 positive (+) in 
contrast to the rct/40 negative (-) strains, which show an increased 
growth of at least 100,000 fold at 36  deg.C over that obtained at 40 
deg.C. Comparative determinations shall be made in suitable culture 
vessels.
    (2) d Marker. Attenuated strains which grow readily at low 
concentrations of bicarbonate under agar are classified as d positive 
(+) in contrast to the d negative (-) strains, which exhibit delayed 
growth under the same conditions. The cultures shall be grown in a 36 
deg.C incubator, in suitable culture vessels in an environment of 5 
percent CO2 in air.
    (c) Final container sterility test. The final container sterility 
test need not be performed provided aseptic techniques are used in the 
filling process.

[56 FR 21432, May 8, 1991; 56 FR 27787, June 17, 1991]



Sec. 630.19  General requirements.

    (a) Vaccine release. No lot of trivalent vaccine shall be released 
by the manufacturer unless each monovalent virus pool contained therein:
    (1) Has been manufactured by the same procedures;
    (2) Has met the criteria of neurovirulence for monkeys prescribed in 
Secs. 630.16(b) or 630.17(b);
    (3) Has met the criteria of in vitro markers prescribed in 
Sec. 630.18(b); and
    (4) Has been released for further manufacturing by the Director, 
Center for Biologics Evaluation and Research unless, at the Director's 
discretion, the Director determines that lot release by the Center for 
Biologics Evaluation and Research is not required. The protocols for all 
monovalent virus pools produced sequentially from the same seed and 
tested, in whole or in part, in accordance with Secs. 630.16(b) or 
630.17(b) shall be submitted to the Director, Center for Biologics 
Evaluation and Research, whether or not release of the pool for further 
manufacturing is requested. For monovalent virus pools not tested under 
Secs. 630.16(b) or 630.17(b),

[[Page 100]]

the manufacturer shall report the reasons for partial manufacture to the 
Director, Center for Biologics Evaluation and Research.
    (b) Labeling. In addition to the items required by other applicable 
labeling provisions of this chapter, the final container label shall 
bear a statement indicating that liquid vaccine may not be used for more 
than 7 days after opening the container. Labeling may include a 
statement indicating that, for frozen vaccine, a maximum of 10 freeze-
thaw cycles is permissible provided the total cumulative duration of 
thaw does not exceed 24 hours, and provided the temperature does not 
exceed 8  deg.C during the periods of thaw.
    (c) Samples and protocols. For each trivalent lot of vaccine and for 
each monovalent virus pool, the following materials shall be submitted 
in accordance with instructions received from the Director, Center for 
Biologics Evaluation and Research, 8800 Rockville Pike, Bethesda, MD 
20892.
    (1) A protocol that consists of a summary of the history of 
manufacture of each trivalent lot or monovalent virus pool, including 
any test results requested by the Director, Center for Biologics 
Evaluation and Research.
    (2) Twenty milliliters of monovalent virus pool before filtration.
    (3) Forty milliliters of monovalent virus pool after filtration. The 
titer of the sample shall be no less than the equivalent of 10 7.5 
TCID 50 per milliliter when titrated in HEp-2 cells; if the titer 
is greater than 10 7.5 TCID 50 per milliliter, a 
correspondingly smaller volume may be submitted.
    (4) A total of at least 50 single doses or the equivalent thereof of 
the trivalent vaccine.
    (5) When deemed appropriate, the Director, Center for Biologics 
Evaluation and Research, may require submission of samples or sample 
volumes other than those specified in paragraphs (c)(2), (c)(3), and 
(c)(4) of this section.
    (d) Public health implications. In interpreting any provision of the 
regulations governing oral poliovirus vaccine, the agency may consider 
any potential effect on individual or public health, including effects 
related to vaccine supply.
    (e) Alternative procedures. (1) The Director, Center for Biologics 
Evaluation and Research, may approve an exception or alternative to any 
requirement in subpart B of part 630 regarding Poliovirus Vaccine Live 
Oral. Requests for such exceptions or alternatives should ordinarily be 
made in writing. However, in limited circumstances such requests may be 
made orally and permission may be given orally by the Director, Center 
for Biologics Evaluation and Research. Oral requests and approvals must 
be followed by written requests and written approvals.
    (2) FDA will publish a list of approved alternative procedures and 
exceptions periodically in the Federal Register.
    (f) Status of vaccine in distribution. Poliovirus Vaccine Live Oral 
released or in distribution prior to May 8, 1991, is deemed to meet the 
requirements of supart B of part 630.



                          Subpart C--[Reserved]



                  Subpart D--Measles Virus Vaccine Live



Sec. 630.30  Measles Virus Vaccine Live.

    (a) Proper name and definition. The proper name of this product 
shall beMeasles Virus Vaccine Live, which shall consist of a preparation 
of live, attenuated, measles virus.
    (b) Criteria for acceptable strains of attenuated measles virus. 
Strains of attenuated measles virus used in the manufacture of vaccine 
shall be identified by (1) historical records, including origin and 
manipulation during attenuation and (2) antigenic specificity as measles 
virus as demonstrated by tissue culture neutralization tests. Strains 
used for the manufacture ofMeasles Virus Vaccine Live, shall have been 
shown to be safe and potent in man by field studies with experimental 
vaccines. The vaccine shall have been demonstrated as safe and potent in 
at least 10,000 susceptible persons. Susceptibility shall be shown by 
the absence of neutralizing or other antibodies against measles virus, 
or by other appropriate methods. Seed virus used for vaccine manufacture 
shall be free of all demonstrable extraneous

[[Page 101]]

viable microbial agents except for unavoidable bacteriophage.
    (c) Neurovirulence safety test of the virus seed strain in monkeys--
(1) The test. A demonstration shall be made in monkeys of the lack of 
neurotropic properties of the seed strain of attenuated measles virus 
used in the manufacture of measles virus vaccine. For this purpose and 
to establish consistency of manufacture of the vaccine, vaccine from 
each of five consecutive lots shall be tested separately in the 
following manner:
    (i) Samples of each of the five lots of vaccine shall be tested in 
measles susceptible monkeys. Immediately prior to initiation of a test 
each monkey shall have been shown to be serologically negative for 
neutralizing antibodies by means of a tissue culture neutralization test 
with undiluted serum from each monkey tested at approximately 100 
TCID50 of Edmonston strain measles virus, or negative for measles 
virus antibodies as demonstrated by tests of equal sensitivity.
    (ii) A test sample of vaccine removed after clarification but before 
final dilution for standardization of virus content shall be used for 
the test.
    (iii) Vaccine shall be injected by combined intracerebral, 
intraspinal, and intramuscular routes into not less than 20 Macaca or 
Cercopithecus monkeys or a species found by the Director, Center for 
Biologics Evaluation and Research, to be equally suitable for the 
purpose. The animals shall be in overt good health and injected under 
deep barbiturate anesthesia. The intramuscular injection shall consist 
of 1.0 milliliter of test sample into the right leg muscles. At the same 
time, 200 milligrams of cortisone acetate shall be injected into the 
left leg muscles, and 1.0 milliliter of procaine penicillin (300,000 
units) into the right arm muscles. The intracerebral injection shall 
consist of 0.5 milliliter of test sample into each thalamic region of 
each hemisphere. The intraspinal injection shall consist of 0.5 
milliliter of test sample into the lumber spinal cord enlargement.
    (iv) The monkeys shall be observed for 17-21 days and symptoms of 
paralysis as well as other neurologic disorders shall be recorded.
    (v) At least 90 percent of the test animals must survive the test 
period without losing more than 25 percent of their weight except that, 
if at least 70 percent of the test animals survive the first 48 hours 
after injection, those animals which do not survive this 48-hour test 
period may be replaced by an equal number of qualified test animals 
which are tested pursuant to paragraphs (c)(1)(i) through (iv) of this 
section. At least 80 percent of the injected animals surviving beyond 
the first 48 hours must show gross or microscopic evidence of 
inoculation trauma in the thalamic area and microscopic evidence of 
inoculation trauma in the lumbar region of the spinal cord. If less than 
70 percent of the test animals survive the first 48 hours, or if less 
than 80 percent of the animals meet the inoculation criteria prescribed 
in this paragraph, the test must be repeated.
    (vi) At the end of the observation period, each surviving monkey 
shall (a) be bled and the serum tested for evidence of serum antibody 
conversion to measles virus and (b) be autopsied and samples of cerebral 
cortex and of cervical and lumbar spinal cord enlargements shall be 
taken for virus recovery and identification if needed pursuant to 
paragraph (c)(1)(vii) of this section. Histological sections shall be 
prepared from both spinal cord enlargements and appropriate sections of 
the brain and examined.
    (vii) Doubtful histopathological findings necessitate (a) 
examination of a sample of sections from several regions of the brain in 
question, and (b) attempts at virus recovery from the nervous systems 
tissues previously removed from the animal.
    (viii) The lot is satisfactory if the histological and other studies 
demonstrate no evidence of changes in the central nervous system 
attributable to unusual neurotropism of the seed virus or of the 
presence of extraneous neurotropic agents.
    (2) Wild virus controls. As a check against the inadvertent 
introduction of wild measles virus, at least four uninoculated measles 
susceptible control monkeys shall be maintained as either cage mates to, 
or within the same immediate area of, the 20 inoculated test animals for 
each lot of vaccine for

[[Page 102]]

the entire period of observation (17-21 days) and an additional 10 days. 
Serum samples from these control contact monkeys drawn at the time of 
seed virus inoculation of the test animals, and again after completion 
of the test, shall be shown to be free of measles neutralizing 
antibodies.
    (3) Test results. (i) For each lot of vaccine under test, at least 
80 percent of the monkeys must show measles antibody serological 
conversion (1:4 or greater) when the serum as obtained from the monkey 
is tested and the control contact monkeys must demonstrate no 
immunological response indicative of measles virus infection.
    (ii) The measles virus seed has acceptable neurovirulence properties 
for use in vaccine manufacture only if for each of the five lots (a) 90 
percent of the monkeys survive the observation period, (b) the 
histological and other studies produce no evidence of changes in the 
central nervous system attributable to unusual neurotropism of the seed 
virus, and (c) there is no evidence of the presence of extraneous 
neurotropic agents.
    (4) Need for additional neurovirulence safety testing. A 
neurovirulence safety test as prescribed in this paragraph shall be 
performed on vaccine from five consecutive lots whenever a new 
production seed lot is introduced or whenever the source of cell culture 
substrate must be reestablished and recertified as prescribed in 
Sec. 630.32(a) and (b) of this part.

[38 FR 32068, Nov. 20, 1973, as amended at 40 FR 11719, Mar. 13, 1975; 
49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 1985; 55 FR 11013, Mar. 
26, 1990; 55 FR 47875, Nov. 16, 1990]



Sec. 630.31  Clinical trials to qualify for license.

    To qualify for license, the antigenicity of the vaccine shall have 
been determined by clinical trials of adequate statistical design, by a 
suitable route of administration of the product. Such clinical trials 
shall be conducted with five lots of measles virus vaccine which have 
been manufactured by the same methods. There shall be a demonstration 
under circumstances in which adequate clinical and epidemiological 
surveillance of illness has been maintained to show that the measles 
virus vaccine, when administered as recommended by the manufacturer, is 
free of harmful effect upon administration to approximately 1,000 
susceptible individuals, in that there were no detectable neutralizing 
antibodies before vaccination and there was serological conversion after 
vaccination. The five lots of vaccine shall be distributed as evenly as 
possible among the 1,000 individuals tested. Demonstration shall be made 
of immunogenic effect by the production of specific measles neutralizing 
antibodies (i.e., sero-conversion from less than 1:4 to 1:8 or greater) 
in at least 90 percent of each of five groups of measles susceptible 
individuals, each having received a virus vaccine dose which is not 
greater than that which was demonstrated to be safe in field studies 
(Sec. 630.30(b)) when used under comparable conditions. Such clinical 
trials shall be conducted in compliance with part 56 of this chapter 
unless exempted under Sec. 56.104 or granted a waiver under Sec. 56.105, 
and with the requirements for informed consent set forth in part 50 of 
this chapter.

[55 FR 47875, Nov. 16, 1990]



Sec. 630.32   Manufacture of live, attenuated Measles Virus Vaccine.

    (a) Virus cultures. Virus shall be propagated in chick embryo tissue 
cultures.
    (b) Virus propagated in chick embryo tissue cultures. Embryonated 
chicken eggs used as the source of chick embryo tissue for the 
propagation of measles virus shall be derived from flocks certified to 
be free of Salmonella pullorum, avian tuberculosis, fowl pox, Rous 
sarcoma, avian leucosis, reticuloendotheliosis virus, and other 
adventitious agents pathogenic for chickens. If eggs are procured from 
flocks that are not so certified, tests shall be performed to 
demonstrate freedom of the vaccine from such agents. (See 
Sec. 630.35(a)(8) for test for avian leucosis.)
    (c) [Reserved]
    (d) Passage of virus strain in vaccine manufacture. Virus in the 
final vaccine shall represent no more than ten tissue culture passages 
beyond the passage used to perform the clinical trials (Sec. 630.30(b)) 
which qualified the manufacturer's vaccine strain for license.

[[Page 103]]

    (e) Tissue culture preparation. Only primary cell tissue cultures 
shall be used in the manufacture of Measles Virus Vaccine. Continuous 
cell lines shall not be introduced or propagated in Measles Virus 
Vaccine manufacturing areas.
    (f) Control vessels. (1) From the tissue used for the preparation of 
tissue cultures for growing attenuated measles virus, an amount of 
processed cell suspension equivalent to that used to prepare 500 ml. of 
tissue culture shall be used to prepare uninfected tissue control 
materials. This material shall be distributed in control vessels and 
observed microscopically for a period of no less than 14 days beyond the 
time of inoculation of the production vessels with measles virus; but if 
the production vessels are held for use in vaccine manufacture for more 
than 14 days, the control vessels shall be held and observed for the 
additional period. At the end of the observation period or at the time 
of virus harvest, whichever is later, fluids from the control cultures 
shall be tested for the presence of adventitious agents as follows:

    Samples of fluid from each control vessel shall be collected at the 
same time as fluid is harvested from the corresponding production 
vessels. If multiple virus harvests are made from the same cell 
suspension, the control samples for each harvest shall be frozen and 
stored at -60 deg. C. until the last viral harvest for that cell 
suspension is completed. The fluid from all the control samples from 
that suspension shall be pooled in proportionate amounts and at least 
five ml. inoculated into human and simian cell tissue culture systems 
and in the tissue culture system used for virus production. The cultures 
shall be observed for the presence of changes attributable to growth of 
adventitious viral agents including hemadsorption viral agents.

    (2) The cell sheets of one quarter to one third of the control 
vessels shall be examined at the end of the observation period (14 days 
or longer) for the presence of hemadsorption viruses by the addition of 
guinea pig red blood cells. If the chick embryo cultures were not 
derived from a certified source (paragraph (b) of this section), the 
remaining tissue culture controls may be used to test for avian leucosis 
virus using either Rubin's procedure for detecting Resistance Inducing 
Factor (RIF) or a method of equivalent effectiveness.
    (3) The test is satisfactory only if there is no evidence of 
adventitious viral agents and if at least 80 percent of the control 
vessels are available for observation at the end of the observation 
period (14 days or longer).
    (g) Test samples. Samples of virus harvests or pools for testing by 
inoculation into animals, into tissue culture systems, into embryonated 
hens' eggs, and into bacteriological media, shall be withdrawn 
immediately after harvesting or pooling but prior to freezing except 
that samples of test materials frozen immediately after harvesting or 
pooling and maintained at -60 deg. C. or below, may be tested upon 
thawing, provided no more than two freeze-thaw cycles are employed. The 
required tests shall be initiated without delay after thawing.

[38 FR 32068, Nov. 20, 1973, as amended at 40 FR 11719, Mar. 13, 1975; 
47 FR 24699, June 8, 1982]



Sec. 630.33   Reference virus.

    A U.S. Reference Measles Virus, Live, Attenuated, shall be obtained 
from the Center for Biologics Evaluation and Research as a control for 
correlation of virus titers.

[38 FR 32068, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]



Sec. 630.34   Potency test.

    The concentration of live measles virus shall constitute the measure 
of potency. The titration shall be performed in a suitable cell culture 
system, free of wild viruses, using either the U.S. Reference Measles 
Virus, Live, Attenuated or a calibrated equivalent strain as a titration 
control. The concentration of live measles virus contained in the 
vaccine of each lot under test shall be no less than the equivalent of 
1,000 TCID50 of the U.S. reference per human dose.



Sec. 630.35   Test for safety.

    (a) Tests prior to clarification of vaccine manufactured in chick 
embryo tissue cultures. Prior to clarification, the following tests 
shall be performed on each virus pool of chick embryo tissue culture:

[[Page 104]]

    (1) Inoculation of adult mice. Each of at least 20 adult mice each 
weighing 15-20 grams shall be inoculated intraperitoneally with 0.5 ml. 
and intracerebrally with 0.03 ml. amounts of each virus pool to be 
tested. The mice shall be observed for 21 days. Each mouse that dies 
after the first 24 hours of the test, or is sacrificed because of 
illness, shall be necropsied and examined for evidence of viral 
infection by direct observation and subinoculation of appropriate tissue 
into at least five additional mice which shall be observed for 21 days. 
The virus pool may be used only if at least 80 percent of the original 
group of mice remain healthy and survive the observation period and if 
none of the mice show evidence of a transmissible agent or other viral 
infection, other than measles virus, attributable to the vaccine.
    (2) Inoculation of suckling mice. Each of at least 20 suckling mice 
less than 24 hours old shall be inoculated intracerebrally with 0.01 ml. 
and intraperitoneally with 0.1 ml. of the virus pool to be tested. The 
mice shall be observed daily for at least 14 days. Each mouse that dies 
after the first 24 hours of the test, or is sacrificed because of 
illness, shall be necropsied and examined for evidence of viral 
infection. Such examination shall include subinoculation of appropriate 
tissue suspensions into an additional group of at least five suckling 
mice by intracerebral and intraperitoneal routes and observed daily for 
14 days. In addition, a blind passage shall be made of a single pool of 
the emulsified tissue (minus skin and viscera) of all mice surviving the 
original 14-day test. The virus pool is satisfactory for Measles Virus 
Vaccine only if at least 80 percent of the original inoculated mice 
remain healthy and survive the entire observation period, and if none of 
the mice used in the test show evidence of a transmissible agent or 
viral infection, other than measles virus, attributable to the vaccine.
    (3) Inoculation of monkey tissue cell cultures. A volume of virus 
suspension of each undiluted virus pool, equivalent to at least 500 
human doses or 50 milliliters, whichever represents a greater volume, 
shall be tested for adventitious agents in Cercopithecus monkey kidney 
tissue culture preparations or Erythrocebus patas monkey kidney tissue 
culture preparations, after neutralization of the measles virus by a 
high titer antiserum of nonhuman, nonsimian and nonchicken origin. The 
immunizing antigen used for the preparation of the measles antiserum 
shall be grown in tissue culture cells that shall be free of extraneous 
viruses which might elicit antibodies that could inhibit growth of 
extraneous viruses present in the measles virus pool. The tissue culture 
of the virus pool shall be observed for no less than 14 days. The virus 
pool is satisfactory for measles virus vaccine only if all the tissue 
culture tests fail to show evidence of any extraneous transmissible 
agent other than measles virus attributable to the vaccine.
    (4) Inoculation of other cell cultures. The measles virus pool shall 
be tested in the same manner as prescribed in paragraph (a)(3) of this 
section in rhesus or cynomolgus monkey kidney, chick embryo, and human 
tissue cell cultures.
    (5) Inoculation of embryonated chicken eggs. A volume of virus 
suspension of each undiluted virus pool, equivalent to at least 100 
doses or 10 milliliters, whichever represents a greater volume, after 
neutralization of the measles virus by a high titer antiserum of 
nonhuman, nonsimian, nonavian origin shall be tested as follows:
    (i) Embryonated eggs, 10 to 11 days old, shall be inoculated by the 
allantoic route using 0.5 milliliter per egg. Follow incubation at 
35 deg. C for 72 hours, the allantoic fluids shall be harvested, pooled, 
and subpassed by the same route into fresh, embryonated eggs, 10 to 11 
days old, using 0.5 milliliter per egg and incubated at 35 deg. C for 72 
hours. Both the initial pool and the subpassage harvest shall be tested 
for the presence of hemagglutinin. The virus pool is satisfactory if the 
embryos appear normal and there is no evidence of hemagglutinating 
agents.
    (ii) Embryonated eggs, 6 to 7 days old, shall be inoculated by the 
yolk sac route using 0.5 milliliter per egg. Following incubation at 
35 deg. C for at least 9 days, the yolk sacs shall be harvested and 
pooled. A 10-percent suspension of

[[Page 105]]

yolk sacs shall be subpassed by the same route into fresh embryonated 
eggs, 6 to 7 days old, using 0.5 milliliter of inoculum per egg and 
incubated at 35 deg. C for at least 9 days. The virus pool is 
satisfactory if the embryos in both the initial test and the subpassage 
appear normal.
    (6) [Reserved]
    (7) Bacteriological tests. Each virus pool shall be tested for 
sterility in accordance with Sec. 610.12 of this chapter. In addition 
each virus pool shall be tested for the presence of M. tuberculosis, 
both avian and human, by appropriate culture methods.
    (8) Test for avian leucosis. If the cultures were not derived from a 
certified source (Sec. 630.32(b)), and the control fluids were not 
tested for avian leucosis (Sec. 630.32(f)), at least 500 doses or 50 
ml., whichever represents a greater volume of each undiluted vaccine 
pool, shall be tested and found negative for avian leucosis, using 
either Rubin's procedure for detecting Resistance Inducing Factor (RIF) 
or another method of equivalent effectiveness.
    (b) [Reserved]
    (c) Clarification. After harvesting and removal of samples for 
testing as prescribed above in this section, the virus fluids shall be 
clarified by centrifugation, by passage through filters of sufficiently 
small porosity, or by any other method that will assure removal of all 
intact tissue cells which may have been collected in the harvesting 
process.

[38 FR 32068, Nov. 20, 1973, as amended at 40 FR 11719, Mar. 13, 1975; 
41 FR 43400, Oct. 1, 1976; 47 FR 24699, June 8, 1982]



Sec. 630.36   General requirements.

    (a) Final container tests. In addition to the tests required 
pursuant to Sec. 610.14 of this chapter, an immunological and 
virological identity test shall be performed on the final container if 
it was not performed on each pool or the bulk vaccine prior to filling.
    (b)--(c) [Reserved]
    (d) Dose. These standards are based on an individual human 
immunizing dose of no less than 1,000 TCID50 of Measles Virus 
Vaccine Live, expressed in terms of the assigned titer of the U.S. 
reference measles virus.
    (e) Labeling. In addition to the items required by other applicable 
labeling provisions of this subchapter, single-dose container labeling 
for vaccine which is not protected against photochemical deterioration 
shall include a statement cautioning against exposure to sunlight.
    (f) [Reserved]
    (g) Photochemical deterioration; protection. Vaccine in multiple 
dose final containers shall be protected against photochemical 
deterioration. Such containers may be colored, or outside coloring or 
protective covering may be used for this purpose, provided (1) the 
method used is shown to provide the required protection, and (2) visible 
examination of the contents is not precluded. Vaccine in single dose 
containers may be protected in the same manner provided the same 
conditions are met.
    (h) Sample and protocols. The following materials shall be submitted 
to the Director, Center for Biologics Evaluation and Research, Food and 
Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892:
    (1) For each lot of vaccine:
    (i) A protocol which consists of a summary of the history of the 
manufacture of the lot, including all results of each test for which 
test results are requested by the Director, Center for Biologics 
Evaluation and Research.
    (ii) A total of no less than two 25-milliliter volumes in a frozen 
state (-60 deg. C) of preclarification bulk vaccine containing no 
preservative or adjuvant.
    (iii) A total of no less than 30 containers of the vaccine from each 
filling of each bulk lot of single-dose containers. A total of no less 
than six 50-dose containers or ten 10-dose containers of the vaccine 
from each filling of each bulk lot of multiple-dose containers.
    (2) In addition to the requirements of paragraph (h)(1) of this 
section, whenever a new production seed lot is introduced, or whenever 
the source of cell culture substrate must be reestablished and 
recertified, samples consisting of no less than 100 milliliters in 10 
milliliter volumes, in a frozen state (-60 deg. C), of postclarification 
bulk vaccine

[[Page 106]]

containing stabilizer but no preservative or adjuvant, taken from each 
of 5 consecutive lots of the bulk vaccine.

[38 FR 32068, Nov. 20, 1973, as amended at 41 FR 10429, Mar. 11, 1976; 
49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 1985; 51 FR 15610, Apr. 
25, 1986; 55 FR 11013, Mar. 26, 1990]



                          Subpart E--[Reserved]



                   Subpart F--Mumps Virus Vaccine Live



Sec. 630.50  Mumps Virus Vaccine Live.

    (a) Proper name and definition. The proper name of this product 
shall be Mumps Virus Vaccine Live, which shall consist of a preparation 
of live, attenuated mumps virus.
    (b) Criteria for acceptable strains of attenuated mumps virus. 
Strains of attenuated mumps virus used in the manufacture of vaccine 
shall be identified by (1) historical records including origin and 
manipulation during attenuation, (2) antigenic specificity as mumps 
virus as demonstrated by tissue culture neutralization tests. Strains 
used for the manufacture of Mumps Virus Vaccine Live shall have been 
shown to be safe and potent in at least 5,000 susceptible individuals by 
field studies with experimental vaccines. Susceptibility shall be shown 
by the absence of neutralizing or other antibodies against mumps virus, 
or by other appropriate methods. Seed virus used for vaccine manufacture 
shall be free of all demonstrable extraneous viable microbial agents 
except for unavoidable bacteriophage.
    (c) Neurovirulence safety test of the virus seed strain in monkeys--
(1) The test. A demonstration shall be made in monkeys of the lack of 
neurotropic properties of the seed strain of attenuated mumps virus used 
in the manufacture of mumps vaccine. For this purpose and to establish 
consistency of manufacture of the vaccine, vaccine from each of five 
consecutive lots shall be tested separately in monkeys shown to be 
serologically negative for mumps virus antibodies in the following 
manner:
    (i) A test sample of vaccine removed after clarification but before 
final dilution for standardization of virus content shall be used for 
the test.
    (ii) Vaccine shall be injected by combined intracerebral, 
intraspinal, and intramuscular routes into not less than 20 Macaca or 
Cercopithecus monkeys or a species found by the Director, Center for 
Biologics Evaluation and Research, to be equally suitable for the 
purpose. The animals shall be in overt good health and injected under 
deep barbiturate anesthesia. The intramuscular injection shall consist 
of 1.0 milliliter of test sample into the right leg muscles. At the same 
time, 200 milligrams of cortisone acetate shall be injected into the 
left leg muscles, and 1.0 milliliter of procaine penicillin (300,000 
units) into the right arm muscles. The intracerebral injection shall 
consist of 0.5 milliliter of test sample into each thalamic region of 
each hemisphere. The intraspinal injection shall consist of 0.5 
milliliter of test sample into the lumbar spinal cord enlargement.
    (iii) The monkeys shall be observed for 17-21 days and symptoms of 
paralysis as well as other neurologic disorders shall be recorded.
    (iv) At least 90 percent of the test animals must survive the test 
period without losing more than 25 percent of their weight except that, 
if at least 70 percent of the test animals survive the first 48 hours 
after injection, those animals which do not survive this 48-hour test 
period may be replaced by an equal number of qualified test animals 
which are tested pursuant to paragraphs (c)(1)(i) through (iii) of this 
section. At least 80 percent of the injected animals surviving beyond 
the first 48 hours must show gross or microscopic evidence of 
inoculation trauma in the thalamic area and microscopic evidence of 
inoculation trauma in the lumbar region of the spinal cord. If less than 
70 percent of the test animals survive the first 48 hours, or if less 
than 80 percent of the animals meet the inoculation criteria prescribed 
in this paragraph, the test must be repeated.
    (v) At the end of the observation period, each surviving animal 
shall be autopsied and samples of cerebral cortex and of cervical and 
lumbar spinal cord enlargements shall be taken for virus recovery and 
identification if

[[Page 107]]

needed pursuant to paragraph (c)(1) (vi) of this section. Histological 
sections shall be prepared from both spinal cord enlargements and 
appropriate sections of the brain and examined.
    (vi) Doubtful histopathological findings necessitate (a) examination 
of a sample of sections from several regions of the brain in question, 
and (b) attempts at virus recovery from the nervous system tissues 
previously removed from the animals.
    (vii) The lot is satisfactory if the histological and other studies 
demonstrate no evidence of changes in the central nervous system 
attributable to unusual neurotropism of the seed virus or of the 
presence of extraneous neurotropic agents.
    (2) Test results. The mumps virus seed has acceptable neurovirulence 
properties for use in vaccine manufacture only if for each of the five 
lots (i) 90 percent of the monkeys survive the observation period, (ii) 
the histological and other studies produce no evidence of changes in the 
central nervous system attributable to unusual neurotropism or 
replication of the seed virus and (iii) there is no evidence of the 
presence of extraneous neurotropic agents.
    (3) Need for additional neurovirulence safety testing. A 
neurovirulence safety test as prescribed in this paragraph shall be 
performed on vaccine from five consecutive lots whenever a new 
production seed lot is introduced or whenever the source of cell culture 
substrate must be reestablished and recertified as prescribed in 
Sec. 630.52(a).

[38 FR 32068, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50 
FR 4138, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 55 FR 47875, Nov. 
16, 1990]



Sec. 630.51  Clinical trials to qualify for license.

    To qualify for license, the antigenicity of Mumps Virus Vaccine Live 
shall be determined by clinical trials, conducted in compliance with 
part 56 of this chapter unless exempted under Sec. 56.104 or granted a 
waiver under Sec. 56.105, and with part 50 of this chapter, that follow 
the procedures prescribed in Sec. 630.31, except that the immunogenic 
effect shall be demonstrated by establishing that a protective antibody 
response has occurred in at least 90 percent of each of the five groups 
of mumps-susceptible individuals, each having received the parenteral 
administration of a virus vaccine dose not greater than that 
demonstrated to be safe in field studies (Sec. 630.50(b)) when used 
under comparable conditions.

[46 FR 8956, Jan. 27, 1981, as amended at 50 FR 4138, Jan. 29, 1985]



Sec. 630.52   Manufacture of Mumps Virus Vaccine Live

    (a) Virus cultures. Mumps virus shall be propagated in chick embryo 
cell cultures. The embryonated chicken eggs used as the source of chick 
embryo tissue for the propagation of mumps virus shall be derived from 
flocks certified or tested as prescribed in Sec. 630.32(b).
    (b) Passage of virus strain in vaccine manufacture. Virus in the 
final vaccine shall represent no more than five cell culture passages 
beyond the passage used to perform the clinical trials (Sec. 630.50(b)) 
which qualified the manufacturer's vaccine strain for license.
    (c) Cell culture preparation. Only primary cell cultures shall be 
used in the manufacture of mumps virus vaccine. Continuous cell lines 
shall not be introduced or propagated in mumps virus vaccine 
manufacturing areas.
    (d) Control vessels. From the tissue used for the preparation of 
cell cultures for growing attenuated mumps virus, an amount of processed 
cell suspension equivalent to that used to prepare 500 ml. of cell 
culture shall be used to prepare uninfected tissue control materials 
which shall be prepared and tested by following the procedures 
prescribed in Sec. 630.32(f).
    (e) Test samples. Test samples of mumps virus harvests or pools 
shall be withdrawn and maintained by following the procedures prescribed 
in Sec. 630.32(g).

[38 FR 32068, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985]



Sec. 630.53   Reference virus.

    An NIH Reference Mumps Virus, Live, shall be obtained from the 
Center for Biologics Evaluation and Research

[[Page 108]]

as a control for correlation of virus titers.

[38 FR 32068, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]



Sec. 630.54   Potency test.

    The concentration of live mumps virus shall constitute the measure 
of potency. The titration shall be performed in a suitable cell culture 
system, free of wild viruses, using either the Reference Mumps Virus, 
Live, or a calibrated equivalent strain as a titration control. The 
concentration of live mumps virus contained in the vaccine of each lot 
under test shall be no less than the equivalent of 5,000 TCID50 of 
the reference virus per human dose.



Sec. 630.55   Test for safety.

    (a) Tests prior to clarification. Prior to clarification, the 
following tests shall be performed on each mumps virus pool prepared in 
chick embryo cell culture:
    (1) Inoculation of adult mice. The test shall be performed in the 
volume and following the procedures prescribed in Sec. 630.35(a)(1), and 
the virus pool is satisfactory only if equivalent test results are 
obtained.
    (2) Inoculation of suckling mice. The test shall be performed in the 
volume and following the procedures prescribed in Sec. 630.35(a)(2), and 
the virus pool is satisfactory only if equivalent test results are 
obtained.
    (3) Inoculation of monkey cell cultures. A mumps virus pool shall be 
tested for adventitious agents in the volume and following the 
procedures prescribed in Sec. 630.35(a)(3), and the virus pool is 
satisfactory only if equivalent test results are obtained.
    (4) Inoculation of other cell cultures. The mumps virus pool shall 
be tested for adventitious agents in the volume and following the 
procedures prescribed in Sec. 630.35(a)(3), in rhesus or cynomolgus 
monkey kidney, in whole chick embryo, and in human cell cultures. In 
addition, each virus pool shall be tested in chick embryo kidney in the 
same manner except that the volume tested in each cell culture shall be 
equivalent to 250 human doses or 25 milliliters, whichever represents a 
greater volume. The mumps virus pool is satisfactory only if results 
equivalent to those in Sec. 630.35(a)(3) are obtained.
    (5) Inoculation of embryonated chicken eggs. A neutralized 
suspension of each undiluted mumps virus pool shall be tested in the 
volume and following the procedures prescribed in Sec. 630.35(a)(5), and 
the virus pool is satisfactory only if there is no evidence of 
adventitious agents.
    (6) Bacteriological tests. In addition to the tests for sterility 
required pursuant to Sec. 610.12 of this chapter, bacteriological tests 
shall be performed on each mumps virus pool for the presence of M. 
tuberculosis, both avian and human, by appropriate culture methods. The 
virus pool is satisfactory only if found negative for M. tuberculosis, 
both avian and human.
    (7) Test for avian leucosis. If the cultures were not derived from a 
certified source and control fluids were not tested for avian leucosis, 
the vaccine shall be tested in the volume and following the procedures 
prescribed in Sec. 630.35(a)(8). The cultures are satisfactory for 
vaccine manufacture if found negative for avian leucosis.
    (b) Clarification. The mumps virus fluids shall be clarified by 
following the procedures prescribed in Sec. 630.35(c).

[38 FR 32068, Nov. 20, 1973, as amended at 55 FR 47876, Nov. 16, 1990]



Sec. 630.56   General requirements.

    (a) Final container tests. In addition to the tests required 
pursuant to Sec. 610.14 of this chapter, an immunological and 
virological identity test shall be performed on the final container if 
it was not performed on each pool or the bulk vaccine prior to filling.
    (b) Dose. These standards are based on an individual human 
immunizing dose of no less than 5,000 TCID50 of Mumps Virus Vaccine 
Live, expressed in terms of the assigned titer of the Reference Mumps 
Virus, Live.
    (c) Labeling. In addition to the items required by other applicable 
labeling provisions of this part, single dose container labeling for 
vaccine which is not protected against photochemical deterioration shall 
include a statement cautioning against exposure to sunlight.
    (d) [Reserved]

[[Page 109]]

    (e) Photochemical deterioration; protection. Mumps Virus Vaccine 
Live, in multiple dose containers, shall be protected against 
photochemical deterioration in accordance with the procedures prescribed 
in Sec. 630.36(g).
    (f) Samples and protocols. For each lot of vaccine, the following 
materials shall be submitted to the Director, Center for Biologics 
Evaluation and Research, Food and Drug Administration, 8800 Rockville 
Pike, Bethesda, MD 20892:
    (1) A protocol which consists of a summary of the history of 
manufacture of each lot including all results of each test for which 
test results are requested by the Director, Center for Biologics 
Evaluation and Research.
    (2) A total of no less than two 25-milliliter volumes, in a frozen 
state (-60 deg. C), of preclarification bulk vaccine containing no 
preservative, stabilizer, or adjuvant.
    (3) A total of no less than 30 containers of the vaccine from each 
filling of each bulk lot of single-dose containers. A total of no less 
than six 50-dose containers or ten 10-dose containers of the vaccine 
from each filling of each bulk lot of multiple-dose containers.

[38 FR 32068, Nov. 20, 1973, as amended at 39 FR 9661, Mar. 13, 1974; 41 
FR 10429, Mar. 11, 1976; 49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 
1985; 51 FR 15610, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990]



                  Subpart G--Rubella Virus Vaccine Live



Sec. 630.60   Rubella Virus Vaccine Live.

    (a) Proper name and definition. The proper name of this product 
shall be Rubella Virus Vaccine Live, which shall consist of a 
preparation of live, attenuated rubella virus.
    (b) Criteria for acceptable strains of attenuated rubella virus. 
Strains of attenuated rubella virus used in the manufacture of vaccine 
shall be identified by (1) historical records including origin and 
manipulation during attenuation and (2) antigenic specificity as rubella 
virus as demonstrated by tissue culture neutralization tests.
    (c) Extraneous agents. Seed virus used for vaccine manufacture shall 
be free of all demonstrable extraneous viable microbial agents except 
for unavoidable bacteriophage.
    (d) Field studies with experimental vaccines. (1) Strains used for 
the manufacture of Rubella Virus Vaccine Live, shall have been shown in 
field studies with experimental vaccines to be safe and potent in the 
group of individuals inoculated, which must include at least 10,000 
susceptible individuals. Susceptibility shall be shown by the absence of 
neutralizing or hemagglutination-inhibiting antibodies against rubella 
virus or by other appropriate methods.
    (2) The virus strain used in the field studies shall be propagated 
in the same cell culture system that will be used in the manufacture of 
the product.
    (3) The field studies shall be so conducted that at least 5,000 of 
the susceptible individuals must reside when inoculated in areas where 
health related statistics are regularly compiled in accordance with 
procedures such as those used by the National Center for Health 
Statistics. Data in such form as will identify each inoculated person 
shall be furnished to the Director, Center for Biologics Evaluation and 
Research.
    (4) Inoculated persons shall be shown not to be contagious for 
contacts through surveillance of rubella susceptible contacts of the 
inoculated persons.
    (e) Neurovirulence safety test of the virus seed strain in monkeys--
(1) The test. A demonstration shall be made in monkeys of the lack of 
neurotropic properties of the seed strain of attenuated rubella virus 
used in the manufacture of rubella vaccine. For this purpose and to 
establish consistency of manufacture of the vaccine, vaccine from each 
of five consecutive lots shall be tested separately in monkeys shown to 
be serologically negative for rubella virus antibodies in the following 
manner:
    (i) A test sample of vaccine removed after clarification but before 
final dilution for standardization of virus content shall be used for 
the test.
    (ii) Vaccine shall be injected by combined intracerebral, 
intraspinal, and intramuscular routes into not less than 20 Macaca or 
Cercopithecus monkeys or a species found by the Director, Center for 
Biologics Evaluation and Research, to be equally suitable for the 
purpose. The animals shall be in overt

[[Page 110]]

good health and injected under deep barbiturate anesthesia. The 
intramuscular injection shall consist of 1.0 milliliter of test sample 
into the right leg muscles. At the same time, 200 milligrams of 
cortisone acetate shall be injected into the left leg muscles, and 1.0 
milliliter of procaine penicillin (300,000 units) into the right arm 
muscles. The intracerebral injection shall consist of 0.5 milliliter of 
test sample into each thalamic region of each hemisphere. The 
intraspinal injection shall consist of 0.5 milliliter of test sample 
into the lumbar spinal cord enlargement.
    (iii) The monkeys shall be observed for 17-21 days and symptoms of 
paralysis as well as other neurologic disorders shall be recorded.
    (iv) At least 90 percent of the test animals must survive the test 
period without losing more than 25 percent of their weight except that, 
if at least 70 percent of the test animals survive the first 48 hours 
after injection, those animals which do not survive this 48-hour test 
period may be replaced by an equal number of qualified test animals 
which are tested pursuant to paragraphs (e)(1)(i) through (iii) of this 
section. At least 80 percent of the injected animals surviving beyond 
the first 48 hours must show gross or microscopic evidence of 
inoculation trauma in the thalamic area and microscopic evidence of 
inoculation trauma in the lumbar region of the spinal cord. If less than 
70 percent of the test animals survive the first 48 hours, or if less 
than 80 percent of the animals meet the inoculation criteria prescribed 
in this paragraph, the test must be repeated.
    (v) At the end of the observation period, each surviving animal 
shall be autopsied and samples of cerebral cortex and of cervical and 
lumbar spinal cord enlargements shall be taken for virus recovery and 
identification if needed pursuant to paragraph (e)(1) (vi) of this 
section. Histological sections shall be prepared from both spinal cord 
enlargements and appropriate sections of the brain and examined.
    (vi) Doubtful histopathological findings necessitate (a) examination 
of a sample of sections from several regions of the brain in question, 
and (b) attempts at virus recovery from the nervous system tissues 
previously removed from the animal.
    (vii) The lot is satisfactory if the histological and other studies 
demonstrate no evidence of changes in the central nervous system 
attributable to the presence of unusual neurotropism of the seed virus 
or of the presence of extraneous neurotropic agents.
    (2) Test results. The rubella virus seed has acceptable 
neurovirulence properties for use in vaccine manufacture only if for 
each of the five lots: (i) 90 percent of the monkeys survive the 
observation period, (ii) the histological and other studies produce no 
evidence of changes in the central nervous system attributable to the 
presence of unusual neurotropism or replication of the seed virus and 
(iii) there is no evidence of the presence of extraneous neurotropic 
agents.
    (3) Need for additional neurovirulence safety testing. A 
neurovirulence safety test as prescribed in this paragraph shall be 
performed on vaccine from five consecutive lots whenever a new 
production seed lot is introduced or whenever the source of cell culture 
substrate must be reestablished and recertified as prescribed in 
Sec. 630.62(a), (b) and (d) of this part.

[38 FR 32068, Nov. 20, 1973, as amended at 40 FR 11719, Mar. 13, 1975; 
49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 1985; 55 FR 11013, Mar. 
26, 1990; 55 FR 47876, Nov. 16, 1990]



Sec. 630.61  Clinical trials to qualify for license.

    To qualify for license, the antigenicity of Rubella Virus Vaccine 
Live, shall be determined by clinical trials, conducted in compliance 
with part 56 of this chapter unless exempted under Sec. 56.104 or 
granted a waiver under Sec. 56.105, and with part 50 of this chapter, 
that follow the procedures prescribed in Sec. 630.31, except that the 
immunogenic effect shall be demonstrated by establishing that a 
protective antibody response has occurred in at least 90 percent of each 
of the five groups of rubella-susceptible individuals, each having 
received the parenteral administration of a virus vaccine dose not 
greater than that demonstrated to be safe in field studies

[[Page 111]]

when used under comparable conditions.

[46 FR 8956, Jan. 27, 1981, as amended at 50 FR 4138, Jan. 29, 1985]



Sec. 630.62   Production.

    (a) Virus cultures. Rubella virus shall be propagated in duck embryo 
cell cultures, rabbit renal cultures, or in a cell line found by the 
Director, Center for Biologics Evaluation and Research, to meet the 
requirements of Sec. 610.18(c) of this chapter.
    (b) Virus propagated in duck embryo tissue cell cultures. 
Embryonated duck eggs used as a source of duck embryo tissue for the 
propagation of rubella virus shall be derived from flocks certified to 
be free of avian tuberculosis, the avian leucosis-sarcoma group of 
viruses, reticuloendotheliosis virus, and other agents pathogenic for 
ducks. Only ducks so certified and in overt good health and which are 
maintained in quarantine shall be used as a source of duck embryo tissue 
used in the propagation of rubella virus. Ducks in the quarantined flock 
that die shall be necropsied and examined for evidence of significant 
pathologic lesions. If any such signs or pathologic lesions are 
observed, eggs from that flock shall not be used for the manufacture of 
Rubella Virus Vaccine Live. Control vessels shall be prepared, observed, 
and tested as prescribed in Sec. 630.32(f).
    (c) [Reserved]
    (d) Virus propagated in rabbit renal tissue cell cultures. Only 
rabbits in overt good health which have been maintained in quarantine 
individually caged in vermin-proof quarters for a minimum of 6 months, 
having had no exposure to other rabbits or animals throughout the 
quarantine period, or rabbits born to rabbits while so quarantined, 
provided the progency have been kept in the same type of quarantine 
continuously from birth shall be used as a source of kidney tissue. 
Animals shall be free of antibodies for agents potentially pathogenic 
for man unless it has been demonstrated in the license application that 
the tests required by Sec. 630.65(c) to be performed on each lot of 
vaccine are capable of detecting contamination of agents capable of 
producing such antibodies.
    (1) Rabbits used for experimental purposes. Rabbits that have been 
used previously for experimental or testing purposes with 
microbiological agents shall not be used as a source of kidney tissue in 
the production of vaccine.
    (2) Quarantine and necropsy. Each rabbit shall be examined 
periodically during the quarantine period as well as at the time of 
necropsy under the direction of a qualified pathologist, physician or 
veterinarian having experience with diseases of rabbits, for the 
presence of signs or symptoms of ill health, particularly for evidence 
of tuberculosis, myxomatosis, fibromatosis, rabbit pox, and other 
diseases indigenous to rabbits. If there are any such signs, symptoms or 
other significant pathological lesions observed, tissues from that 
colony shall not be used in the production of vaccine.
    (3) Control vessels. Control vessels shall be prepared, observed and 
tested as prescribed in Sec. 630.32(f).
    (e) Passage of virus strain in vaccine manufacture. Virus in the 
final vaccine shall represent no more than five cell culture passages 
beyond the passage used as the seed strain for the manufacture of the 
vaccine used to perform the field studies (Sec. 630.60(d)), which 
qualified the manufacturer's vaccine strain for license.
    (f) Cell cultures in vaccine production areas. Only the cell 
cultures used in the propagation of rubella virus vaccine shall be 
introduced into rubella virus vaccine production areas.
    (g) Test samples. Test samples of rubella virus harvests or pools 
shall be withdrawn and maintained by following the procedures prescribed 
in Sec. 630.32(g).

[38 FR 32068, Nov. 20, 1973, as amended at 40 FR 11719, Mar. 13, 1975; 
47 FR 24699, June 8, 1982; 50 FR 4138, Jan. 29, 1985; 55 FR 47876, Nov. 
16, 1990]



Sec. 630.63   Reference virus.

    A Reference Rubella Virus, Live, shall be obtained from the Center 
for Biologics Evaluation and Research as a control for correlation of 
virus titers.

[38 FR 32068, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]

[[Page 112]]



Sec. 630.64   Potency test.

    The concentration of live rubella virus shall constitute the measure 
of potency. The titration shall be performed in a suitable cell culture 
system, using either the Reference Rubella Virus, Live, or a calibrated 
equivalent strain as a titration control. The concentration of live 
rubella virus contained in the vaccine of each lot under test shall be 
no less than the equivalent of 1,000 TCID50 of the reference virus 
per human dose.



Sec. 630.65   Test for safety.

    (a) Tests prior to clarification of vaccine manufactured in duck 
embryo cell cultures. Prior to clarification, the following tests shall 
be performed on each rubella virus pool prepared in duck embryo cell 
cultures:
    (1) Inoculation of adult mice. The test shall be performed in the 
volume and following the procedures prescribed in Sec. 630.35(a)(1), and 
the virus pool is satisfactory only if equivalent test results are 
obtained.
    (2) Inoculation of suckling mice. The test shall be performed in the 
volume and following the procedures prescribed in Sec. 630.35(a)(2), and 
the virus pool is satisfactory only if equivalent test results are 
obtained.
    (3) Inoculation of monkey tissue cell cultures. A rubella virus pool 
shall be tested for adventitious agents in the volume and following the 
procedures prescribed in Sec. 630.35(a)(3), except that the virus need 
not be neutralized by antiserum. The rubella virus pool is satisfactory 
only if equivalent test results are obtained.
    (4) Inoculation of other cell cultures. The rubella virus pool shall 
be tested for adventitious agents in the volume and following the 
procedures prescribed in Sec. 630.35(a)(3), in rhesus or cynomolgus 
monkey kidney, in chick embryo, duck embryo, and in human cell cultures 
except that the virus need not be neutralized by antiserum. The rubella 
virus pool is satisfactory only if results equivalent to those in 
Sec. 630.35(a)(3) are obtained.
    (5) Inoculation of embryonated chicken eggs. A suspension of each 
undiluted rubella virus pool shall be tested in the volume and following 
the procedures prescribed in Sec. 630.35(a)(5) except that the virus 
need not be neutralized by antiserum. The virus pool is satisfactory 
only if there is no evidence of adventitious agents.
    (6) Inoculation of embryonated duck eggs. A suspension of each 
undiluted rubella virus pool shall be tested in embryonated duck eggs, 
following the procedures prescribed in Sec. 630.35(a)(5), except that 
the virus need not be neutralized by antiserum and the volume of 
inoculum per egg shall not exceed 1.0 milliliter. The virus pool is 
satisfactory only if there is no evidence of adventitious agents.
    (7) Bacteriological tests. In addition to the tests for sterility 
required pursuant to Sec. 610.12 of this chapter, bacteriological tests 
shall be performed on each rubella virus pool for the presence of M. 
tuberculosis, both avian and human, by appropriate culture methods. The 
virus pool is satisfactory only if found negative for M. tuberculosis, 
both avian and human.
    (8) Test for avian leucosis. The vaccine shall be tested for avian 
leucosis, in the volume and following the procedures prescribed in 
Sec. 630.35(a)(8). The cultures are satisfactory for vaccine manufacture 
if found negative for avian leucosis.
    (9) Inoculation of cell cultures and embryonated eggs after 
neutralization of the virus with antiserum. Each of the tests prescribed 
in paragraphs (a)(3), (4), (5), and (6) of this section shall be carried 
out also with rubella virus that has been neutralized by the addition of 
high titer antiserum of nonhuman, nonsimian and nonavian origin except 
that the volume of virus suspension of each undiluted virus pool tested 
shall be no less than 5 ml. The rubella antiserum shall have been 
prepared by using a rubella virus propagated in a cell culture system 
other than that used for the manufacture of the vaccine under test, and 
the cell culture system shall be free of extraneous agents which might 
elicit antibodies that could inhibit growth of any known extraneous 
agents which might be present in the vaccine under test. These tests may 
be performed either before or after clarification of the virus. The 
virus pool is satisfactory only if the results obtained are

[[Page 113]]

equivalent to those required in those subparagraphs.
    (b) [Reserved]
    (c) Tests prior to clarification of vaccine manufactured in rabbit 
renal cell cultures. Prior to clarification each rubella virus pool 
prepared in rabbit renal cell cultures shall be tested as follows:
    (1) Inoculation of adult mice. The test shall be performed in the 
volume and following the procedures prescribed in Sec. 630.35(a)(1), and 
the virus pool is satisfactory only if equivalent test results are 
obtained.
    (2) Inoculation of suckling mice. The test shall be performed in the 
volume and following the procedures prescribed in Sec. 630.35(a)(2), and 
the virus pool is satisfactory only if equivalent test results are 
obtained.
    (3) Inoculation of monkey tissue cell cultures. A rubella virus pool 
shall be tested for adventitious agents in the volume and following the 
procedures prescribed in Sec. 630.35(a)(3), except that the virus need 
not be neutralized by antiserum. The rubella virus pool is satisfactory 
only if equivalent test results are obtained.
    (4) Inoculation of other cell cultures. The tests shall be performed 
in the volume and following the procedures prescribed in 
Sec. 630.35(a)(3) in rhesus or cynomolgus monkey kidney tissue, rabbit 
renal tissue and human tissue cell cultures, except that the virus need 
not be neutralized by antiserum. The rubella virus pool is satisfactory 
only if equivalent test results are obtained.
    (5) Inoculation of embryonated chicken eggs. A suspension of each 
undiluted rubella virus pool shall be tested in the volume and following 
the procedures prescribed in Sec. 630.35(a)(5) except that the virus 
need not be neutralized by antiserum. The virus pool is satisfactory 
only if there is no evidence of adventitious agents.
    (6) Inoculation of rabbits. A minimum of 15 ml. of each virus pool 
shall be tested by inoculation into at least five healthy rabbits, each 
weighing 1500-2500 grams. Each rabbit shall be injected intradermally in 
multiple sites with a total of 1.0 ml. and subcutaneously with 2.0 ml., 
of the virus pool, and the animals observed for at least 30 days. Each 
rabbit that dies after the first 24 hours of the test or is sacrificed 
because of illness shall be necropsied and the brain and organs removed 
and examined. The virus pool is satisfactory only if at least 80 percent 
of the rabbits remain healthy and survive the entire period and if all 
the rabbits used in the test fail to show lesions of any kind at the 
sites of inoculation and fail to show evidence of any viral infection.
    (7) Inoculation of guinea pigs. Each of at least five guinea pigs, 
each weighing 350-450 grams, shall be inoculated intracerebrally with 
0.1 ml. and intraperitoneally with 5 ml. of the undiluted virus pool. 
The animals shall be observed for at least 42 days. Each animal that 
dies after the first 24 hours of the test or is sacrificed because of 
illness, shall be necropsied. All remaining animals shall be sacrificed 
and necropsied at the end of the observation period. The virus pool is 
satisfactory only if at least 80 percent of all animals remain healthy 
and survive the observation period and if all the animals used in the 
test fail to show evidence of infection with M. tuberculosis or any 
viral infection.
    (8) Bacteriological tests. In addition to the tests for sterility 
required pursuant to Sec. 610.12 of this chapter, bacteriological tests 
shall be performed on each rubella virus pool for the presence of M. 
tuberculosis, human, by appropriate culture methods. The rubella virus 
pool is satisfactory only if found negative for M. tuberculosis, human.
    (9) Tests for adventitious agents. Each virus pool shall be tested 
for the presence of such known adventitious agents of rabbits as 
toxoplasma, encephalitozoon, herpes cuniculi, the vacuolating virus of 
rabbits, rabbit syncytial virus, myxoviruses and reoviruses. The virus 
pool is satisfactory only if the results of all tests show no evidence 
of any extraneous agent attributable to the rabbit renal tissue or the 
vaccine.
    (10) Inoculation of cell cultures and embryonated eggs after 
neutralization of the virus with antiserum. Each of the tests prescribed 
in paragraphs (c)(3), (4), and (5) of this section shall be carried out 
also with rubella virus that has been neutralized by the addition of

[[Page 114]]

high titer antiserum of nonhuman, nonsimian and nonrabbit origin 
following the procedures and in the volume prescribed in paragraph 
(a)(9) of this section. The virus pool is satisfactory only if the 
results obtained are equivalent to those required by that paragraph.
    (d) Clarification. The rubella virus fluids shall be clarified by 
following the procedures prescribed in Sec. 630.35(c).

[38 FR 32068, Nov. 20, 1973, as amended at 40 FR 11719, Mar. 13, 1975; 
40 FR 25813, June 19, 1975]



Sec. 630.66   General requirements.

    (a) Final container tests. In addition to the tests required 
pursuant to Sec. 610.14 of this chapter, an immunological and 
virological identity test shall be performed on the final container if 
it was not performed on each pool or on the bulk vaccine prior to 
filling.
    (b) Dose. These standards are based on an individual human 
immunizing dose of no less than 1,000 TCID50 of Rubella Virus 
Vaccine Live, expressed in terms of the assigned titer of the Reference 
Rubella Virus, Live.
    (c) Labeling. In addition to the items required by other applicable 
labeling provisions of this subchapter, single dose container labeling 
for vaccine which is not protected against photochemical deterioration 
shall include a statement cautioning against exposure to light.
    (d) Photochemical deterioration; protection. Rubella Virus Vaccine 
Live, in multiple dose containers, shall be protected against 
photochemical deterioration in accordance with the procedures prescribed 
in Sec. 630.36(g).
    (e) Samples; protocols; offical release. The following shall be 
submitted to the Director, Center for Biologics Evaluation and Research, 
Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892:
    (1) For each lot of vaccine:
    (i) A protocol, which consists of a summary of the history of the 
manufacture of the lot, including all results of each test for which 
test results are requested by the Director, Center for Biologics 
Evaluation and Research.
    (ii) A total of no less than two 25-milliliter volumes, in a frozen 
state (-60 deg. C.), of preclarification bulk vaccine containing no 
preservative or adjuvant.
    (iii) A total of no less than 30 containers of the vaccine from each 
filling of each bulk lot of single-dose containers. A total of no less 
than six 50-dose containers or ten 10-dose containers of the vaccine 
from each filling of each bulk lot of multiple-dose containers.
    (2) In addition to the requirements of paragraph (e)(1) of this 
section, whenever a new production seed lot is introduced, or whenever 
the source of cell culture substrate must be reestablished and 
recertified, samples consisting of no less than 100 milliliters in 10-
milliliter volumes, in a frozen state (-60 deg. C.), of 
postclarification bulk vaccine containing stabilizer but no preservative 
or adjuvant, taken from each of 5 consecutive lots of the bulk vaccine.
    (3) The product shall not be issued by the manufacturer until 
written notification of official release of the lot is received from the 
Director, Center for Biologics Evaluation and Research.

[38 FR 32068, Nov. 20, 1973, as amended at 41 FR 10430, Mar. 11, 1976; 
42 FR 27582, May 31, 1977; 49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 
29, 1985; 51 FR 15610, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990]



                       Subpart H--Smallpox Vaccine



Sec. 630.70   Smallpox Vaccine.

    (a) Proper name and definition. The proper name of this product 
shall be Smallpox Vaccine, which shall be a preparation of live vaccinia 
virus obtained from inoculated calves or chicken embryos.
    (b) Strains of virus. The strain of seed virus used in the 
manufacture of Smallpox Vaccine shall be identified by historical 
records including origin and manipulation, and shall meet the sterility 
test requirements when tested by the procedure prescribed in Sec. 610.12 
of this chapter. The strain of seed virus and every third passage shall 
be tested by a rabbit scarification procedure and shown to maintain its 
original dermatropic properties. The test procedure is available upon 
request from the Director, Center for Biologics Evaluation and Research. 
Any new strain shall be shown not to produce a

[[Page 115]]

reactivity in man exceeding that produced by the Reference Smallpox 
Vaccine.

[38 FR 32068, Nov. 20, 1973, as amended at 41 FR 51010, Nov. 19, 1976; 
49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]



Sec. 630.71   Production.

    Vaccinia virus used for the manufacture of vaccine shall be obtained 
from vesicles on the skin of an inoculated calf or from inoculated 
chorioallantoic membranes of chicken embryos, as set forth below:
    (a) Virus from calves--(1) Quarantine. Only calves which, prior to 
being placed in quarantine have reacted negatively to tuberculin, were 
afebrile and free of ectoparasites, and which shall have met all other 
applicable quarantine requirements of Sec. 600.11(f)(2)(i) of this 
chapter, shall be used for vaccinia virus production. The quarantine 
period shall be at least 14 days. During the last 7 days of the 
quarantine period daily morning and afternoon rectal temperatures shall 
be taken and calves that do not remain afebrile during that period shall 
not be used for virus production.
    (2) Inoculation. A larger area of the calf than will be used for 
production purposes shall be prepared in a manner comparable to that 
appropriate for aseptic surgery, except that the area to be inoculated 
must be washed free of all antiseptics that may have a deleterious 
effect on virus propagation. The instrument and method used for 
scarification must produce a uniform penetration into the epidermis but 
must not extend through into the corium.
    (3) Incubation. The inoculated calf shall remain in the incubation 
room confined to its stall and daily morning and afternoon rectal 
temperatures shall be taken to determine that only the expected febrile 
condition occurs. If any signs of disease other than vesiculation at the 
inoculation site occur, the virus from that calf shall not be used for 
vaccine manufacture.
    (4) Harvesting. Before harvesting, the calf shall be anesthetized 
and killed by exsanguination. Prior to harvesting, the inoculated area 
shall be thoroughly cleansed by aseptic techniques. Only the vesicular 
material shall be harvested.
    (5) Necropsy. A necropsy shall be made of each production calf. The 
harvested material shall not be used from any animal suspected of having 
an infection other than vaccinia.
    (b) Virus from embryonated chicken eggs--(1) Eggs for production. 
Embryonated chicken eggs used for propagation of vaccinia virus shall be 
derived from flocks found to be free of, and continuously monitored for 
freedom from Salmonella pullorum, Mycoplasma species, avian 
tuberculosis, fowl pox, Newcastle disease virus, Rous sarcoma virus, 
avian leucosis complex of viruses, and other agents pathogenic for 
chickens, or appropriate tests shall be performed to demonstrate freedom 
of the vaccine from such agents.
    (2) Harvesting. Aseptic techniques shall be used in harvesting the 
chorioallantoic membranes exhibiting vesicles characteristic of vaccinia 
infection.



Sec. 630.72   Reference vaccine.

    Reference Smallpox Vaccine and reconstitution fluid shall be 
obtained from the Center for Biologics Evaluation and Research and shall 
be used in all tests for determining the potency of Smallpox Vaccine.

[38 FR 32068, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]



Sec. 630.73   Potency test.

    Each filling of Smallpox Vaccine shall be tested for potency by the 
``pock count'' method as follows:
    (a) [Reserved]
    (b) Pock counting in embryonated chicken eggs--(1) Dilutions shall 
be made starting with no less than 0.5 ml. of the test vaccine and of 
the reference vaccine. The same diluent shall be used for all dilutions 
of both vaccines. The sample of vaccine in capillary tubes shall be 
obtained by pooling the contents of no less than 50 capillaries into a 
sterile vessel.
    (2) Inoculation of embryonated chicken eggs. One-tenth milliliter of 
each dilution of test vaccine shall be inoculated onto the 
chorioallantoic membrane of each of at least five embryonated chicken 
eggs. The reference vaccine shall be tested in the same manner.

[[Page 116]]

After inoculation, all eggs shall be incubated at 
37 deg.Cplus-minus1 deg.C for 48 hours.
    (3) Estimation of potency. Only membranes from living embryos shall 
be removed and the number of specific lesions thereon shall be counted 
and recorded. The number of pock forming units in 1.0 ml. of vaccine 
shall be calculated from the number of lesions, the dilution factor and 
the volume used, to determine the titer of the undiluted vaccine. The 
accuracy of the titration shall be confirmed in each test by performing 
simultaneously the same type of titration with the reference vaccine 
which shall demonstrate its assigned titer.
    (4) Potency requirements--(i) Vaccine intended for multiple pressure 
administration. Vaccine intended for multiple pressure administration 
shall have a titer at least equivalent to the reference vaccine.
    (ii) Vaccine intended for jet injection. Vaccine intended for 
administration by jet injector shall have a number of pock forming units 
in one human dose at least equivalent to that contained in 0.1 ml. of 
the reference vaccine diluted 1:30.
    (iii) Heated liquid vaccine. Samples of liquid vaccine from final 
containers taken at random shall be incubated at 35 deg. to 37 deg. C. 
for at least 18 hours, after which the heated sample shall be tested in 
parallel with a sample of unheated vaccine of the same lot, as 
prescribed in this paragraph. The vaccine is satisfactory if the heated 
sample retains at least one tenth of the potency of the unheated sample.
    (iv) Heated dried vaccine. Samples of dried vaccine from final 
containers taken at random shall be incubated at 35 deg. to 37 deg. C. 
for 30 days, after which the heated sample shall be tested in parallel 
with a sample of unheated vaccine of the same lot, as prescribed in this 
paragraph. The vaccine is satisfactory if the heated sample retains at 
least one-tenth of the potency of the unheated sample.

[38 FR 32068, Nov. 20, 1973, as amended at 41 FR 51010, Nov. 19, 1976]



Sec. 630.74   Tests for safety.

    (a) Anaerobes. A 10-milliliter sample representative of the 
homogenized viral harvest or pool of several viral harvests shall be 
tested for the presence of anaerobes in the following manner: Before the 
addition of preservatives other than glycerin, the test sample shall be 
inoculated into freshly heated Fluid Thioglycollate Medium using a ratio 
of inoculum to culture medium sufficient for optimal bacterial growth. 
The test vessels shall be incubated at 35 deg. to 37 deg. C and observed 
daily for 10 days for evidence of bacterial growth. If bacterial growth 
is observed, the organism(s) shall be identified as to genus. Within 24 
to 48 hours of an indication that there may be anaerobic growth, 1.0-
milliliter samples from each vessel showing growth shall be inoculated 
subcutaneously into each of at least three mice weighing not more than 
20 grams each, and into each of three guinea pigs weighing not more than 
350 grams each. The animals shall be observed daily for 6 days for signs 
of tetanus or presence of other anaerobes. If the animals show no signs 
of tetanus or presence of other anaerobes, additional groups of the same 
types and numbers of animals shall be injected 9 days after evidence of 
anaerobic bacterial growth is observed in the original planting with 
1.0-milliliter samples from each test vessel showing growth. The animals 
shall be observed daily for 6 days for signs of tetanus or presence of 
other anaerobes. If any animals die within 3 days without having shown 
signs of tetanus or presence of other anaerobes, the test shall be 
repeated within 18 hours of the deaths, with 0.1-milliliter samples of 
the culture from which that animal was inoculated. Samples from the 
culture shall be injected into each of three additional test animals of 
the same species, and the animals shall be observed daily for 6 days. If 
there is any evidence of the presence of pathogenic anaerobes, the viral 
harvest may not be used in the manufacture of Smallpox Vaccine.
    (b) [Reserved]
    (c) Coliform organisms. A 5.0 ml. sample of bulk vaccine shall be 
tested for the presence of coliform organisms by the method published by 
the American Public Health Association, Inc., in ``Standard Methods for 
the Examination of Water and Wastewater'' (13th edition, 1971), section 
entitled ``Multiple-Tube Fermentation Technic for

[[Page 117]]

Members of the Coliform Group,'' pages 662-678 and any amendments or 
revisions thereof, which section is hereby incorporated by reference and 
deemed published herein. Said publication is available at most medical 
and public libraries and copies of the pertinent section will be 
provided to any manufacturer affected by the provisions of this part 
upon request to the Director, Center for Biologics Evaluation and 
Research, or to the appropriate Information Center Officer listed in 45 
CFR part 5. In addition, an official historic file of the material 
incorporated by reference is maintained in the Office of the Director, 
Center for Biologics Evaluation and Research, or available for 
inspection at the Office of the Federal Register, 800 North Capitol 
Street NW., suite 700, Washington, DC 20408. A method different than 
that contained in the above cited section may be used to test for the 
presence of coliform organisms upon a showing that it is of equal or 
greater sensitivity. The ratio of the volume of inoculum to the volume 
of culture medium shall be such as will dilute the preservative to a 
level that does not inhibit growth of contaminating organisms. The 
vaccine is satisfactory if there is no evidence of coliform organisms.
    (d) Hemolytic streptococci and coagulase-positive staphylococci. 
Each of three 1.0 ml. samples of bulk vaccine shall be spread uniformly 
on the surface of separate blood agar plates. The plates shall be 
incubated for 48 hours at 35 deg. to 37 deg. C. The vaccine is 
satisfactory if there is no evidence of the presence of either hemolytic 
streptococci or coagulase-positive staphylococci.
    (e) Viable bacteria--(1) Vaccine intended for multiple pressure 
administration. Samples of each lot of both bulk and final container 
vaccine shall be tested for viable bacteria by a procedure designed to 
detect both aerobic and anaerobic growth through a period of 7 days. At 
least three 1.0 ml. samples of bulk vaccine and three 0.2 ml. samples of 
vaccine derived from not less than three final containers or dilutions 
thereof shall be inoculated into a volume of culture medium sufficient 
for optimal bacterial growth. The vaccine is satisfactory if it contains 
no more than 200 viable organisms per ml.
    (2) Vaccine intended for jet injection. Samples of each lot of both 
bulk and final container vaccine shall be tested for viable bacteria in 
Fluid Thioglycollate Medium prepared in accordance with 
Sec. 610.12(e)(1)(i) of this chapter for at least a 7-day test period. A 
sample of at least 10.0 ml. of bulk vaccine and 1.0 ml. from each of at 
least 20 final containers shall be tested. The ratio of the volume of 
the inoculum to the volume of culture medium shall be such as will 
dilute the preservative in the inoculum to a level that does not inhibit 
growth of contaminating micro-organisms. The vaccine is satisfactory if 
it contains no more than one organism per 100 doses of vaccine.
    (f) Sterile vaccine. The tests prescribed in paragraphs (c), (d), 
and (e) of this section need not be performed on a lot of Smallpox 
Vaccine that meets the sterility requirements prescribed in Sec. 610.12 
of this chapter.

[38 FR 32068, Nov. 20, 1973, as amended at 41 FR 51010, Nov. 19, 1976; 
47 FR 9397, Mar. 5, 1982; 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 
26, 1990]



Sec. 630.75   General requirements.

    (a) General safety. Each lot of vaccine shall be tested for safety 
as prescribed in Sec. 610.11 of this chapter and shall meet the safety 
requirements of that section, except that for liquid Smallpox Vaccine 
distributed in capillaries, the test may be performed with a sample of 
bulk vaccine taken at the time of filling into final containers.
    (b) Preservative. A preservative that meets the requirements of 
Sec. 610.15 of this chapter may be used, provided that if the 
preservative is phenol, its concentration shall not exceed 0.5 percent.
    (c) Labeling. In addition to complying with all other applicable 
labeling provisions of this subchapter the package label shall bear the 
following:
    (1) Vaccine intended for jet injection. (i) A conspicuous statement 
that the vaccine is intended for administration by jet injector.
    (ii) A statement that the vaccine has been shown by appropriate test 
methods to contain not more than one organism per 100 doses or reference 
to an enclosed circular that contains such

[[Page 118]]

information, except that such a statement is not required for vaccine 
which meets the sterility requirements of Sec. 610.12 of this chapter.
    (2) Vaccine intended for multiple pressure administration. A 
statement that the vaccine has been shown by appropriate test methods to 
contain not more than 200 organisms per ml. or reference to an enclosed 
circular that contains such information, except that such a statement is 
not required for vaccine which meets the sterility requirements of 
Sec. 610.12 of this chapter.
    (d) Samples; protocols; official release. (1) For each lot of 
vaccine the following shall be submitted to the Director, Center for 
Biologics Evaluation and Research, Food and Drug Administration, 8800 
Rockville Pike, Bethesda, MD 20892:
    (i) A protocol which consists of a summary of the history of 
manufacture of each filling including all results of each test for which 
test results are requested by the Director, Center for Biologics 
Evaluation and Research.
    (ii) Three hundred capillaries from the first filling of a lot of 
liquid vaccine, and 200 capillaries from each subsequent filling.
    (iii) Two 10 ml. samples of bulk liquid vaccine to be submitted 
along with the capillaries from the first filling and taken from the 
same vessel from which such capillaries were filled.
    (iv) For vaccine intended for jet gun injection, a sample from each 
drying consisting of no less than eight 100-dose vials or eight 500-dose 
vials of vaccine in final labeled containers, plus sufficient diluent in 
final labeled containers to reconstitute the vaccine.
    (v) For vaccine intended for multiple pressure administration, a 
sample from each drying consisting of no less than eighty 10-dose vials, 
ninety 25-dose vials, or eighty 100-dose vials of vaccine in final 
labeled containers, plus sufficient diluent in final labeled containers 
to reconstitute the vaccine.
    (2) The product shall not be issued by the manufacturer until 
written notification of official release of the lot is received from the 
Director, Center for Biologics Evaluation and Research.

[38 FR 32068, Nov. 20, 1973, as amended at 42 FR 27582, May 31, 1977; 42 
FR 56112, Oct. 21, 1977; 49 FR 23834, June 8, 1984; 51 FR 15610, Apr. 
25, 1986; 55 FR 11013, Mar. 26, 1990]



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.
640.3  Suitability of donor.
640.4  Collection of the blood.
640.5  Testing the blood.
640.6  Modifications of Whole Blood.

                       Subpart B--Red Blood Cells

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

                          Subpart C--Platelets

640.20  Platelets.
640.21  Suitability of donors.
640.22  Collection of source material.
640.23  Testing the blood.
640.24  Processing.
640.25  General requirements.
640.27  Emergency provisions.

                            Subpart D--Plasma

640.30  Plasma.
640.31  Suitability 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  Suitability 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.

[[Page 119]]

                        Subpart G--Source Plasma

640.60  Source Plasma.
640.61  Informed consent.
640.62  Medical supervision.
640.63  Suitability of donor.
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.
640.70  Labeling.
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--Measles Immune Globulin (Human)

640.110  Measles Immune Globulin (Human).
640.111  General requirements.
640.112  Manufacture of Measles Immune Globulin (Human).
640.113  The final product.
640.114  Potency.

                    Subpart L--Alternative Procedures

640.120  Alternative procedures.

    Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360, 
371); secs. 215, 351, 352, 353, 361 of the Public Health Service Act (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 he 
finds are of such a nature as to assure compliance otherwise with the 
provisions of this subchapter.
    (b) Periodic check on sterile technique. Where blood is collected in 
an open system, that is, where the blood container is entered, at least 
one container of such blood that upon visual examination appears normal 
shall be tested each month between the 18th and 24th day after 
collection (between the 32d and 38th day after collection when CPDA-1 
solution is used as the anticoagulant), as a continuing check on 
technique of blood collection, as follows: The test shall be performed 
with a total sample of no less than 10 milliliters of blood and a total 
volume of fluid thioglycollate medium 10 times the volume of the sample 
of blood. The test sample shall be inoculated into one or more test 
vessels in a ratio of blood to medium of 1 to 10 for each vessel, mixed 
thoroughly, incubated for 7 to 9 days at a temperature of 30 deg. to 
32 deg. C, and examined for evidence of growth of microorganisms every 
workday throughout the test period. On the

[[Page 120]]

third, fourth, or fifth day, at least 1 milliliter of material from each 
test vessel shall be subcultured in additional test vessels containing 
the same culture medium and in such proportion as will permit 
significant visual inspection, mixed thoroughly, incubated for 7 to 9 
days at a temperature of 30 deg. to 32 deg. C, and examined for evidence 
of growth of microorganisms every workday throughout the test period. If 
growth is observed in any test vessel, the test shall be repeated to 
rule out faulty test procedure, using another sample of blood from 
either, (1) the container from which the initial test sample was taken; 
(2) the residual cells or plasma from that blood; or (3) two different 
containers of blood, each 18 to 24 days old (32 to 38 days old when 
CPDA-1 solution is used as the anticoagulant) and each tested 
separately. The formula for Fluid Thioglycollate Medium shall be as 
prescribed in Sec. 610.12(e)(1) of this chapter. Media and design of 
container shall meet the requirements prescribed in Sec. 610.12(e)(2) 
(i) and (ii) of this chapter. In lieu of performing one test using an 
incubation temperature of 30 deg. to 32 deg. C, two tests may be 
performed: Each in all respects as prescribed in this paragraph, one at 
an incubation temperature of 18 deg. to 22 deg. C and one at an 
incubation temperature of 35 deg. to 37 deg. C.
    (c) Final container. The original blood container shall be the final 
container and shall not be entered prior to issue for any purpose except 
for blood collection. Such container shall be uncolored and transparent 
to permit visual inspection of the contents and any closure shall be 
such as will maintain an 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.
    (d) [Reserved]
    (e) 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) An original pilot sample is properly attached and has not been 
removed, except that blood lacking a pilot sample may be reissued in an 
emergency provided it is accompanied by instructions for sampling and 
for use within six hours after entering the container for sampling;
    (3) The blood has been stored continuously at 1 deg. to 6 deg. C. 
and shipped between 1 deg. 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.
    (f) Issue prior to determination of test results. Notwithstanding 
the provisions of Sec. 610.1 of this chapter, blood may be issued by the 
manufacturer on the request of a physician, hospital, or other medical 
facility before results of all tests prescribed in Sec. 640.5, the test 
for hepatitis B surface antigen prescribed in Sec. 610.40(a) of this 
chapter, and a test for antibody to Human Immunodeficiency Virus (HIV) 
prescribed in Sec. 610.45(a) of this chapter have been completed, where 
such issue is essential to allow time for transportation to ensure 
arrival of the blood by the time it is needed for transfusion: Provided, 
That (1) the blood is shipped directly to such physician or medical 
facility, (2) the records of the manufacturer contain a full explanation 
of the need for such issue, and (3) the label on each container of such 
blood bears the information required by Sec. 606.121(h) of this chapter.

(Information collection requirements approved by the Office of 
Management and Budget under number 0910-0227)

[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]



Sec. 640.3   Suitability of donor.

    (a) Method of determining. The suitability of a donor as a source of 
Whole Blood shall be determined by a qualified physician or by persons 
under his supervision and trained in determining suitability. Such 
determination shall

[[Page 121]]

be made on the day of collection from the donor by means of medical 
history, a test for hemoglobin level, and such physical examination as 
appears necessary to a physician who shall be present on the premises 
when examinations are made, except that the suitability of donors may be 
determined when a physician is not present on the premises, provided the 
establishment (1) maintains on the premises, and files with the Center 
for Biologics Evaluation and Research, a manual of standard procedures 
and methods, approved by the Director of the Center for Biologics 
Evaluation and Research, that shall be followed by employees who 
determine suitability of donors, and (2) maintains records indicating 
the name and qualifications of the person immediately in charge of the 
employees who determine the suitability of donors when a physician is 
not present on the premises.
    (b) Qualifications of donor; general. Except as provided in 
paragraph (f), a person may not serve as a source of Whole Blood more 
than once in 8 weeks. In addition, donors shall be in good health, as 
indicated in part by:
    (1) Normal temperature;
    (2) Demonstration that systolic and diastolic blood pressures are 
within normal limits, unless the examining physician is satisfied that 
an individual with blood pressures outside these limits is an otherwise 
qualified donor under the provisions of this section;
    (3) A blood hemoglobin level which shall be demonstrated to be no 
less than 12.5 gm. of hemoglobin per 100 ml. of blood;
    (4) Freedom from acute respiratory diseases;
    (5) Freedom from any infectious skin disease at the site of 
phlebotomy and from any such disease generalized to such an extent as to 
create a risk of contamination of the blood;
    (6) Freedom from any disease transmissible by blood transfusion, 
insofar as can be determined by history and examinations indicated 
above; and
    (7) Freedom of the arms and forearms from skin punctures or scars 
indicative of addiction to self-injected narcotics.
    (c) Additional qualifications of donor; viral hepatitis. No 
individual shall be used as a source of Whole Blood if he has--
    (1) A history of viral hepatitis;
    (2) A history of close contact within six months of donation with an 
individual having viral hepatitis;
    (3) A history of having received within six months human blood, or 
any derivative of human blood which the Food and Drug Administration has 
advised the licensed establishment is a possible source of viral 
hepatitis.
    (d) Therapeutic bleedings. Blood withdrawn in order to promote the 
health of a donor otherwise qualified under the provisions of this 
section, shall not be used as a source of Whole Blood unless the 
container label conspicuously indicates the donor's disease that 
necessitated withdrawal of blood.
    (e) Immunized donors. Blood withdrawn from donors known to have been 
immunized to human blood cell antigens shall not be used for Whole Blood 
unless the container label conspicuously indicates such information.
    (f) Qualifications; donations within less than 8 weeks. A person may 
serve as a source of Whole Blood more than once in 8 weeks only if at 
the time of donation the person is examined and certified by a physician 
to be in good health, as indicated in part in paragraph (b) of this 
section.

[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50 
FR 4138, Jan. 29, 1985; 51 FR 15611, Apr. 25, 1986; 55 FR 11013, Mar. 
26, 1990]



Sec. 640.4   Collection of the blood.

    (a) Supervision. Blood shall be drawn from the donor by a qualified 
physician or under his supervision by assistants trained in the 
procedure. A physician shall be present on the premises when blood is 
being collected, except that blood may be collected when a physician is 
not present on the premises, provided the establishment (1) maintains on 
the premises, and files with the Center for Biologics Evaluation and 
Research, a manual of standard procedures and methods, approved by the 
Director of the Center for Biologics Evaluation and Research, that shall 
be followed by employees who collect blood, and (2) maintains records 
indicating the name and qualifications of the person immediately in 
charge of

[[Page 122]]

the employees who collect blood when a physician is not present on the 
premises.
    (b) The donor clinic. The pertinent requirements of Secs. 600.10 and 
600.11 of this chapter shall apply at both the licensed 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. One of the following formulae shall be used in 
the indicated volumes:
    (1) Anticoagulant citrate dextrose solution (ACD).

------------------------------------------------------------------------
                                         Solution A        Solution B   
------------------------------------------------------------------------
Tri-sodium citrate (Na3C6H5O72H2O).                                                          
Citric acid (C6H8O7H2O)..  8.0 gm...........  4.8 gm.         
Dextrose (C6H12O6H2O)....  24.5 gm..........  14.7 gm.        
Water for injection (U.S.P.) to      1,000 ml.........  1,000 ml.       
 make.                                                                  
Volume per 100 ml. blood...........  15 ml............  25 ml.          
------------------------------------------------------------------------

    (2) Anticoagulant heparin solution.

Heparin sodium (U.S.P.)...................  75,000 units.               
Sodium chloride injection (U.S.P.) to make  1,000 ml.                   
Volume per 100 ml. blood..................  6 ml.                       
                                                                        

A buffer to maintain stability shall be added, if necessary.
    (3) Anticoagulant citrate phosphate dextrose solution (CPD).

Tri-sodium citrate (Na3C6H5O72H2O).                                                          
Citric acid (C6H8O7H2O).........  3.27 gm.                    
Dextrose (C6H12O6H2O)...........  25.5 gm.                    
Monobasic sodium phosphate (NaH2PO4H2O).                                                           
Water for injection (U.S.P.) to make......  1,000 ml.                   
Volume per 100 ml. blood..................  14 ml.                      
                                                                        

    (4) Anticoagulant citrate phosphate dextrose adenine solution (CPDA-
1).

Tri-sodium citrate (Na3C6H5O72H2O).                                                          
Citric acid (C6H8O7H2O).........  3.27 gm.                    
Dextrose (C6H12O6H2O)...........  31.9 gm.                    
Monobasic sodium phosphate (NaH2PO4H2O).                                                           
Adenine (C5H5N5)..........................  0.275 gm.                   
Water for injection (U.S.P.) to make......  1,000 ml.                   
Volume per 100 ml blood...................  14 ml.                      
                                                                        

    (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. 640.3.
    (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) Pilot samples for laboratory tests. Pilot samples for laboratory 
tests shall meet the following standards:
    (1) One or more pilot samples shall be provided with each unit of 
blood when issued or reissued except as provided in Sec. 640.2(e)(2) and 
all pilot samples 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 pilot samples accompanying a unit of blood shall be collected at 
the time of filling the final container by the person who collects the 
unit of blood.
    (3) All containers for all samples shall bear the donor's 
identification before collecting the samples.
    (4) All containers for pilot samples accompanying a unit of blood 
shall be attached to the whole blood container before blood collection, 
in a tamperproof manner that will conspicuously indicate removal and 
reattachment.
    (5) When CPDA-1 is used, pilot samples for compatibility testing 
shall contain blood mixed with CPDA-1.
    (h) Phlebotomy for Heparin Whole Blood. Heparin Whole Blood shall be 
collected with minimal damage to and minimal manipulation of the donor's 
tissue, and with a single, uninterrupted, freeflowing venipuncture.
    (i) Storage. Immediately after collection, unless the blood is to be 
used as a source for Platelets, it shall be placed in storage at a 
temperature between 1 deg. and 6 deg. C unless it must be transported 
from the donor clinic to the processing laboratory. In the latter case, 
the blood shall be placed in temporary storage having sufficient 
refrigeration

[[Page 123]]

capacity to cool the blood continuously toward a range between 1 deg. 
and 6 deg. C until it arrives at the processing laboratory, where it 
shall be stored at a temperature between 1 deg. and 6 deg. C. Blood from 
which Platelets is to be prepared shall be held in an environment 
maintained at a temperature range 20 deg. to 24 deg. C until the 
platelets are separated. The red blood cells shall be placed in storage 
at a temperature between 1 deg. and 6 deg. C immediately after the 
platelets are separated.

[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]



Sec. 640.5   Testing the blood.

    All laboratory tests shall be made on a pilot sample specimen of 
blood taken from the donor at the time of collecting the unit of blood, 
and these tests shall include the following:
    (a) Serological test for syphilis. Whole Blood shall be negative to 
a serological test for syphilis.
    (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 
pilot 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 
this test is negative, the results shall be confirmed by further testing 
which may include tests for the Rho variant (Du) and for other 
Rh-Hr factors. Blood maybe labeled ``Rh Negative'' if negative to tests 
for the Rho (D) and Rho variant (Du) factors. If the test 
using Anti-D Blood Grouping Reagent is negative, but not tested for the 
Rho variant (Du), the label must indicate that this test was 
not done. Only Anti-Rh 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.
    (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 antibody to HIV. Whole Blood shall be tested for 
antibody to HIV as prescribed in Sec. 610.45 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]



Sec. 640.6   Modifications of Whole Blood.

    Upon approval by the Director, Center for Biologics Evaluation and 
Research, of a supplement to the product license application for Whole 
Blood a manufacturer may prepare Whole Blood from which the 
antihemophilic factor has been removed, provided the 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.
    (c) If containers for pilot samples are detached from the blood 
container during removal of the antihemophilic factor the pilot samples 
shall be reattached to the unit of Whole Blood Cryoprecipitate Removed 
as soon as the plasma is returned to the red blood

[[Page 124]]

cells. The reattachment of the pilot samples shall be in a tamperproof 
manner that will conspicuously indicate removal and reattachment.

[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]



                       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 deg. 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   Suitability of donor.

    The source blood for Red Blood Cells shall be obtained from a donor 
who meets the criteria for donor suitability prescribed in Sec. 640.3.

[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4139, Jan. 29, 1985]



Sec. 640.13   Collection of the blood.

    (a) The source blood shall be collected as prescribed in Sec. 640.4, 
except that paragraphs (d)(2), and (g), and (h) shall not apply.
    (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]



Sec. 640.14  Testing the blood.

    Blood from which Red Blood Cells are prepared shall be tested as 
prescribed in Secs. 610.40 and 610.45 of this chapter and Sec. 640.5 
(a), (b), and (c).

[53 FR 117, Jan. 5, 1988]



Sec. 640.15   Pilot samples.

    Pilot samples collected in integral tubing or in separate pilot 
tubes shall meet the following standards:
    (a) One or more pilot samples of either the original blood or of the 
Red Blood Cells being processed shall be provided with each unit of Red 
Blood Cells when issued or reissued.
    (b) Before they are filled, all pilot sample tubes shall be marked 
or identified so as to relate them to the donor of that unit of red 
cells.
    (c) Before the final container is filled or at the time the final 
product is prepared, the pilot sample tubes to accompany a unit of cells 
shall be attached securely to the final container in a tamper proof 
manner that will conspicuously indicate removal and reattachment.
    (d) All pilot sample tubes 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, in each instance by the person who performs 
the collection or preparation.

[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4139, Jan. 29, 1985]



Sec. 640.16  Processing.

    (a) Separation. Within 21 days from date of blood collection (within 
35 days from date of blood collection when CPDA-1 solution is used as 
the anticoagulant), 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 
is added for prolonged storage.
    (b) Sterile system. All surfaces that come in contact with the red 
cells shall be sterile and pyrogen-free. If an open system is used, that 
is, where the

[[Page 125]]

transfer container is not integrally attached to the blood container, 
and the blood container is entered after blood collection, the plasma 
shall be separated from the red blood cells with positive pressure 
maintained on the original container until completely sealed. If the 
method of separation involves a vented system, that is, when an airway 
must be inserted in the container for withdrawal of the plasma, the 
airway and vent shall be sterile and constructed so as to exclude 
microorganisms and maintain a sterile system.
    (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 
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]



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]



                          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 shall be plasma which 
may be obtained by whole blood collection, by plasmapheresis, or by 
plateletpheresis.

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



Sec. 640.21   Suitability of donors.

    (a) Whole blood donors shall meet the criteria for suitability 
prescribed in Sec. 640.3.
    (b) Plasmapheresis donors shall meet the criteria for suitability 
prescribed in Sec. 640.63, excluding the phrase ``other than malaria'' 
in paragraph (c)(9). Informed consent shall be required as prescribed in 
Sec. 640.61.
    (c) Plateletpheresis donors shall meet criteria for suitability as 
described in a license application or a supplement to the product 
license, and must have the written approval of the Director, Center for 
Biologics Evaluation and Research, Food and Drug Administration.

[40 FR 4304, Jan. 29, 1975, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994]



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, except that paragraphs (d)(2) and (h) shall 
not apply.
    (b) If plasmapheresis is used, the procedure for collection shall be 
prescribed in Secs. 640.62, 640.64 (except paragraph (c)(3)), and 
640.65.
    (c) If plateletpheresis is used, the procedure for collection shall 
be as described in a license application or a supplement to a product 
license, and must have the written approval of the Director, Center for 
Biologics Evaluation and Research, Food and Drug Administration.

[[Page 126]]

    (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]



Sec. 640.23   Testing the blood.

    (a) Blood from which plasma is separated for the preparation of 
Platelets shall be tested as prescribed in Secs. 610.40 and 610.45 of 
this chapter and Sec. 640.5 (a), (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]



Sec. 640.24   Processing.

    (a) Separation of plasma and platelets and resuspension of the 
platelets shall be in a closed system. Platelets shall not be pooled 
during processing.
    (b) Immediately after collection, the whole blood or plasma shall be 
held in storage between 20 deg. to 24 deg. C, unless it must be 
transported from the donor clinic 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 deg. and 24 deg. 
C until it arrives at the processing laboratory where it shall be held 
between 20 deg. and 24 deg. C until the platelets are separated. The 
platelet concentrate shall be separated within 4 hours after the 
collection of the unit of whole blood or plasma.
    (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 1010 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 6.0 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 deg. to 24 deg. C.
    (2) 1 deg. 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]



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 deg. 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 deg. 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 6.0 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

[[Page 127]]

of the Clinical Laboratories Improvement Act of 1967 (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]



Sec. 640.27   Emergency provisions.

    The use of the plateletpheresis procedure to obtain a product for a 
specific recipient may be at variance with Secs. 640.21(c) and 
640.22(c): Provided, That: (a) A licensed physician has determined that 
the recipient must be transfused with the platelets from a specific 
donor, and (b) the plateletpheresis procedure is performed under the 
supervision of a qualified licensed physician who is aware of the health 
status of the donor and the physician has certified in writing that the 
donor's health permits plateletpheresis.

[40 FR 53544, Nov. 18, 1975]



                            Subpart D--Plasma



Sec. 640.30  Plasma.

    (a) Proper name and definition. The proper name of this product 
shall be Plasma. The product is defined as the fluid portion of one unit 
of human blood intended for intravenous use which in a closed system, 
has been collected, stabilized against clotting, and separated from the 
red blood cells.
    (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]



Sec. 640.31  Suitability of donors.

    (a) Whole blood donors shall meet the criteria for donor suitability 
prescribed in Sec. 640.3.
    (b) Plasmapheresis donors shall meet the criteria for donor 
suitability prescribed in Sec. 640.63, excluding the phrase ``other than 
malaria'' in paragraph (c)(9) of that section. Informed consent shall be 
required as prescribed in Sec. 640.61.
    (c) Donors shall not be suitable if they are known to have been 
immunized within the past 6 months by injection with human red blood 
cells.

[42 FR 59878, Nov. 22, 1977]



Sec. 640.32  Collection of source material.

    (a) Whole blood shall be collected, transported, and stored as 
prescribed in Sec. 640.4, except that paragraphs (d)(2) and (h) of that 
section shall not apply. When whole blood is intended for Plasma, Fresh 
Frozen Plasma, and Liquid Plasma, it shall be maintained at a 
temperature between 1 deg. and 6 deg. C until the plasma is removed. 
Whole blood intended for Platelet Rich Plasma, shall be maintained as 
prescribed in Sec. 640.24 until the plasma is removed. The red blood 
cells shall be placed in storage at

[[Page 128]]

a temperature between 1 deg. and 6 deg. C immediately after the plasma 
is separated.
    (b) Plasma obtained by plasmapheresis shall be collected as 
prescribed in Secs. 640.62, 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]



Sec. 640.33  Testing the blood.

    (a) Blood from which plasma is separated shall be tested as 
prescribed in Secs. 610.40 and 610.45 of this chapter and Sec. 640.5 
(a), (b), and (c).
    (b) Manufacturers of Plasma collected by plasmapheresis shall have 
testing and recordkeeping responsibilities equivalent to those 
prescribed in Secs. 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]



Sec. 640.34  Processing.

    (a) Plasma. Plasma shall be separated from the red blood cells 
within 26 days after phlebotomy (within 40 days after phlebotomy when 
CPDA-1 solution is used as the anticoagulant), and shall be stored at 
-18 deg. C or colder within 6 hours after transfer to the final 
container, 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 
shall be separated from the red blood cells, frozen solid within 6 hours 
after phlebotomy, and stored at -18 deg. C or colder.
    (c)  Liquid Plasma. Liquid Plasma shall be separated from the red 
blood cells within 26 days after phlebotomy (within 40 days after 
phlebotomy when CPDA-1 solution is used as the anticoagulant) and shall 
be stored at a temperature of 1 deg. to 6 deg. C within 4 hours after 
filling the final container.
    (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 phlebotomy. The time and speed of 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 deg. 
to 24 deg. C or between 1 deg. and 6 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 deg. 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 solid within 6 hours after phlebotomy.
    (2) Cryoprecipitated AHF shall be removed as prescribed in Subpart F 
of part 640. The remaining plasma may be labeled Plasma.
    (3) Plasma remaining after both Platelets and Cryoprecipitated AHF 
have been removed may be labeled Plasma.
    (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

[[Page 129]]

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 of 
the product during storage or breakage of the container.
    (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]



                          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]



Sec. 640.51  Suitability of donors.

    (a) Whole blood donors shall meet the criteria for suitability 
prescribed in Sec. 640.3.
    (b) Plasmaphersis donors shall meet the criteria for suitability 
prescribed in Sec. 640.63, excluding the phrase ``other than malaria'' 
in paragraph (c) (9) of that section. Informed consent shall be required 
as prescribed in Sec. 640.61.
    (c) Donors shall not be suitable if they are known to have been 
immunized by injection with human red blood cells within the last 6 
months.

[42 FR 21774, Apr. 29, 1977]



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, except that paragraphs (d) (2), 
(g), and (h) of that section shall not apply. 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 Secs. 640.62, 640.64 (except that paragraph (c)(3) of 
that section shall not apply), and 640.65.

[42 FR 21774, Apr. 29, 1977, as amended by 50 FR 4139, Jan. 29, 1985]



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 Secs. 610.40 and 
610.45 of this chapter and Sec. 640.5 (a), (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 Secs. 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]



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 frozen solid within 6 hours after blood 
collection. 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.

[[Page 130]]

    (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]



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, Food 
and Drug Administration, for use in the preparation of a working 
reference to be employed in a 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]



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 Act of 1967 (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]



                        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. 640.61   Informed consent.

    The written consent of a prospective donor shall be obtained after a 
qualified licensed physician has explained the hazards of the procedure 
to the prospective donor. The explanation shall include the risks of a 
hemolytic transfusion reaction if he is given the cells of another 
donor, and the hazards involved if he is hyperimmunized. The explanation 
shall consist of such disclosure and be made in such a manner that 
intelligent and informed consent

[[Page 131]]

be given and that a clear opportunity to refuse is presented.



Sec. 640.62   Medical supervision.

    A qualified licensed physician shall be on the premises when donor 
suitability is being determined, immunizations are being made, whole 
blood is being collected, and red blood cells are being returned to the 
donor.



Sec. 640.63   Suitability of donor.

    (a) Method of determining. The suitability of a donor for Source 
Plasma shall be determined by a qualified licensed physician or by 
persons under his supervision and trained in determining donor 
suitability. Such determination shall be made on the day of collection 
from the donor by means of a medical history, tests, and such physical 
examination as appears necessary to the qualified licensed physician.
    (b) Initial medical examinations. (1) Each donor shall be examined 
by a qualified licensed physician 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.
    (2)(i) A donor who is to be immunized for the production of high-
titer plasma shall be examined by a qualified licensed physician. The 
medical examination shall be performed within no more than 1 week before 
the first immunization injection. The medical examination for 
plasmapheresis need not be repeated, if the first donation occurs within 
3 weeks after the first injection.
    (ii) A donor who is an active participant in a plasmapheresis 
program, and has been examined in accordance with paragraph (b)(1) of 
this section, need not be reexamined before immunization for the 
production of high-titer plasma.
    (3) Each donor shall be certified to be in good health by the 
examining physician. The certification of good health shall be on a form 
supplied by the licensed establishment and shall indicate that the 
certification applies to the suitability of the individual to be a 
plasmapheresis donor and, when applicable, an immunized donor.
    (c) Qualification of donor. Donors shall be in good health on the 
day of donation, as indicated in part by:
    (1) Normal temperature;
    (2) Demonstration that systolic and diastolic blood pressures are 
within normal limits, unless the examining physician is satisfied that 
an individual with blood pressures outside these limits is an otherwise 
qualified donor under the provisions of this section;
    (3) A blood hemoglobin level of no less than 12.5 grams of 
hemoglobin per 100 milliliters of blood;
    (4) A normal pulse rate;
    (5) A total serum protein of no less than 6.0 grams per 100 
milliliters of serum;
    (6) Weight, which shall be at least 110 pounds;
    (7) Freedom from acute respiratory diseases;
    (8) Freedom from any infectious skin disease at the site of 
phlebotomy and from any such disease generalized to such an extent as to 
create a risk of contamination of the plasma;
    (9) Freedom from any disease, other than malaria, transmissible by 
blood transfusion, insofar as can be determined by history and 
examinations indicated in this section;
    (10) Freedom of the arms and forearms from skin punctures or scars 
indicative of addiction to self-injected narcotics;
    (11) Freedom from a history of viral hepatitis;
    (12) Freedom from a history of close contact within six months of 
donation with an individual having viral hepatitis;
    (13) Freedom from a history of having received, within six months, 
human blood or any derivative of human blood which the Food and Drug 
Administration has advised the licensed establishment is a possible 
source of viral hepatitis, except for specific immunization performed in 
accordance with Sec. 640.66 of this part.
    (d) General. Any donor who, in the opinion of the interviewer, 
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, shall not be considered a suitable donor.
    (e) Failure to return red blood cells. Any donor who has not had the 
red blood cells returned from a unit of

[[Page 132]]

blood collected during a plasmapheresis procedure or who has been a 
donor of a unit of whole blood shall not be subjected to plasmapheresis 
for a period of 8 weeks, unless:
    (1) The donor has been examined by a qualified licensed physician 
and certified by the physician to be acceptable for further 
plasmapheresis before expiration of the 8-week period;
    (2) The donor possesses an antibody that is (i) transitory, (ii) of 
a highly unusual or infrequent specificity, or (iii) of an unusually 
high titer; and
    (3) The special characteristics of the antibody and the need for 
plasmapheresing the donor are documented.

[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10768, Mar. 12, 1976; 
43 FR 9805, Mar. 10, 1978; 43 FR 12311, Mar. 24, 1978; 46 FR 57480, Nov. 
24, 1981; 50 FR 4140, Jan. 29, 1985]



Sec. 640.64   Collection of blood for Source Plasma.

    (a) Supervision. All blood for the collection of Source Plasma shall 
be drawn from the donor by a qualified licensed physician or by persons 
under his supervision trained in the procedure.
    (b) 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.
    (c) The anticoagulant solution. The anticoagulant solution shall be 
sterile and pyrogen-free. One of the following formulas shall be used in 
the indicated volumes, except that a different formula may be used for 
plasma for manufacture into noninjectable products if prior written 
approval is obtained from the Director of the Center for Biologics 
Evaluation and Research at the time of licensing or in the form of a 
supplement to the Source Plasma product license.
    (1) Anticoagulant citrate dextrose solution (ACD).

Tri-sodium citrate (Na3C6H5O72H2O).                                                          
Citric acid (C6H8O7H2O)........  8.0 grams.                   
Dextrose (C6H12O6H2O)....................  24.5 grams.                  
Water for injection (U.S.P.) to make.....  1,000 milliliters.           
Volume per 100 milliliters blood.........  15 milliliters.              
                                                                        

    (2) Anticoagulant citrate phosphate dextrose solution (CPD).

Tri-sodium citrate (Na3C6H5O72H2O).                                                          
Citric acid (C6H8OH2O).........  3.27 grams.                  
Dextrose (C6H12O6H2O)....................  25.5 grams.                  
Monobasic sodium phosphate (NaH2PO4H2O).                                                           
Water for injection (U.S.P.) to make.....  1,000 milliliters.           
Volume per 100 milliliters blood.........  14 milliliters.              
                                                                        

    (3) Anticoagulant sodium citrate solution.

Tri-sodium citrate (Na3C6H5O72H2O).                                                          
Water for injection (U.S.P.) to make.....  1,000 milliliters.           
Volume per 100 milliliters of blood......  10 milliliters.              
                                                                        

    (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]



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 product license application.
    (b) Procedures-specific requirements. The plasmapheresis procedure 
shall meet the following requirements:
    (1)(i) A sample of blood shall be drawn from each donor on the day 
of the first medical examination or plasmapheresis, whichever comes 
first and at least every 4 months thereafter by a qualified licensed 
physician or by persons under his supervision and trained in such 
procedure. A serologic test for

[[Page 133]]

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 physician on the premises 
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) The accumulated laboratory data, including tracings, if any, 
of the plasma or serum protein electrophoresis pattern, the calculated 
values of each component, and the collection records shall be reviewed 
by a qualified licensed physician within 21 days after the sample is 
drawn to determine whether or not the donor may continue in the program. 
The review shall be signed by the reviewing physician. If the protein 
composition is not within normal limits established by the testing 
laboratory, or if the total protein is less than 6.0 grams per 100 
milliliters of samples, the donor shall be removed from the program 
until these values return to normal.
    (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 physician on the premises 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 physician on the premises 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 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 plasmapheresis procedure or in any 48-hour 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 plasmapheresis 
procedure or in any 48-hour period shall not exceed 1,200 milliliters.
    (5) The amount of whole blood, not including anticoagulant, removed 
from a donor within a seven-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 the donor during a seven-day period shall not exceed 2,400 
milliliters.

[[Page 134]]

    (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.

[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976]



Sec. 640.66   Immunization of donors.

    If specific immunization of a donor is to be performed, the 
selection and scheduling of the injection of the antigen, and the 
evaluation of each donor's clinical response, shall be by a qualified 
licensed physician or physicians. The administration of the antigen may 
be performed by a licensed physician or a trained person under his 
supervision. 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]



Sec. 640.67  Laboratory tests.

    (a) Hepatitis B surface antigen. Each unit of Source Plasma shall be 
nonreactive to a test for hepatitis B surface antigen as prescribed in 
Secs. 610.40 and 610.41 of this chapter, except insofar as permitted in 
Sec. 610.40(d)(1) and (d)(2) of this chapter.
    (b) Antibody to HIV. Each unit of Source Plasma shall be negative by 
a test for antibody to HIV as prescribed in Sec. 610.45 of this chapter, 
except as provided in Sec. 610.45(c) of this chapter.

[53 FR 117, Jan. 5, 1988, as amended at 57 FR 10814, Mar. 31, 1992]



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. 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

[[Page 135]]

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) Pilot samples. If pilot samples are provided, they shall meet 
the following standards:
    (1) Prior to filling, all pilot samples shall be marked or 
identified so as to relate them directly to the donor of that unit of 
plasma.
    (2) All pilot samples shall be filled at the time the final product 
is prepared by the person who prepares the final product.
    (3) All pilot samples shall be representative of the contents of the 
final product.
    (4) All pilot samples shall be collected in a manner that does not 
contaminate the contents of the final container.

[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]



Sec. 640.70   Labeling.

    (a) In addition to the labeling requirements of Sec. 610.62 of this 
chapter, and in lieu of the requirements in Secs. 606.121, 610.60, and 
610.61 of this chapter, the following information shall appear on the 
label affixed to each container of Source Plasma:
    (1) The proper name of the product.
    (2) The statement ``Caution: For Manufacturing Use Only'' for 
products intended for further manufacturing into injectable products, or 
the statement, ``Caution: For Use In Manufacturing Noninjectable 
Products Only'', for products intended for further manufacturing into 
noninjectable products. The statement shall follow the proper name in 
the same size and type of print as the proper name.
    (3) The statement ``Store at --20 deg. C. or colder'': Provided, 
That where plasma is intended for manufacturing into noninjectable 
products, this statement may be omitted if replaced by a statement of 
the temperature appropriate for the final product to be prepared from 
the plasma.
    (4) The total volume or weight of plasma and total quantity and type 
of anticoagulant used.
    (5) The donor number or individual bleed number, or both. If plasma 
is pooled from two or more donors, either all donor numbers, all bleed 
numbers, or a pool number that is traceable to each individual unit 
comprising the pool.
    (6) The expiration date of the plasma. If plasma intended for 
manufacturing into noninjectable products is pooled from two or more 
donors the expiration date is determined from the collection date of the 
oldest unit in the pool, and the pooling records shall show the 
collection date for each unit constituting the pool.
    (7) A statement as to whether the plasma was collected from normal 
donors or from immunized donors. In the case of immunized donors, the 
label shall state the immunizing antigen.

[[Page 136]]

    (8) The test for hepatitis B surface antigen used for the results, 
or the statement ``Nonreactive for HBsAg by FDA required test''.
    (9) When plasma collected from a donor is reactive for the 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.
    (10) Name, address, and license number of the manufacturer.
    (11) The statement ``Negative by a test for antibody to HIV'', or 
equivalent statement.
    (b) Source Plasma diverted for Source Plasma Salvaged shall be 
relabeled ``Source Plasma Salvaged'' as prescribed in Sec. 640.76. 
Immediately following the proper name of the product, the labeling shall 
conspicuously state as applicable, ``STORAGE TEMPERATURE EXCEEDED --
20 deg. C'' or ``SHIPPING TEMPERATURE EXCEEDED --5 deg. C''.

[41 FR 10770, Mar. 12, 1976, as amended at 41 FR 27034, July 1, 1976; 41 
FR 35062, Aug. 19, 1976; 47 FR 30969, July 16, 1982; 50 FR 4140, Jan. 
29, 1985; 50 FR 35471, Aug. 30, 1985; 53 FR 117, Jan. 5, 1988]



Sec. 640.71   Manufacturing responsibility.

    (a) All steps in the manufacture 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 the 
following tests may be performed by personnel of an establishment 
licensed for blood or 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 Act of 1967 (CLIA) 
(42 U.S.C. 263a): Provided, The establishment or the clinical laboratory 
is qualified to perform the assigned test(s).
    (1) The test for hepatitis B surface antigen.
    (2) The total plasma or serum protein and the quantitative test for 
plasma or serum proteins or for immunoglobulins.
    (3) The serologic test for syphilis.
    (4) A test for antibody to HIV.
    (b) Such testing shall not be considered divided manufacturing, 
which requires two product licenses for Source Plasma: Provided, That
    (1) The results of such tests are maintained by the establishment 
licensed for Source Plasma whereby such results may be reviewed by a 
licensed physician as required in Sec. 640.65(b)(2) 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]



Sec. 640.72   Records.

    (a) In addition to the recordkeeping requirements of this 
subchapter, the following records shall be maintained:
    (1) Documentation compiled every 3 months establishing that the 
shipping temperature requirements of Sec. 600.15 of this title and 
Sec. 640.74(b)(2) are being met for Source Plasma intended for 
manufacture into injectable products.
    (2) For each donor, a separate and complete record of all initial 
and periodic examinations, tests, laboratory data, interviews, etc., 
undertaken pursuant to Secs. 640.63, 640.65, 640.66, and 640.67, except 
that negative test results for hepatitis B surface antigen, negative 
test results for antibody to HIV, and the volume or weight of plasma 
withdrawn from a donor need not be kept on the individual donor record: 
Provided, That 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 of the donor's written consent for 
participation in the plasmapheresis program or for immunization.

[[Page 137]]

    (4) The certification of the donor's good health as prescribed in 
Sec. 640.63(b)(3).
    (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.
    (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.

(Collection of information requirements approved by the Office of 
Management and Budget under control number 0910-0227)

[41 FR 10770, Mar. 12, 1976, as amended at 50 FR 4140, Jan. 29, 1985; 53 
FR 117, Jan. 5, 1988]



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 
product license 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 product licensee 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. 640.70(a) 
but excluding Sec. 640.70(a)(3), 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]



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

[[Page 138]]

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 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 component of human blood.
    (b) Source material. The source material of Albumin (Human) shall be 
blood, plasma, serum or placentas from human donors determined at the 
time of donation to have been free from disease-causative agents that 
are not destroyed or removed by the processing method, as determined by 
the medical history of the donor and from such physical examination and 
clinical tests as may appear necessary for each donor at the time the 
blood was obtained. Where source material is a product for which 
additional standards are effective, the requirements of those additional 
standards shall determine the propriety of the source material for use 
in the production of Albumin (Human). Where no additional standards are 
effective with respect to source material for the production of Albumin 
(Human), such source material shall:
    (1) Be collected by a procedure which is designed to assure the 
integrity and to minimize the risk of contamination of the source 
material. The manufacturer of Albumin (Human) shall ensure that the 
collection procedure shall be as described in its license.
    (2) Be identified to relate it accurately to the individual donor 
and the dates of collection.
    (3) Not contain a preservative.
    (4) Be stored and transported in a manner designed to prevent 
contamination by microorganisms, pyrogens, or other impurities.
    (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

[[Page 139]]

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]



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 either 
microorganisms or other deleterious matter. 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 Albumin 
(Human) shall begin within 24 hours after completion of filling. Heat 
treatment shall be conducted so that the solution is heated for not less 
than 10 or more than 11 hours at an attained temperature of 
60 deg.plus-minus0.5 deg. C.
    (f) Stabilizer. Either 0.16 millimole sodium acetyltryptophanate, or 
0.08 millimole sodium acetyltryptophanate and 0.08 millimole sodium 
caprylate shall be added per gram of albumin as a stabilizer.
    (g) Incubation. All final containers of Albumin (Human) shall be 
incubated at 20 deg. 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]



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 content. Final product shall conform to one of the 
following concentrations: 4.0plus-minus0.25 percent; 
5.0plus-minus0.30 percent; 20.0plus-minus1.2 percent; and 
25.0plus-minus1.5 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) Hydrogen ion concentration. The pH shall be 
6.9plus-minus0.5 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 content. The sodium content of the final product shall be 
130 to 160 milliequivalents per liter.
    (e) Heme content. The absorbance at 403 nanometers of a solution of 
the final product diluted to a concentration of 1 percent protein in a 
cell with a 1-centimeter light path shall not exceed 0.25.
    (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]

[[Page 140]]



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 Secs. 610.60, 610.61, 
and 610.62 of this chapter,
    (a) The container and package labels shall contain the following 
information:
    (1) The osmotic equivalent in terms of plasma, and the sodium 
content in terms of a value or a range in milliequivalents per liter;
    (2) 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.'';
    (3) The need for additional fluids when 20 percent or 25 percent 
albumin is administered to a patient with marked dehydration;
    (4) The protein content, expressed as a 4 percent, 5 percent, 20 
percent, or 25 percent solution.
    (b) The type of source material, expressed as venous plasma, 
placental plasma, or both, used to manufacture the final product shall 
appear on either the container or package label or in the package 
insert.

[42 FR 27582, May 31, 1977, as amended at 49 FR 2244, Jan. 19, 1984]



               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 
blood.
    (b) Source material. The source material of Plasma Protein Fraction 
(Human) shall be blood, plasma, or serum from human donors determined at 
the time of donation to have been free from disease-causative agents 
that are not destroyed or removed by the processing method, as 
determined by the medical history of the donor and from such physical 
examination and clinical tests as may appear necessary for each donor at 
the time the blood was obtained. When source material is a product for 
which additional standards are effective, the requirements of those 
additional standards shall determine the propriety of the material for 
use in the production of Plasma Protein Fraction (Human). When no 
additional standards are effective with respect to source material for 
the production of Plasma Protein Fraction (Human), such source material 
shall:
    (1) Be collected by a procedure which is designed to assure the 
integrity and to minimize the risk of contamination of the source 
material. The manufacturer of Plasma Protein Fraction (Human) shall 
ensure that the collection procedure shall be as described in its 
license;
    (2) Be identified to relate it accurately to the individual donor 
and to the dates of collection;
    (3) Not contain a preservative; and
    (4) Be stored and transported in a manner designed to prevent 
contamination by microorganisms, pyrogens, or other impurities.
    (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.



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

[[Page 141]]

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 
coefficent 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 contimination from either 
microorganisms or other deleterious matter. 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 for not less than 10 or more than 11 hours at an attained 
temperature of 60 deg.plus-minus0.5 deg. C.
    (f) Stabilizer. Either 0.16 millimole sodium acetyltryptophanate, or 
0.08 millimole sodium acetyltryptophanate and 0.08 millimole sodium 
caprylate shall be added per gram of protein as a stabilizer.
    (g) Incubation. All final containers of Plasma Protein Fraction 
(Human) shall be incubated at 20 deg. 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, the types of organisms shall be identified 
as to genus and the material from such containers shall not be used for 
further manufacturing.



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 content. The final product shall be a 
5.0plus-minus0.3 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) Hydrogen ion concentration. The pH shall be 
7.0plus-minus0.3 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 content. The sodium content of the final product shall be 
130 to 160 milliequivalents per liter.
    (e) Potassium content. The potassium content 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]



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

[[Page 142]]

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 Secs. 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 
content in terms of a value or a range in milli- equivalents 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]



                   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 blood.
    (b) Source material. The source of Immune Globulin (Human) shall be 
blood, plasma or serum from human donors determined at the time of 
donation to have been free of causative agents of diseases that are not 
destroyed or removed by the processing methods, as determined by the 
donor's history and from such physical examination and clinical tests as 
appear necessary for each donor at the time the blood was obtained. The 
source blood, plasma or serum shall not contain a preservative and shall 
be stored in a manner that will prevent contamination by microorganisms, 
pyrogens or other impurities.
    (c) Additives in source material. Source blood, plasma or serum 
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]



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) Hydrogen ion concentration. The pH of final container material 
shall be 6.8plus-minus0.4 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.
    (3) The lot is or is not suitable for use with Measles Virus Vaccine 
Live.
    (4) The lot is or is not recommended for poliomyelitis.
    (f) Samples and protocols. For each lot of Immune Globulin (Human) 
the following material shall be submitted to the Director, Center for 
Biologics Evaluation and Research, Food and Drug Administration, 8800 
Rockville Pike, Bethesda, MD 20892:
    (1) A 50 ml. sample of the final product.
    (2) All protocols relating to the history of each lot and all 
results of all tests prescribed in these additional standards.

[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]



Sec. 640.102   Manufacture of Immune Globulin (Human).

    (a) Processing method. The processing method shall be one that has 
been

[[Page 143]]

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 30 deg. to 32 deg. C. 
for more than 72 hours.

[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4140, Jan. 29, 1985]



Sec. 640.103   The final product.

    (a) Final solution. The final product shall be a 
16.5plus-minus1.5 percent solution of globulin containing 0.3 molar 
glycine and a preservative.
    (b) Protein composition. At least 90 percent of the globulin shall 
have an electrophoretic mobility not faster than -2.8 x 10-5 
centimeters2 per volt per second, when measured at a 1 percent 
protein concentration in sodium diethylbarbiturate buffer at pH 8.6 and 
0.1 ionic strength.



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 of no less than 0.50 times 
the level of the Reference Immune Serum Globulin, except that when 
recommended for use with Measles Virus Vaccine Live, the measles 
antibody level shall be as prescribed in Sec. 640.114.
    (3) A poliomyelitis neutralizing antibody level of no less than 1.0 
for Type 1, 1.0 for Type 2, and 2.5 for Type 3, times the antibody level 
of the Reference Immune Serum Globulin.
    (c) Reference materials. The following reference materials shall be 
obtained from the Center for Biologics Evaluation and Research:
    (1) Reference Immune Serum Globulin for correlation of measles 
antibody titers.
    (2) Reference Immune Serum 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]



               Subpart K--Measles Immune Globulin (Human)



Sec. 640.110   Measles Immune Globulin (Human).

    (a) Proper name and definition. The proper name of the product shall 
be Measles Immune Globulin (Human). It shall consist of a sterile 
solution of 10 to 18 percent globulin derived from human blood, having 
the same measles antibody level as the Reference Measles Immune 
Globulin. Measles Immune Globulin shall be made from a sterile 16.5 
plus-minus1.5 percent solution of human globulin.

[[Page 144]]

    (b) Source material. The source of Measles Immune Globulin (Human) 
shall be blood, plasma or serum from human donors determined at the time 
of donation to have been free of causative agents of diseases that are 
not destroyed or removed by the processing method, as determined by the 
donor's history and from such physical examination and clinical tests as 
appear necessary for each donor at the time the blood was obtained. The 
source blood, plasma or serum shall not contain a preservative and shall 
be stored in a manner that will prevent contamination by microorganisms, 
pyrogens or other impurities.
    (c) Additives in source material. Source blood, plasma or serum 
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 39 FR 9661, Mar. 13, 1974]



Sec. 640.111   General requirements.

    (a) Heat stability test. Approximately 2 ml of final container 
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 four 
hours.
    (b) Hydrogen ion concentration. The pH of final container material 
shall be 6.8plus-minus0.4 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 antibody test as required in 
Sec. 640.114.
    (e)--(f) [Reserved]
    (g) Samples and protocols. For each lot of globulin, the following 
materials shall be submitted to the Director, Center for Biologics 
Evaluation and Research, Food and Drug Administration, 8800 Rockville 
Pike, Bethesda, MD 20892.
    (1) 30 ml of final product.
    (2) All protocols relating to the history of the manufacture of each 
lot and all results of all tests prescribed in these additional 
standards.

[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 51 
FR 15611, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990]



Sec. 640.112   Manufacture of Measles Immune Globulin (Human).

    (a) Processing method. The globulin shall be prepared by a 
processing method that (1) has been shown to be capable of concentrating 
tenfold from source material at least two different antibodies, (2) does 
not affect the integrity of the globulins and is capable of consistently 
yielding a product which is safe for subcutaneous and intramuscular 
injections and (3) will not transmit viral hepatitis.
    (b) Reference materials. The following reference material shall be 
obtained from the Center for Biologics Evaluation and Research: 
Reference Measles Immune Globulin for correlation of measles antibody 
titers with globulin products.
    (c) 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.
    (d) Bulk storage. The globulin fraction may be stored in bulk prior 
to further processing provided it is stored in well-marked hermetically 
closed vessels. Purified globulin as either a liquid concentrate or a 
solid and containing alcohol or more than 5 percent moisture shall be 
stored at a temperature not to exceed -10 deg. C. Purified globulin as a 
solid free from alcohol and containing less than 5 percent moisture, 
shall be stored at temperatures not to exceed 0 deg. C.
    (e) Determination of the lot. Each lot of Measles Immune Globulin 
(Human) shall represent a pooling of material from not less than 1,000 
donors.
    (f) Sterilization and dilution. The product shall be prepared 
initially as a 16.5 percent solution and this preparation shall be 
sterilized promptly after solution. After sterilization the product 
shall not be exposed to temperatures above 45 deg. C. for more than a 
total of 72 hours. Dilution of this sterile globulin

[[Page 145]]

solution shall be made only to adjust the required measles antibody 
level.

[38 FR 32089, Nov. 20, 1973, as amended at 39 FR 9661, Mar. 13, 1974; 49 
FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]



Sec. 640.113   The final product.

    (a) Final solution. The final product shall be a 10 to 18 percent 
solution of globulin containing 0.3 molar glycine and a preservative.
    (b) Protein composition. No less than 90 percent of the globulin 
shall have an electrophoretic mobility not faster than -2.8 x 10-5 
centimeters2 per volt per second, when measured at a 1 percent 
protein concentration in sodium diethylbarbiturate at pH 8.6 and 0.1 
ionic strength.



Sec. 640.114   Potency.

    Antibody levels and tests. Each lot of final product shall contain 
no less than the minimum levels of antibodies for diphtheria and measles 
as follows:
    (a) The product shall contain no less than 2 units of diphtheria 
antitoxin per ml, adjusted for dilution from the 16.5 percent solution.
    (b) Each lot of final product shall contain the same measles 
antibody level as the Reference Measles Immune Globulin. The measles 
antibody potency shall be determined by simultaneous determinations of 
the neutralizing antibody titers of the globulin on tests and of a 
reference preparation against 100 TCID50 (50-500 TCID50 when 
based upon a single test) of measles virus in a tissue culture system. 
The potency test shall also include a determination of virus titer and 
controls for globulin toxicity and cell culture viability. Twofold 
serial dilutions of the globulin under test and of the reference 
preparation shall be employed in this determination. In applying these 
requirements a plus or minus variation of one twofold dilution is 
acceptable.

[38 FR 32089, Nov. 20, 1973, as amended at 39 FR 9661, Mar. 13, 1974]



                    Subpart L--Alternative Procedures



Sec. 640.120  Alternative procedures.

    (a) The Director, Center for Biologics Evaluation and Research, may 
approve 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. Requests for such exceptions 
or alternatives should ordinarily be made in writing. However, in 
limited circumstances such requests may be made orally and permission 
may be given orally by the Director. Oral requests and approvals must be 
followed by written requests and written approvals. Approval of a 
request for an exception or alternative must be obtained from the 
Director prior to the distribution of any affected blood, blood 
component, or blood product.
    (b) FDA will publish a list of approved alternative procedures and 
exceptions periodically in the Federal Register.

[55 FR 10423, Mar. 21, 1990]



PART 650--ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR DERMAL TESTS--Table of Contents




               Subpart A--Diphtheria Toxin for Schick Test

Sec.
650.1  Diphtheria Toxin for Schick Test.
650.2  U.S. Standard preparation.
650.3  Manufacture of Diphtheria Toxin for Schick Test.
650.4  Potency test.
650.5  Stability test.
650.6  Samples; protocols; official release.

                          Subpart B--Tuberculin

650.10  Tuberculin.
650.11  General requirements.
650.12  U.S. Standard preparations.
650.13  Production.
650.14  Potency testing in animals.
650.15  Potency testing in humans.

    Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360, 
371); secs. 215, 351, 352, 353, 361 of the Public Health Service Act (42 
U.S.C. 216, 262, 263, 263a, 264).

    Source: 38 FR 32097, 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.

[[Page 146]]



               Subpart A--Diphtheria Toxin for Schick Test



Sec. 650.1   Diphtheria Toxin for Schick Test.

    The proper name of this product shall be Diphtheria Toxin for Schick 
Test, which shall be a preparation of a diphtheria toxin obtained from 
the growth of Corynebacterium diphtheriae.



Sec. 650.2   U.S. Standard preparation.

    The U.S. Standard Diphtheria Toxin for Schick Test shall be used to 
determine the Schick test dose of the product. The Schick test dose of 
the standard is that amount of the standard that, when mixed with 0.001 
unit of the U.S. Standard Diphtheria Antitoxin and injected 
intradermally in a guinea pig, will induce an erythematous reaction of 
10 mm. in diameter.



Sec. 650.3   Manufacture of Diphtheria Toxin for Schick Test.

    (a) Propagation of bacteria. The culture medium for propagation of 
the Corynebacterium diphtheriae for preparation of the parent toxin 
shall not contain ingredients known to be capable of producing 
allergenic effects in human subjects.
    (b) The parent toxin. Diphtheria Toxin for Schick Test shall be 
prepared from a parent toxin which has been demonstrated to be stable 
and which contains no less than 400 minimum lethal doses per milliliter 
or 400,000 minimum reaction doses per milliliter. A minimum lethal dose 
is the smallest amount of toxin that will kill a guinea pig weighing 
approximately 250 gm. on the fourth day after its subcutaneous 
injection. A minimum reaction dose is that amount of toxin which when 
injected intradermally into a guinea pig induces an erythematous 
reaction 10 mm. in diameter.



Sec. 650.4   Potency test.

    The dermal reactivity of each lot of the product shall be determined 
from the results of simultaneous guinea pig intradermal potency tests of 
the product under test and of the standard. The test shall be performed 
as follows:
    (a) Guinea pigs. At least four healthy female guinea pigs shall be 
used, all of the same strain and each of a size that will permit a 
random distribution of eight intradermal injections. The hair shall be 
removed from the back and both sides of each guinea pig without 
producing abrasions of the skin. The denuded skin of each animal shall 
be sectioned into four equal areas at right angles to the vertebral 
column to provide two injection sites in each of the four areas, one on 
each side of the vertebra. The test is not valid if the guinea pigs do 
not show a graded response to the graded dilutions of the Schick test 
dose of the standard toxin.
    (b) Preparation of the test doses. Four dilutions, two of the 
product under test and two of the U.S. Standard Diphtheria Toxin for 
Schick Test, shall be prepared in sterile buffered saline pH 7.4 
containing 0.2 percent gelatin. The low and high dilutions of the 
standard shall be those amounts of a Schick test dose of the standard 
which in a dose of 0.1 ml. are capable of eliciting graded erythematous 
dermal reactions between 10 mm. and 20 mm. in diameter. The low and high 
dilutions of the Schick test dose of the toxin under test shall be the 
same as those of the standard toxin and estimated to have the same 
dermal reactivity.
    (c) Inoculation. The low and high dilutions of the product (chart 
designation PL and PH) and the low and high dilutions of the 
standard (chart designations SL and SH) shall be injected 
intradermally in a volume of 0.1 ml. into each of the four guinea pigs 
according to either the following scheme, or in another scheme, provided 
it will permit comparable randomization of injection sites:

----------------------------------------------------------------------------------------------------------------
                                                               Guinea Pig Number                                
                              ----------------------------------------------------------------------------------
             Area                        1                    2                    3                   4        
                              ----------------------------------------------------------------------------------
                                  Left      Right       Left      Right     Left      Right     Left      Right 
----------------------------------------------------------------------------------------------------------------
A............................  SL         SL         SH         SH        PL        PL        PH        PH      
B............................  SH         SH         SL         SL        PH        PH        PL        PL      

[[Page 147]]

                                                                                                                
C............................  PL         PL         PH         PH        SL        SL        SH        SH      
D............................  PH         PH         PL         PL        SH        SH        SL        SL      
----------------------------------------------------------------------------------------------------------------

    (d) Calculation of test results. Between 40 and 66 hours following 
injection, a diameter of the reaction for each injection site shall be 
calculated by averaging two diameters of the reaction measured at right 
angles to each other. The average reaction for each dilution for each 
animal shall be determined, then the average diameters of the reactions 
of all of the guinea pigs for each dilution shall be calculated. The 
ratios of the reactions are determined by dividing the average diameter 
of the low dilution of the product under test by the average diameter of 
the low dilution of the standard and by dividing the average diameter of 
the high dilution of the product by the average diameter of the high 
dilution of the standard.
    (e) Potency requirement. The potency of the product under test is 
satisfactory if each calculated ratio of the reactions of the product 
under test and of the standard is 1.0. The potency of the lot under test 
is considered to be equal to that of the standard if the ratios are not 
lower than 0.77 or higher than 1.30, provided that in a single test the 
ratios are substantially the same.



Sec. 650.5   Stability test.

    A sample of each lot of the product shall be held at 37 deg. C for 
not less than 24 hours and then tested for potency as prescribed in 
Sec. 650.4. The stability of the product is satisfactory if test results 
of the sample meet the potency requirement prescribed in Sec. 650.4(e).



Sec. 650.6   Samples; protocols; official release.

    For each lot of the product, the following material shall be 
submitted to the Director, Center for Biologics Evaluation and Research:
    (a) A protocol which consists of a summary of the history of 
manufacture of each lot including all results of all tests for which 
test results are requested by the Director, Center for Biologics 
Evaluation and Research.
    (b) A sample of no less than 20 milliliters of the product.
    (c) The product shall not be issued by the manufacturer until 
written notification of official release of the lot is received from the 
Director, Center for Biologics Evaluation and Research.

[38 FR 32097, Nov. 20, 1973, as amended at 42 FR 27584, May 31, 1977; 49 
FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]



                          Subpart B--Tuberculin



Sec. 650.10   Tuberculin.

    The proper name of this product shall be Tuberculin, which shall be 
a preparation derived from Mycobacterium tuberculosis or M. Bovis.



Sec. 650.11   General requirements.

    (a) General safety. Each lot of Tuberculin shall be tested for 
safety as prescribed in Sec. 610.11 of this chapter, except that the 
sample of tuberculin from multiple puncture devices shall be obtained by 
removing the tuberculin in a manner that will permit the injection of 
material from at least five devices into each of two guinea pigs and 
from at least two devices into each of two mice.
    (b) Labeling. In addition to complying with all other applicable 
labeling provisions of this subchapter, the package label shall state 
the following:
    (1) For Tuberculin for Mantoux testing, the number of U.S. units 
(TU) per dose.
    (2) For Tuberculin for multiple puncture testing, a statement 
indicating that the activity per test is comparable to a stated number 
of U.S. units (TU) administered by the Mantoux method.
    (3) The applicable type of Tuberculin placed immediately following 
and of no less prominence than the proper name, as follows:
    (i) ``Old,'' or

[[Page 148]]

    (ii) ``Purified Protein Derivative'' or ``PPD.''
    (c) Samples; protocols; official release. For each lot of Tuberculin 
the following shall be submitted to the Director, Center for Biologics 
Evaluation and Research, Food and Drug Administration, 8800 Rockville 
Pike, Bethesda, MD 20892:
    (1) A protocol which consists of a summary of the history of 
manufacture of each lot including all results of each test for which 
test results are requested by the Director, Center for Biologics 
Evaluation and Research.
    (2) Tuberculin distributed on a multiple puncture device, as 
follows:
    (i) A total of no less than 50 devices.
    (ii) A total of no less than 6 milliliters of bulk tuberculin.
    (3) A total of no less than 20 ml. of liquid tuberculin.
    (4) Sufficient dried tuberculin in final containers so that upon 
reconstitution as recommended in labeling it will yield at least 20 
milliliters.
    (5) The product shall not be issued by the manufacturer until 
written notification of official release of the lot is received from the 
Director, Center for Biologics Evaluation and Research.

[38 FR 32097, Nov. 20, 1973, as amended at 39 FR 9661, Mar. 13, 1974; 42 
FR 27584, May 31, 1977; 42 FR 54546, Oct. 7, 1977; 49 FR 23834, June 8, 
1984; 51 FR 15611, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990]



Sec. 650.12   U.S. Standard preparations.

    (a) The U.S. Standard Tuberculin, Old, shall be used for determining 
the potency of nonfractionated tuberculins, as prescribed in 
Sec. 650.14. One U.S. Tuberculin unit is 0.1 ml. of a 1:10,000 dilution 
of this standard.
    (b) The U.S. Standard Tuberculin, Purified Protein Derivative, shall 
be used in determining the potency of tuberculins made from protein 
fractions, as prescribed in Sec. 650.14. One U.S. Tuberculin unit is 0.1 
ml. of a 1:5,000 dilution of this standard.



Sec. 650.13   Production.

    (a) Propagation of mycobacteria. The medium used for production of 
mycobacteria shall not contain ingredients known to be capable of 
producing allergenic effects in human subjects.
    (b) Tests for viable mycobacteria. The culture filtrate from each 
strain in its most concentrated form shall be shown to be free of viable 
mycobacteria by the following tests:
    (1) Animal test. A 1.0 ml. sample of the filtrate shall be injected 
intraperitoneally into each of at least three healthy guinea pigs 
weighing between 300 and 400 gm. At least two-thirds of the animals must 
survive an observation period of at least 6 weeks and must show a normal 
weight gain. After the observation period the animals shall be 
necropsied and examined for signs indicative of tuberculosis except that 
animals that die during the observation period shall be necropsied and 
examined as soon as feasible after death. The filtrate is satisfactory 
for Tuberculin manufacture if none of the animals in the test show 
evidence of tuberculosis infection.
    (2) Culture test. A 2.0 ml. sample of the filtrate shall be 
inoculated onto Lowenstein-Jensen's egg medium or other media 
demonstrated to be equally capable of supporting growth. A control test 
on the culture medium shall be conducted simultaneously with the sample 
under test and shall be shown to be capable of supporting the growth of 
small numbers of the production strain(s). All the test vessels shall be 
incubated at a suitable temperature for a period of 6 weeks under 
conditions that will prevent drying of the medium, after which the 
cultures shall be examined for evidence of mycobacterial colonies. The 
filtrate is satisfactory for Tuberculin manufacture if the test shows no 
evidence of mycobacteria.
    (c) Chemical characterization. Each batch of powdered tuberculin 
material shall be chemically characterized, including protein, 
carbohydrate, lipid, and nucleic acid content to assess consistency of 
production.

[38 FR 32097, Nov. 20, 1973, as amended at 44 FR 40289, July 10, 1979]



Sec. 650.14   Potency testing in animals.

    The potency of each lot of Tuberculin shall be estimated from a 
comparison of the responses obtained by the intradermal injection into 
sensitized guinea pigs weighing over 500 gm. of a sample of the lot 
under test and of the

[[Page 149]]

appropriate standard preparation. The U.S. Standard Tuberculin, Old, 
shall be used in determining the potency of tuberculins made from the 
concentrated filtrate of the soluble products of the growth of the 
mycobacteria. The U.S. Standard Tuberculin, Purified Protein Derivative, 
shall be used in determining the potency of tuberculins made from 
protein fraction of the soluble products of the growth of the 
mycobacteria. The test shall be performed as follows:
    (a) Sensitization of test animals. At least four white guinea pigs 
shall be sensitized with M. tuberculosis or M. bovis. The degree of 
sensitivity shall be such that an intradermal injection of one U.S. unit 
of the appropriate standard preparation will produce in each test animal 
an erythematous reaction approximately 100 mm2 within 18-24 hours.
    (b) Test Procedure. The hair shall be removed from both sides of the 
sensitized test animals without producing abrasions of the skin. 
Dilutions of the standard containing 0.5, 1, 2, and 4 U.S. units in the 
test dose of 0.1 ml. and four comparable levels of activity of the lot 
under test shall be injected intradermally into opposite and parallel 
sites of each animal. Only three dilutions need be used when the initial 
concentration of the lot under test does not contain four units in 0.1 
ml. Within 18-24 hours following injection, measurements of the greater 
and lesser diameters of erythema measured to the closest millimeter 
shall be made at each site. The mean value of the product of the 
diameters for each dilution shall be calculated. The number of U.S. 
units in the lot under test shall be estimated from its relationship to 
the reactivity of the appropriate standard preparation using results 
from all valid tests performed.
    (c) Potency. The potency of the lot is satisfactory if the results 
are within plus-minus 20 percent of the U.S. units claimed by the 
manufacturer in the license application and the product labeling.

[38 FR 32097, Nov. 20, 1973, as amended at 42 FR 38567, July 29, 1977; 
44 FR 40289, July 10, 1979]



Sec. 650.15  Potency testing in humans.

    (a) The sensitivity of each batch of tuberculin material for use on 
multiple puncture devices for screening purposes shall be demonstrated 
to be sufficient to elicit an induration of 2 millimeters or more at one 
or more of the puncture sites or at a coalescence of more than one site 
in at least 95 percent of at least 50 persons who are known to have had 
bacteriologically confirmed tuberculosis and who are tuberculin positive 
as demonstrated by a simultaneous Mantoux test that elicits an 
induration of 5 millimeters or more when tested with 5 TU of Tuberculin, 
Purified Protein Derivative.
    (b) The product effectiveness of each batch of tuberculin material 
for use by the Mantoux method shall include comparison of the product 
with the standard by means of (1) dose response curves, and (2) 
distribution of reaction sizes in persons presumed to be uninfected with 
Mycobacterium tuberculosis or other mycobacteria, in persons known to be 
infected with Mycobacterium tuberculosis, and in persons presumed to be 
infected with other mycobacteria.
    (c) All trials in paragraphs (a) and (b) of this section shall be 
performed in a randomized double-blind fashion whenever possible and all 
reactions in each test subject shall be read by more than one competent 
and responsible individual.

[44 FR 40289, July 10, 1979]



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.

[[Page 150]]

                          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  Suitability of the 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.
660.42  Reference panel.
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.

                        Subparts G-J--[Reserved]

                   Subpart K--Limulus Amebocyte Lysate

660.100  Limulus Amebocyte Lysate.
660.101  U.S. Standard/Reference preparations.
660.102  Potency test.
660.103  General requirements.
660.104  Labeling.
660.105  Samples and protocols; official release.

    Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360, 
371); secs. 215, 351, 352, 353, 361 of the Public Health Service Act (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. In addition to the items required by other applicable 
labeling provisions of this subchapter, the following shall also be 
included:
    (1) Indication of the source of the product immediately following 
the

[[Page 151]]

proper name on both the final container and package label, e.g., human, 
guinea pig.
    (2) 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).
    (3) 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.
    (4) 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.
    (5) The package shall include a package enclosure providing (i) 
adequate instructions for use, (ii) a description of all recommended 
test methods, and (iii) warnings as to possible hazards, including 
hepatitis, in handling the product and any ancillary reagents and 
materials accompanying the product.
    (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 (125I) 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 
with125I 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]



Sec. 660.3   Reference panel.

    A Reference Hepatitis B Surface Antigen Panel shall be obtained from 
the Center for Biologics Evaluation and Research 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]



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 125I 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 125I 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

[[Page 152]]

the Director, Center for Biologics Evaluation and Research (HFB-1), 8800 
Rockville Pike, Bethesda, MD 20892, 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) Offical 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 and 11014, Mar. 26, 1990]



                          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 prepared by a method demonstrated to yield consistently 
a sterile product and containing one or more of the blood grouping 
antibodies listed in Sec. 660.28(d).
    (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.



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 each group 
of products manufactured in the same fashion.

[[Page 153]]

    (2) Only that material that has been fully processed, thoroughly 
mixed in a single vessel, and sterile filtered shall constitute a lot.
    (3) A lot may be subdivided into clean, sterile vessels. Each 
subdivision shall constitute a sublot. 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.
    (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 (HFN-830), Food 
and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892.
    (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 product license application.
    (e) Date of manufacture. The date of manufacture shall be the date 
the manufacturer begins the last entire group of potency tests.

(Information collection requirements approved by the Office of 
Management and Budget under control number 0910-0209)



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 Center for Biologics Evaluation and Research (HFN-
890), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 
20892, and shall be used as described in the accompanying package insert 
for determining the potency of Blood Grouping Reagents.

(Information collection requirements approved by the Office of 
Management and Budget under control number 0910-0209)



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 (HFN-830), Food 
and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892.
    (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 
(HFN-830), Food and Drug Administration, 8800 Rockville Pike, Bethesda, 
MD 20892.
    (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-Kpa, Anti-Kpb, Anti-Jsa, Anti-
Jsb, Anti-Fyb, Anti-N, Anti-Lea, Anti-Leb, Anti-
Lua, Anti-Lub, Anti-Dia, Anti-Mg, Anti-Jkb, 
Anti-Cob, Anti-Wra, and Anti-Xga, 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

[[Page 154]]

antigen. The dilution shall be made with an equal volume of compatible 
serum or approved diluent.
    (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.

(Information collection requirements approved by the Office of 
Management and Budget under control number 0910-0209)



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 (HFN-830), Food and Drug Administration, 8800 Rockville Pike, 
Bethesda, MD 20892.

(Information collection requirements approved by the Office of 
Management and Budget under control number 0910-0209)



Sec. 660.28  Labeling.

    In addition to the applicable labeling requirements of Secs. 610.62 
through 610.65 and Sec. 809.10, and in lieu of the requirements in 
Secs. 610.60 and 610.61, the following requirements shall be met:
    (a) Final container label--(1) 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 (HFN-830), 
Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892. 
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.                      
------------------------------------------------------------------------

    (2) 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:
    (i) Name of the antibody or antibodies present as set forth in 
paragraph (d) of this section.
    (ii) Name, address (including ZIP code), and license number of the 
manufacturer.
    (iii) Lot number, including sublot designations.
    (iv) Expiration date.
    (v) Source of product if other than human plasma or serum.
    (vi) Test method(s) recommended.
    (vii) Recommended storage temperature in degrees Celsius.
    (viii) Volume of product if a liquid, or equivalent volume for a 
dried product if it is to be reconstituted.
    (ix) 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.''
    (3) 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.
    (4) 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

[[Page 155]]

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.
    (b) 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.
    (1) Proper name of the product.
    (2) Name of the antibody or antibodies present as set forth in 
paragraph (d) of this section.
    (3) Name, address (including ZIP Code), and license number of the 
manufacturer.
    (4) Lot number, including sublot designations.
    (5) Expiration date.
    (6) Preservative used and its concentration.
    (7) Number of containers, if more than one.
    (8) Volume or equivalent volume for dried products when 
reconstituted, and precautions for adequate mixing when reconstituting.
    (9) Recommended storage temperature in degrees Celsius.
    (10) Source of the product if other than human serum or plasma.
    (11) Reference to enclosed package insert.
    (12) If a dried product, a statement indicating the period within 
which the product may be used after reconstitution.
    (13) The statement: ``FOR IN VITRO DIAGNOSTIC USE.''
    (14) The statement: ``MEETS FDA POTENCY REQUIREMENTS.''
    (15) 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.''
    (16) 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.
    (c) 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.
    (d) Names of antibodies.

------------------------------------------------------------------------
               Blood group designation for container label              
-------------------------------------------------------------------------
  Anti-A                                                                
  Anti-A1                                                               
  Anti-A, B                                                             
  Anti-A and B                                                          
  Anti-B                                                                
  Anti-C                                                                
  Anti-Cw                                                               
  Anti-c                                                                
  Anti-CD                                                               
  Anti-CDE                                                              
  Anti-Cob                                                              
  Anti-D                                                                
  Anti-DE                                                               
  Anti-Dia                                                              
  Anti-E                                                                
  Anti-e                                                                
  Anti-Fya                                                              
  Anti-Fyb                                                              
  Anti-I                                                                
  Anti-Jka                                                              
  Anti-Jkb                                                              
  Anti-Jsa                                                              
  Anti-Jsb                                                              
  Anti-K                                                                
  Anti-k                                                                
  Anti-Kpa                                                              
  Anti-Kpb                                                              
  Anti-Lea                                                              
  Anti-Leb                                                              
  Anti-Lua                                                              
  Anti-Lub                                                              
  Anti-M                                                                
  Anti-Mg                                                               
  Anti-N                                                                
  Anti-P1                                                               
  Anti-S                                                                
  Anti-s                                                                
  Anti-U                                                                
  Anti-Wra                                                              
  Anti-Xga                                                              
------------------------------------------------------------------------


[53 FR 12764, Apr. 19, 1988, as amended at 59 FR 23637, May 6, 1994]

(Information collection requirements approved by the Office of 
Management and Budget under control number 0910-0209)



                   Subpart D--Reagent Red Blood Cells

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

[[Page 156]]



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 Secs. 660.31 and 660.32, or 
from umbilical cord cells which shall be collected and prepared 
according to the manufacturer's product license application.



Sec. 660.31  Suitability of the donor.

    Donors of peripheral blood for Reagent Red Blood Cells shall meet 
the criteria for donor suitability under Sec. 640.3 of this chapter, 
except that paragraphs (b)(5) and (6), (d), and (e) of Sec. 640.3 shall 
not apply.



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.



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 
product 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, Fya, Fyb, Jka, Jkb, Lea, Leb, 
P1, M, N, S, and s.

[52 FR 37450, Oct. 7, 1987, as amended at 55 FR 11013, Mar. 26, 1990]



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

[[Page 157]]

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.

(Approved by the Office of Management and Budget under control number 
0910-0073)

[52 FR 37450, Oct. 7, 1987, as amended at 55 FR 11013, Mar. 26, 1990]



Sec. 660.35  Labeling.

    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:
    (a)(1) 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, oustide of the main panel.
    (2) 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.
    (b) 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''.

    (c) 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.
    (d) 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 
pretransfusion tests, done in lieu of a major crossmatch, to detect 
unexpected antibodies in patients' samples.
    (e) 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.
    (f) 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.
    (g) 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.
    (h) The package label or package insert shall bear the cautionary 
statement: ``The reactivity of the product may decrease during the 
dating period.''
    (i) 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

[[Page 158]]

controlled nor predicted by the manufacturer.
    (j) The package insert shall provide adequate directions for use.
    (k) 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.''

    (l) 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.
    (m) 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.

(Approved by the Office of Management and Budget under control number 
0910-0073)



Sec. 660.36  Samples and protocols.

    (a) The following shall be submitted to the Office of Biological 
Product Review Sample Custodian (ATTN: HFB-215), Bldg. 29A, Rm. 1C02, 
Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892, 
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:
    (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, 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. The sample should contain a minimum volume of 
0.5 milliliter of red blood cells.

(Approved by the Office of Management and Budget under control number 
0910-0073)

[52 FR 37450, Oct. 7, 1987, as amended at 55 FR 11013 and 11015, Mar. 
26, 1990]



                 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.

[[Page 159]]



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]



Sec. 660.42  Reference panel.

    A Reference Hepatitis B Antiserum Panel shall be obtained from the 
Center for Biologics Evaluation and Research, 8800 Rockville Pike, 
Bethesda, MD 20892, and shall be used for determining the potency and 
specificity of Hepatitis B Surface Antigen.

[44 FR 36382, June 22, 1979, as amended at 49 FR 23834, June 8, 1984; 51 
FR 15611, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990]



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.

    In addition to the requirements of Secs. 610.60, 610.61, and 809.10 
of this chapter, the labeling shall bear the following:
    (a) 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.
    (b) 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).
    (c) 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.
    (d) The package shall include a package insert providing (1) 
detailed instructions for use, (2) an adequate description of all 
recommended test

[[Page 160]]

methods, and (3) warnings as to possible hazards, including hepatitis 
transmitted in handling the product and any ancillary reagents and 
materials accompanying the product.



Sec. 660.46  Samples; protocols; official release.

    (a) Samples. (1) For the purposes of this section, a sample of 
product not iodinated with 125I 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 125I 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 (HFB-1), 8800 
Rockville Pike, Bethesda, MD 20892, 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 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 and 11014, Mar. 26, 1990]



                     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(d) and be

[[Page 161]]

prepared by a method demonstrated to yield consistently a sterile 
product.
    (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]



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 sterile filtered shall constitute a lot. 
Each lot shall be identified by a lot number.
    (4) A lot may be subdivided into clean, sterile vessels. Each 
subdivision shall constitute a sublot 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 and on the protocol. 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.

(Approved by the Office of Management and Budget under control number 
0910-0208)

[50 FR 5579, Feb. 11, 1985, as amended at 50 FR 16474, Apr. 26, 1985]



Sec. 660.52  Reference preparations.

    Reference Anti-Human Globulin preparations shall be obtained from 
the Center for Biologics Evaluation and Research (HFB-221), Food and 
Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892, and shall 
be used as described in the accompanying package insert for determining 
the potency of Anti-Human Globulin.

(Approved by the Office of Management and Budget under control number 
0910-0208)

[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]



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 (HFB-1), Food 
and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892.

(Approved by the Office of Management and Budget under control number 
0910-0208)

[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]



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 
(HFB-1), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 
20892:
    (a) Potency tests for determining anti-IgG and anti-complement 
activity.
    (b) Specificity tests, tests for heterospecific antibodies, and 
additional tests for nonspecific properties.

(Approved by the Office of Management and Budget under control number 
0910-0208)

[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]

[[Page 162]]



Sec. 660.55  Labeling.

    In addition to the applicable labeling requirements of Secs. 610.62 
through 610.65 and Sec. 809.10 of this chapter, and in lieu of the 
requirements in Secs. 610.60 and 610.61 of this chapter, the following 
requirements shall be met:
    (a) Final container label--(1) 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.
    (2) 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:
    (i) Name of the antibody or antibodies present as set forth in 
paragraph (d) 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.
    (ii) Name, address, and license number of the manufacturer.
    (iii) Lot number, including any sublot designations.
    (iv) Expiration date.
    (v) Source of the product.
    (vi) Recommended storage temperature in degrees Celsius.
    (vii) Volume of product.
    (viii) 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.''

    (ix) If the final container is not enclosed in a package, all items 
required for a package label shall appear on the container label.
    (3) 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 (HFB-1). The prefix anti- and other 
parts of the name such as polyspecific may appear in smaller type.
    (4) 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.
    (b) Package label. The following items shall appear either on the 
package label or on the final container label if see-through packaging 
is used:
    (1) Proper name of the product, and the name of the antibody or 
antibodies as listed in paragraph (d) of this section.
    (2) Name, address (including zip code), and license number of the 
manufacturer.
    (3) Lot number, including any sublot designations.
    (4) Expiration date.
    (5) Preservative(s) used and its concentration.
    (6) Number of containers, if more than one.
    (7) Recommended storage temperature in degrees Celsius.
    (8) Source of the product.
    (9) Reference to enclosed package insert.
    (10) The statement: ``For In Vitro Diagnostic Use.''
    (11) The statement: ``Meets FDA Potency Requirements.''
    (12) 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.
    (13) Appropriate cautions.
    (c) Package insert. Each final container of Anti-Human Globulin 
shall be

[[Page 163]]

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.
    (d) Names of antibodies.

------------------------------------------------------------------------
   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.                      
------------------------------------------------------------------------

    Anti-Human Globulin preparations may contain one or more of the 
antibody specificities listed in this paragraph as described in 
paragraph (a)(2)(i) of this section.

(Approved by the Office of Management and Budget under control number 
0910-0208)

[50 FR 5579, Feb. 11, 1985; 50 FR 9800, Mar. 12, 1985, as amended at 50 
FR 16474, Apr. 26, 1985; 55 FR 11014, Mar. 26, 1990]



                        Subparts G-J--[Reserved]



                   Subpart K--Limulus Amebocyte Lysate



Sec. 660.100  Limulus Amebocyte Lysate.

    The proper name of this product shall be Limulus Amebocyte Lysate. 
The product is defined as an extract that is derived from the blood of 
Limulus polyphemus and is capable of detecting bacterial endotoxins.

[45 FR 32299, May 16, 1980]



Sec. 660.101  U.S. Standard/Reference Preparations.

    The following U.S. Standard/Reference preparations shall be obtained 
from the Center for Biologics Evaluation and Research, Food and Drug 
Administration, 8800 Rockville Pike, Bethesda, MD 20892, for use as 
prescribed in this subpart:
    (a) A U.S. Standard Endotoxin for determining the sensitivity of 
Limulus Amebocyte Lysate.
    (b) A U.S. Reference Limulus Amebocyte Lysate for establishing the 
potency of Limulus Amebocyte Lysate.

[45 FR 32299, May 16, 1980, as amended at 49 FR 23834, June 8, 1984; 51 
FR 15611, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990]



Sec. 660.102  Potency test.

    A sample of each final filling of each lot of Limulus Amebocyte 
Lysate and the U.S. Reference Lysate shall be tested in parallel with 
the U.S. Standard Endotoxin. If the product is freeze-dried after 
filling, the test shall be conducted on samples from each filling in 
each drying chamber run. The procedure for rehydrating and mixing the 
lysate for the potency test shall be that specified in the 
manufacturer's package insert. A minimum of 8 vials and a maximum of 28 
vials from each filling or, if freeze-dried, from each drying chamber 
run representing all parts of the chamber load, shall be tested in 
parallel with an equal number of tests from 1 or more vials of the U.S. 
Reference Lysate. The test shall be performed as follows:
    (a) Dilution of U.S. Standard Endotoxin. A single series of 
consecutive two-fold dilutions, beginning with a concentration of the 
U.S. Standard Endotoxin at least four-fold above the endpoint, shall be 
prepared with a range selected to bracket the endpoint for both the U.S. 
Reference Lysate and test lysate filling in each test performed.
    (b) Test procedure. (1) Transfer 0.1 milliliter of each 
concentration of U.S. Standard Endotoxin, as prepared in paragraph (a) 
of this section, into each of two test tubes having an inside diameter 
not greater than 10 millimeters, unless the use of another size test

[[Page 164]]

tube has been approved by the Director, Center for Biologics Evaluation 
and Research.
    (2) Add 0.1 milliliter of the U.S. Reference Lysate to one of the 
tubes containing the lowest concentration of U.S. Standard Endotoxin. 
Add 0.1 milliliter of test lysate to the second tube containing the 
lowest concentration of U.S. Standard Endotoxin.
    (3) Repeat the procedure in paragraphs (b)(1) and (2) of this 
section for each dilution of the U.S. Standard Endotoxin and for each 
vial of lysate to be tested from each filling of the test lot, 
progressing from the lowest endotoxin concentration to the highest.
    (4) Immediately following addition of the lysate to each tube, mix 
the contents gently and place in a 37 deg. C water bath for 1 hour.
    (c) Validity of the test. (1) Record the reaction in each tube as 
either positive or negative. A positive reaction is demonstrated by a 
firm gel that remains intact, at least momentarily, when the tube is 
inverted 180 degrees. For Limulus Amebocyte Lysate that does not require 
gelation as an indicator of reactions, the endpoint shall be determined 
by the method specified in the labeling for the product.
    (2) For each parallel test obtain the ratio of endpoints of 
reference and test lysates. Calculate the standard deviations (S.D.) of 
log ratios.
    (3) The test is valid if the S.D. is less than or equal to the value 
for the 99 percent fiducial upper limit of the S.D. of the sample size 
tested. The S.D. table is shown in paragraph (d) of this section.
    (4) If the S.D. is greater than the tabulated value, the test may be 
expanded up to the maximum of 28 parallel tests and a new S.D. for log 
ratios may be calculated.
    (5) The tests are invalid due to excessive variability if the S.D. 
is greater than the value in the S.D. table corresponding to the sample 
size tested.
    (6) If the S.D. is within the limits, the geometric mean (G.M.) of 
the ratios shall be calculated.
    (7) The endpoints of U.S. Reference and test lysates, ratios of 
endpoints, S.D. of log ratios, and G.M. of ratios shall be calculated 
and reported on the protocol submitted to the Director, Center for 
Biologics Evaluation and Research.
    (d) S.D. table. Ninety-nine percent fiducial upper limit on S.D. of 
log2 (ratio):

------------------------------------------------------------------------
                                                                 Upper  
                         Sample size                             limit  
------------------------------------------------------------------------
                                                                        
4...........................................................    \1\ 1.02
8...........................................................        0.86
12..........................................................        0.79
16..........................................................        0.75
20..........................................................        0.73
24..........................................................        0.71
28..........................................................        0.69
------------------------------------------------------------------------
\1\ Limits can be converted to log10 by multiplying each value by 0.3.  

[45 FR 32299, May 16, 1980, as amended at 49 FR 23834, June 8, 1984; 52 
FR 39637, Oct. 23, 1987; 55 FR 11013, Mar. 26, 1990]



Sec. 660.103  General requirements.

    (a) Handling the horseshoe crabs. The horseshoe crabs (Limulus 
polyphemus), from which blood is collected for production of the lysate, 
shall be handled in a manner so as to minimize injury to each crab. The 
horseshoe crabs shall be returned alive to their natural environment 
after a single collection of their blood.
    (b) Processing. The processing methods shall be those which have 
been shown to yield consistently a potent and detection-specific final 
product free of properties that would adversely affect the accuracy of 
the test results when the Limulus Amebocyte Lysate is used by the 
methods recommended by the manufacturer in the package insert.
    (c) Final containers. Final containers at the time of filling shall 
be sterile, nonpyrogenic, colorless, and transparent.
    (d) Date of manufacture. The date of manufacture of each filling of 
each lot shall be the date the manufacturer initiated the last valid 
potency test for such filling. The results from this test shall be 
reported on the protocol submitted to the Director, Center for Biologics 
Evaluation and Research.
    (e) Sterility test. A sterility test shall be performed on the bulk 
lot and on each filling as prescribed in Sec. 610.12 of this chapter.
    (f) Test for quality. A test for lysate quality shall be performed 
as follows:

[[Page 165]]

    (1) Samples from each of eight final containers from each filling 
or, if freeze-dried, from each filling in each drying chamber run 
representing all parts of the chamber load, shall be used.
    (2) The volume of lysate required for a single test from each of the 
final containers and a volume of distilled water equal to the volume of 
sample used for a single test are combined into each of an appropriate 
number of test tube and incubated for 24 hours in a 37 deg. C water 
bath.
    (3) The test passes if none of the samples yield a positive test.
    (g) Test for residual moisture. (1) If the weight of the contents of 
each final container is 3 milligrams or more, the test for residual 
moisture shall be performed as prescribed in Sec. 610.13(a) of this 
chapter.
    (2)(i) If the weight of the contents of each final container is less 
than 3 milligrams, the product is exempt from the test for residual 
moisture. However, the manufacturer of such exempt product shall perform 
the potency test described in Sec. 660.102 on at least 4 vials at 4-
month intervals on representative samples from each filling throughout 
the dating period.
    (ii) Upon the completion of each potency test, the results of all 
tests performed shall be submitted to the Director, Center for Biologics 
Evaluation and Research.
    (h) Ancillary reagents and materials. All ancillary reagents and 
materials accompanying the product that are used in the performance of a 
test, as described by the manufacturer's recommended test procedures, 
shall not affect adversely the performance of the Limulus Amebocyte 
Lysate within the prescribed dating period.

[45 FR 32299, May 16, 1980, as amended at 49 FR 23834, June 8, 1984; 52 
FR 39637, Oct. 23, 1987; 55 FR 11013, Mar. 26, 1990]



Sec. 660.104  Labeling.

    In addition to the applicable labeling provisions of this chapter, 
the following information is required:
    (a) Final container labels. The final container label shall include 
the following additional information:
    (1) The sensitivity (geometric mean of the end points of the lot) 
expressed as units/milliliter or nanograms/milliliter of the U.S. 
Standard Endotoxin, determined by the potency test procedure in 
Sec. 660.102.
    (2) For final containers intended for multiple tests, a designated 
area adequate for the user to identify the time that the product is 
reconstituted.
    (3) For final containers intended for multiple tests, a statement 
identifying the period within which the product may be used after 
reconstitution.
    (4) For final containers intended for multiple tests, a statement 
specifying storage conditions after reconstitution.
    (b) Package label. The package label shall include the following 
additional information:
    (1) A reference to the package insert for the test method(s) to be 
employed when using Limulus Amebocyte Lysate.
    (2) A statement that the product shall not be rehydrated until 
immediately prior to use.
    (3) For products in final containers intended for multiple tests, a 
statement identifying the period within which the product may be used 
after reconstitution.
    (4) For products in final containers intended for multiple tests, a 
statement specifying storage conditions after reconstitution.
    (c) Package insert. The package insert shall include the following 
additional information:
    (1) A statement that if the container of diluent used to rehydrate 
the lysate has been entered previously or was not supplied by the 
manufacturer of the lysate, the diluent must be tested, without addition 
of test material.
    (2) A warning statement that the tubes of material on test should 
not be removed from incubation or disturbed prior to the time specified 
for reading the test.
    (3) A statement that the product shall not be rehydrated until 
immediately prior to use.
    (4) For products in final containers intended for multiple tests, a 
statement identifying the period within which the product may be used 
after reconstitution.

[[Page 166]]

    (5) For products in final containers intended for multiple tests, a 
statement specifying storage conditions after reconstitution.

[45 FR 32299, May 16, 1980]



Sec. 660.105  Samples and protocols; official release.

    (a) For each final filling of each lot of Limulus Amebocyte Lysate, 
or if freeze dried, from each drying chamber run representing all parts 
of the chamber load, the following material shall be submitted to the 
Director, Center for Biologics Evaluation and Research, Food and Drug 
Administration, 8800 Rockville Pike, Bethesda, MD 20892:
    (1) Samples. Not fewer than the number of vials of lysate used for 
the potency test in Sec. 660.102, two of which shall be complete market 
packages, packaged for distribution and including all ancillary reagents 
and materials.
    (2) Protocols. A protocol consisting of a complete summary of the 
history of manufacture of each filling, the dates of testing, and the 
results of all required tests.
    (b) Official release. Limulus Amebocyte Lysate shall not be 
distributed by the manufacturer until written notification of official 
release of each filling is received from the Director, Center for 
Biologics Evaluation and Research.

[45 FR 32299, May 16, 1980, as amended at 49 FR 23834, June 8, 1984; 51 
FR 15611, Apr. 25, 1986; 52 FR 39637, Oct. 23, 1987; 55 FR 11013, Mar. 
26, 1990]



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




                     Subpart A--Allergenic Products

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

                 Subpart B--Trivalent Organic Arsenicals

680.10  Tests prior to release.
680.11  Pretesting by Center; sample of each lot.
680.12  Expiration date.
680.13  Composition of product.
680.14  Container.
680.15  Final container label.
680.16  Outside label.

                    Subpart C--Blood Group Substances

680.20  Blood Group Substances.
680.21  Reference preparations.
680.22  Potency and identity tests.
680.23  Other tests.
680.24  General requirements.
680.25  Labeling.
680.26  Samples; protocols; official release.

    Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360, 
371); secs. 215, 351, 352, 353, 361 of the Public Health Service Act (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.



                     Subpart A--Allergenic Products



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.
    (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.

[[Page 167]]

    (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 (HFB-1).
    (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 (HFB-1).
    (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 (HFB-1), the name and address of each 
of the manufacturer's 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 (HFB-1).

[[Page 168]]

    (2) Nonlicensed source material suppliers are exempt from drug 
registration.

(Approved by the Office of Management and Budget under control number 
09l0-0124 for paragraph (b)(2)(iii) and control number 0910-0161 for 
paragraph (c))

[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]



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 (OMB 
control number 0910-0139) 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]



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) Safety. A safety test shall be performed on the contents of a 
final container of each lot of each product as prescribed in Sec. 610.11 
of this chapter, except for the following:
    (1) For lots consisting of no more than 20 final containers or 20 
sets of individual dilutions, or where the final container contains no 
more than one intended human dose, the safety test need not be performed 
on the contents of a final container provided the safety test is 
performed on each lot of stock concentrate and on each lot of diluent 
contained in the final product. Only stock concentrates and diluents 
which have passed the general safety test shall be kept in the work 
areas used for the manufacture of Allergenic Products. A stock 
concentrate is an extract derived from a single allergenic source and 
used in the manufacture of more than one lot of product, and from which 
final dilutions or mixtures, are prepared directly.
    (2) For powders for scratch tests, a sample shall be suspended in a 
suitable diluent and injected into each animal, and the sample size 
shall be the single human dose recommended.
    (c) Sterility. A sterility test shall be performed on each lot of 
each Allergenic Product as prescribed in Sec. 610.12 of this chapter, 
with the following exceptions:
    (1) When bulk material is not prepared, the sterility test 
prescribed for bulk material shall be performed on each container of 
each stock concentrate at the time a stock concentrate is prepared, and 
the test sample shall be no less than 1 ml. from each stock concentrate 
container.
    (2) For lots consisting of no more than 5 final containers, the 
final container test shall be performed in accordance with 
Sec. 610.12(g)(6) of this chapter using the sample therein prescribed or 
using a sample of no less than 0.25 ml. of product from each final 
container, divided in approximately equal

[[Page 169]]

proportions for testing in Fluid Thioglycollate and Soybean-Casein 
Digest Media. The test sample in the later alternative method may be an 
overfill in the final container.
    (3) For products prepared in sets of individual dilution series, a 
test sample of 0.25 ml. shall be taken from a final container of each 
dilution, which samples may be pooled and one half of the pooled 
material used for the test with Fluid Thioglycollate Medium and one half 
used for the test with Soybean-Casein Digest Medium.
    (4) Tablets and capsules need not be tested for sterility provided 
aseptic techniques are employed in their manufacture.
    (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 Secs. 211.165, 
211.167, 211.188, and 211.194 of this chapter.

(Information collection requirements in this section were approved by 
the Office of Management and Budget under control number 0910-0139)

[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]



                 Subpart B--Trivalent Organic Arsenicals



Sec. 680.10   Tests prior to release.

    Tests required to be made, prior to the release of each lot of a 
licensed product, shall be supplemented in the case of the trivalent 
organic arsenicals by tests for:
    (a) Stability,
    (b) Solubility,
    (c) Arsenic content,
    (d) Moisture,
    (e) Relative nontoxicity.



Sec. 680.11   Pretesting by Center; sample of each lot.

    Prior to the release of any lot of the product, the manufacturer 
shall forward to the Director, Center for Biologics Evaluation and 
Research, no less than 15 ampoules of the largest single-dose size in 
such lot, together with protocols showing the results of each test 
required prior to release.

[38 FR 32100, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, 11015, Mar. 26, 1990]



Sec. 680.12   Expiration date.

    Notification from the Director, Center for Biologics Evaluation and 
Research, that lot samples forwarded in accordance with Sec. 680.11 have 
satisfactorily passed prescribed tests shall indicate a date which may 
be taken as the date of manufacture for the purpose of fixing the 
expiration date. The date of issue shall be the same as the date of 
manufacture.

[38 FR 32100, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 55 
FR 11013, Mar. 26, 1990]



Sec. 680.13   Composition of product.

    Solutions or solutions of mixtures in the concentrations recommended 
for clinical administration shall be of such hydrogen ion value and 
tonicity as to be physiologically compatible with human blood.



Sec. 680.14   Container.

    The product shall be hermetically sealed under vacuum or under a dry 
nonoxidizing gas in glass ampoules. The contents of any final container 
shall not exceed 10 maximum human doses.



Sec. 680.15   Final container label.

    In addition to the labeling requirements stated in Sec. 610.60 of 
this chapter, the final container label of the trivalent organic 
arsenicals shall bear the statements required in Sec. 680.16 (b) and (c) 
and an additional statement giving the amount of the drug contained in 
the ampoule.

[[Page 170]]



Sec. 680.16   Outside label.

    The outside label, in addition to the complete proper name and all 
other items required for products generally shall show conspicuously:
    (a) If the product is dispensed as a mixture or solution, the name 
of all admixed substances.
    (b) If the ampoule is a multiple dose container, the fact that it is 
a multiple dose container.
    (c) Specific method of preparation, if any, required prior to 
administration, as, for example alkalinization.



                    Subpart C--Blood Group Substances

    Source: 44 FR 20674, Apr. 6, 1979, unless otherwise noted.



Sec. 680.20  Blood Group Substances.

    (a) Proper names and definitions. The proper names of these products 
shall be Blood Group Substance A, Blood Group Substance B, and Blood 
Group Substance AB. Each Blood Group Substance product shall consist of 
a sterile, pyrogen-free, nonanaphylactogenic, aqueous solution of 
purified polysaccharideamino acid complexes for use in immunization.
    (b) Source. Blood Group Substance A shall be prepared from porcine 
stomachs; Blood Group Substance B and Blood Group Substance AB shall be 
prepared from equine stomachs.



Sec. 680.21  Reference preparations.

    The following reference preparations shall be obtained from the 
Center for Biologics Evaluation and Research, Food and Drug 
Administration, 8800 Rockville Pike, Bethesda, MD 20892, for use in 
determining the potency of Blood Group Substance as described in 
Sec. 680.22 and in the manufacturer's package insert:

Reference Anti-A Blood Grouping Serum.
Reference Anti-B Blood Grouping Serum.
Reference Blood Group Substance A.
Reference Blood Group Substance B.

[44 FR 20674, Apr. 6, 1979; 48 FR 13026, Mar. 29, 1983, as amended at 49 
FR 23834, June 8, 1984; 51 FR 15611, Apr. 25, 1986; 55 FR 11013, Mar. 
26, 1990]



Sec. 680.22  Potency and identity tests.

    An inhibition test for potency shall be performed on the contents of 
a final container of each lot of each product as follows:
    (a) Cell suspensions. Separate 1 percent suspensions of A1 and 
B red blood cells in isotonic saline shall be prepared daily after 
washing the cells at least twice with isotonic saline and shall result 
in a clear supernate. The cell suspensions shall be prepared from blood 
within 7 days after collection.
    (b) Reference serum. (1) Reference Anti-A and Reference Anti-B Blood 
Grouping Serums shall be used in the inhibition test.
    (2) Twofold dilutions (1:2, 1:4, 1:8, etc.) of each of the reference 
serums shall be prepared in isotonic saline containing a final 
concentration of 1 to 2 percent bovine albumin.
    (3) A clean pipette shall be used for each dilution and each serum. 
Mechanical devices that avoid carryover may be used.
    (c) The test for selection of serum dilution for use in the 
inhibition test for potency. (1) Reference Anti-A and Anti-B Blood 
Grouping Serums shall each be tested using A1 and B cells, 
respectively.
    (2) To a series of clean small test tubes (approximately 10 x 75 
millimeters), add 0.1 milliliter of each successive serum dilution 
prepared as described in paragraph (b)(2) of this section and 0.1 
milliliter of the appropriate 1 percent cell suspension prepared as 
described in paragraph (a) of this section.
    (3) Mix thoroughly and centrifuge immediately for 1 minute at 
approximately 150 relative centrifuge force (rcf) or at approximately 
1,000 rcf for 20 seconds.
    (d) Interpretation of the test. The cell buttons shall be gently 
dislodged and observed macroscopically. The reactions shall be graded as 
follows:

4+ Cell button remains in one clump.
3+ Cell button dislodges into several clumps.
2+ Cell button dislodges into many small clumps of nearly equal size.
1+ Cell button dislodges into finely granular, but definite, small 
clumps.

    (e) Selection of serum dilution for use in the inhibition test. The 
proper dilution

[[Page 171]]

of the reference serum for use in the inhibition test is the next to the 
highest dilution showing a 4+ agglutination reaction (e.g., with the 
following dilution/reaction table:

Dilution.......................  Un.          1:2         1:4         1:8         1:16        1:32        1:64        1:128       1:256       1:512     
--------------------------------------------------------------------------------------------------------------------------------------------------------
Reaction.......................  4+           4+          4+          4+          4+          3+          2+          1+          0           0         
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                        

the proper dilution is 1:8).
    (f) Preparation for the inhibition test for potency--(1) Reference 
serum dilution. A minimum of 3 milliliters of Reference Blood Grouping 
Serum shall be prepared in a proper dilution as described in paragraph 
(e) of this section.
    (2) Blood Group Substance dilution. (i) A series of 11 separate 
threefold dilutions (1:3, 1:9, 1:27, etc.) of Blood Group Substance 
shall be prepared in isotonic saline in concentrations ranging from 1:1 
(undiluted) to 1:59, 049.
    (ii) A clean pipette shall be used for each dilution. Mechanical 
devices that avoid carryover may be used.
    (g) Performance of the inhibition tests for potency--(1) Blood Group 
Substance A. (i) Transfer 0.1 milliliter of each dilution of Blood Group 
Substance A prepared as described in paragraph (f)(2) of this section to 
each one of 11 small test tubes (approximately 10 x 75 millimeters).
    (ii) Place 0.1 milliliter of isotonic saline into a 12th test tube.
    (iii) To each of the 12 test tubes, add 0.1 milliliter of the 
properly diluted Reference Anti-A Blood Grouping Serum prepared as 
described in paragraph (f)(1) of this section.
    (iv) Mix thoroughly and incubate at room temperature (20 deg. to 
24 deg. C) for 10 minutes.
    (v) To each of the 12 test tubes, add 0.1 milliliter of the 1 
percent A1 cell suspension described in paragraph (a) of this 
section.
    (vi) Mix gently and incubate at room temperature (20 deg. to 24 deg. 
C) for 15 minutes.
    (vii) Centrifuge for 1 minute at approximately 150 relative 
centrifugal force (rcf) or at approximately 1,000 rcf for 20 seconds.
    (viii) Repeat steps in paragraphs (g)(1)(i) through (vii) of this 
section using Reference Blood Group Substance A.
    (ix) Repeat steps in paragraphs (g)(1)(i) through (vii) of this 
section using Reference Anti-B Blood Grouping Serum, the B cell 
suspension, and the Blood Group Substance A under test.
    (2) Blood Group Substance B. For Blood Group Substance B or for 
Blood Group Substance AB, repeat steps in paragraphs (g)(1)(i) through 
(vii) of this section, using each of the following sets of reagents.
    (i) Blood Group Substance B plus Reference Anti-B Blood Grouping 
Serum plus B cell suspension.
    (ii) Blood Group Substance B plus Reference Anti-A Blood Grouping 
Serum plus A1 cell suspension.
    (iii) Reference Blood Group Substance B plus Reference Anti-B Blood 
Grouping Serum plus B cell suspension.
    (iv) Reference Blood Group Substance A plus Reference Anti-A Blood 
Grouping Serum plus A1 cell suspension.
    (h) Interpretation of the test. The cell buttons shall be gently 
dislodged and observed macroscopically. The reactions shall be graded as 
described in paragraph (d) of this section. The highest dilution of 
Blood Group Substance that totally inhibits agglutination is taken as 
the inhibition end point.
    (i) Potency test requirements. Blood Group Substance A shall have a 
potency inhibition titer value equal to or greater than that of the 
Reference Blood Group Substance A. Blood Group Substance B shall have a 
potency inhibition titer value equal to or greater than that of the 
Reference Blood Group Substance B and less than that of Reference Blood 
Group Substance A. Blood Group Substance AB shall have potency 
inhibition titer values equal to or greater than those of Reference 
Blood Group Substance A and Reference Blood Group Substance B.



Sec. 680.23  Other tests.

    (a) Safety. A safety test shall be performed on the contents of 
final containers of each lot of each product as prescribed in 
Sec. 610.11 of this chapter.

[[Page 172]]

    (b) Sterility. A sterility test shall be performed on the contents 
of final containers of each lot of each product as prescribed in 
Sec. 610.12 of this chapter.
    (c) Pyrogens. A pyrogen test shall be performed on the contents of 
final containers of each lot of each product as prescribed in 
Sec. 610.13(b) of this chapter.
    (d) Anaphylaxis. An anaphylactic test shall be performed on the 
contents of a sufficient number of final containers of each lot of each 
product to perform the test as follows:
    (1) The contents of one final container shall be injected 
intraperitoneally into each of 10 normal guinea pigs.
    (2) After 3 weeks, each guinea pig shall be challenged intravenously 
with a 0.2-milliliter sample of the same product.
    (3) None of the 10 sensitized guinea pigs shall exhibit anaphylactic 
shock.



Sec. 680.24  General requirements.

    (a) Processing. (1) The processing method shall be one that has been 
shown consistently to yield a specific, potent final product, free of 
properties that would affect the product for its intended use throughout 
the dating period.
    (2) Only material that has been fully processed, sterile filtered 
into a single vessel, and thoroughly mixed in that vessel shall 
constitute a lot.
    (3) Each lot shall be filled in a single continuous operation.
    (b) Total nitrogen. Blood Group Substances shall contain not more 
than 8 percent total nitrogen when determined on moisture-free and ash-
free samples.
    (c) Preservative. A preservative shall not be incorporated into bulk 
manufactured Blood Group Substance or into final containers. However, 
phenol may be present as a residual from manufacturing.
    (d) Final containers. Final containers shall be sterile, pyrogen 
free, colorless, and transparent. The contents of the final container 
shall not exceed 1 milliliter of product containing not more than one 
immunizing dose of Blood Group Substance powder.
    (e) Date of manufacture. The date of manufacture shall be the date 
the manufacturer initiates the last valid potency test that is reported 
on a protocol and submitted to the Director, Center for Biologics 
Evaluation and Research.
    (f) Dose. A single human dose for intramuscular, subcutaneous or 
intradermal injection shall not exceed the contents of a final 
container.

[44 FR 20674, Apr. 6, 1979; 48 FR 13026, Mar. 29, 1983, as amended at 49 
FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]



Sec. 680.25  Labeling.

    In addition to the labeling requirements of Sec. 610.62 of this 
chapter and in lieu of the requirements in Secs. 610.60 and 610.61 of 
this chapter, the following shall appear on the label of Blood Group 
Substances:
    (a) Label affixed to each final container. (1) Proper name of the 
product.
    (2) Name, address (including zip code), and license number of the 
manufacturer.
    (3) Lot number.
    (4) Expiration date.
    (5) The statement ``ONE IMMUNIZING DOSE''.
    (6) Recommended storage temperature.
    (7) The statement ``SEE DIRECTIONS FOR USE''.
    (b) Container not enclosed in a package. If the final container is 
not enclosed in a package, e.g., the container is enclosed only in an 
unlabeled shipping carton, all information required for the package 
label in paragraph (c) of this section shall accompany and be attached 
to each final container.
    (c) Package label. (1) Proper name of the product.
    (2) Name, address (including zip code), and license number of the 
manufacturer.
    (3) Lot number.
    (4) Expiration date.
    (5) The statement ``CONTAINS NO PRESERVATIVE''.
    (6) Number of containers, if more than one.
    (7) The statement ``DERIVED FROM PORCINE (OR EQUINE) STOMACHS'', as 
applicable.
    (8) The statement ``EACH FINAL CONTAINER CONTAINS ONE IMMUNIZING 
DOSE''.
    (9) Recommended storage temperature.

[[Page 173]]

    (10) The statement ``DO NOT ADMINISTER INTRAVENOUSLY''.
    (11) The statement ``DO NOT ADMINISTER TO FERTILE WOMEN''.
    (12) Recommendations for use.
    (13) For Blood Group Substance B, the statement ``CAUTION: MAY 
CONTAIN IMMUNOGENIC A ACTIVITY''.
    (14) The statement ``CAUTION: FEDERAL LAW PROHIBITS DISPENSING 
WITHOUT A PRESCRIPTION''.
    (15) Reference to enclosed package insert.



Sec. 680.26  Samples; protocols; official release.

    For each lot of product, the following material shall be submitted 
to the Director, Center for Biologics Evaluation and Research, Food and 
Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892:
    (a) Samples. Randomly selected samples consisting of 40 final 
containers packaged for distribution.
    (b) Protocol. A protocol consisting of a summary of the history of 
the manufacture of the product, including the dates and results of all 
tests that are required by regulations.
    (c) Official release. The product shall not be issued by the 
manufacturer until written notification of official release is received 
from the Director, Center for Biologics Evaluation and Research.

[44 FR 20674, Apr. 6, 1979; 48 FR 13026, Mar. 29, 1983, as amended at 49 
FR 23834, June 8, 1984; 51 FR 15611, Apr. 25, 1986; 55 FR 11013, Mar. 
26, 1990]

[[Page 174]]


                         SUBCHAPTER G--COSMETICS


PART 700--GENERAL--Table of Contents




                      Subpart A--General Provisions

Sec.
700.3  Definitions.

         Subpart B--Requirements for Specific Cosmetic Products

700.10  Shampoo preparations containing egg as one of the ingredients.
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.

    Authority: Secs. 201, 301, 502, 505, 601, 602, 701, 704 of the 
Federal Food, Drug, and Cosmetic Act (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 175]]

    (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. 700.10   Shampoo preparations containing eggs as one of the ingredients.

    The present views of the Food and Drug Administration concerning the 
status of shampoo preparations containing egg as one of the ingredients 
are as follows:
    (a) An article designated as ``egg shampoo'' should contain one egg 
(or the equivalent amount of dried whole egg) in that quantity of the 
article which would be used in one shampooing of the hair.
    (b) An article that contains less than one egg per ``shampoo'' 
should not be referred to as an ``egg shampoo'' and the word ``egg'' 
should not be used as part of the name of the article. At the present 
time, the Food and Drug Administration is not raising objection to the 
marketing of an article containing less than one egg per ``shampoo,'' 
provided the word ``egg'' does not appear in the name of the article, 
the reference to the egg ingredient, such as ``plus egg,'' appears in a 
subordinate position on the label and is in type which is substantially 
reduced in size in comparison with the title of the article, and the 
reference to the presence of egg reveals the amount of the egg 
ingredient.
    (c) In the case of an article containing less than 2 percent egg, 
the amount of egg is so small as to be insignificant, and it is 
therefore considered that it would be misleading for the labeling to 
make any mention of the presence of egg in such a product.



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

[[Page 176]]

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 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

[[Page 177]]

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 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

[[Page 178]]

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 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,

[[Page 179]]

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 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

[[Page 180]]

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 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.



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: Secs. 201, 502, 601, 602, 603, 701, 704 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 352, 361, 362, 363, 371, 
374); secs. 5, 6 of the Fair Packaging and Labeling Act (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.



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

[[Page 181]]

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 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

[[Page 182]]

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 available for inspection at the 
Office of the Federal Register, 800 North Capitol Street, NW., suite 
700, Washington, DC 20408), which is incorporated by reference, except 
for the following deletions and revisions:
    (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 available for inspection at the Office of the 
Federal Register, 800 North Capitol Street, NW., suite 700, Washington, 
DC 20408.)
    (iii) National Formulary, 14th 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 available for inspection at the Office of the Federal 
Register, 800 North Capitol Street, NW., suite 700, Washington, DC 
20408).
    (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, 200 C St. SW., Washington, DC 20204, or 
available for inspection at the Office of the Federal Register, 800 
North Capitol Street, NW., suite 700, Washington, DC 20408.
    (v) USAN and the USP dictionary of drug names, USAN 1975, 1961-1975

[[Page 183]]

cumulative list. (Copies are available from the U.S. Pharmacopeial 
Convention, Inc., 12601 Twinbrook Parkway, Rockville, MD 20852, or 
available for inspection at the Office of the Federal Register, 800 
North Capitol Street, NW., suite 700, Washington, DC 20408.)
    (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 a drug, the declaration shall 
first declare the active drug ingredients as required under section 
502(e) of the Federal Food, Drug, and Cosmetic Act, and shall then 
declare the cosmetic ingredients.
    (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.
    (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

[[Page 184]]

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 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

[[Page 185]]

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.
    (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

[[Page 186]]

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 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

[[Page 187]]

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]



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 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''

[[Page 188]]

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.
    (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,

[[Page 189]]

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 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

[[Page 190]]

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 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

[[Page 191]]

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

    (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 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

[[Page 192]]

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.           
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: Secs. 201, 301, 601, 602, 701, 704 of the Federal Food, 
Drug, and Cosmetic Act (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

[[Page 193]]

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, Department 
of Health and Human Services, Washington, DC 20204, or at any Food and 
Drug Administration district office. The completed form should be mailed 
to Cosmetic Product Establishment Registration, Food and Drug 
Administration, Department of Health and Human Services, Washington, DC 
20204.



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 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, Department of Health 
and Human Services, Washington, DC 20204.



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,

[[Page 194]]

pilot plant production, teaching, or chemical analysis, and who do not 
sell these products.



PART 720--VOLUNTARY FILING OF COSMETIC PRODUCT INGREDIENT AND COSMETIC RAW MATERIAL 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: Secs. 201, 301, 601, 602, 701, 704 of the Federal Food, 
Drug, and Cosmetic Act (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, Department of Health and 
Human Services, Washington, DC 20204, 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, 
Department of Health and Human Services, Washington, DC 20204, according 
to the instructions provided with the forms.

[57 FR 3129, Jan. 28, 1992]



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

[[Page 195]]

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.
    (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).

[[Page 196]]

    (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 Secs. 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 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.

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

[57 FR 3130, Jan. 28, 1992]



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 Secs. 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 and in Sec. 20.44 of this chapter. The request for 
confidentiality will also be subject to the provisions of Sec. 20.111 of 
this chapter, as well as to the

[[Page 197]]

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 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 
withdraw the records for which FDA has tentatively denied a request for 
confidentiality or 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 21 CFR 20.61, and 
the petitioner does not withdraw the records for which a request for 
confidentiality has been denied, the records involved will be made a 
part of FDA files and will be available for public disclosure upon 
request.

[51 FR 11444, Apr. 3, 1986, as amended at 57 FR 3130, Jan. 28, 1992]



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

[[Page 198]]

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 730--VOLUNTARY FILING OF COSMETIC PRODUCT EXPERIENCES--Table of Contents




Sec.
730.1  Who should file.
730.2  Time for filing.
730.3  How and where to file.
730.4  Information requested.
730.5  Additions or amendments to reports.
730.6  Notification to person submitting reports.
730.7  Confidentiality of reports.
730.8  Misbranding by reference to filing; filing does not constitute an 
          admission.

    Authority: Secs. 201, 301, 601, 602, 701, 704 of the Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 321, 331, 361, 362, 371, 374).

    Source: 39 FR 10062, Mar. 15, 1974, unless otherwise noted.



Sec. 730.1   Who should file.

    Every person who is a manufacturer, packer, or distributor of a 
cosmetic product is requested to file a Form FD-2704 (Cosmetic Product 
Experience Report), with respect to all reportable experiences which 
have been reported to him concerning any of his cosmetic products in 
commercial distribution, regardless of whether he is a participant in 
the voluntary program to register cosmetic product establishments 
pursuant to part 710 of this chapter, and regardless of whether he is a 
participant in the voluntary program to file cosmetic product ingredient 
and raw material composition statements pursuant to part 720 of this 
chapter. In addition, every person who is a manufacturer, packer, or 
distributor of a cosmetic product, whether or not he has received any 
information concerning a reportable experience in regard to any of his 
cosmetic products in his system of commercial distribution, is requested 
to file a Form FD-2706 (Summary Report of Cosmetic Product Experience by 
Product Categories). This request extends to any foreign manufacturer, 
packer, or distributor of a cosmetic product imported into any State. No 
filing fee is required.

[39 FR 10062, Mar. 15, 1974, as amended at 46 FR 38073, July 24, 1981]



Sec. 730.2  Time for filing.

    (a) Reportable experiences should be reported on an annual basis, 
for the period January through December, not later than 60 days after 
the close of the reporting period.
    (b) A summary report of cosmetic product experience by product 
categories should be filed on an annual basis, for the period January 
through December, not later than 60 days after the close of the 
reporting period.

[51 FR 25687, July 16, 1986]



Sec. 730.3  How and where to file.

    Form FDA 2704 (Cosmetic Product Experience Report) and Form FDA 2706 
(Summary Report of Cosmetic Product Experience by Product Categories) 
are obtainable from, and the completed forms should be mailed or 
delivered to, Cosmetic Product Experience Report, Center for Food Safety 
and Applied Nutrition (HFS-100), Food and Drug Administration, 200 C St. 
SW., Washington, DC 20204.

[51 FR 25687, July 16, 1986, as amended at 61 FR 14481, Apr. 2, 1996]



Sec. 730.4   Information requested.

    (a) Form FD-2704 (Cosmetic Product Experience Report) requests the 
following information:
    (1) The name of the person (manufacturer, packer, or distributor) 
designated on the label of the cosmetic product.
    (2) Time period covered by the report.
    (3) The complete name of the cosmetic product exactly as it appears 
on the label of the product.
    (4) The cosmetic product category, as set forth in Sec. 720.4(c) of 
this chapter and on the form, which best describes the product's 
intended use.
    (5) Total number of reportable experiences during this reporting 
period and number of these experiences requiring professional medical 
attention.
    (6) Total number of product units of the cosmetic product estimated 
to have been distributed to consumers during this reporting period.

[[Page 199]]

    (7)-(8) [Reserved]
    (9) The cosmetic product ingredient statement number (CPIS No.) 
assigned to the product under Sec. 720.7 of this chapter, if known. If a 
number is pending, but has not been assigned, the firm should so 
indicate. Where the firm submitting the report knows that a cosmetic 
product ingredient statement pursuant to part 720 of this chapter has 
not been filed, it should so indicate.
    (10) Any additional evaluation of the experiences or other pertinent 
data or information as the person filing wishes to provide to assist the 
Food and Drug Administration in evaluating the report.
    (b) [Reserved]
    (c) Form FD-2706 (Summary Report of Cosmetic Product Experience by 
Product Categories) requests the following information:
    (1) The name and address (include country, if other than the United 
States), including post office ZIP code of the person (manufacturer, 
packer, or distributor) designated on the label of the cosmetic 
products.
    (2) Time period covered by the report.
    (3) Total number of product units within each product category, as 
set forth in Sec. 720.4(c) of this chapter and on the form, estimated to 
have been distributed to consumers during this reporting period.
    (4) Total number of reportable experiences within each product 
category during this reporting period, if any.
    (d) The person filing a Form FD-2704 (Cosmetic Product Experience 
Report)or Form FD-2706 (Summary Report of Product Experience by Product 
Categories) should:
    (1) Provide the information requested in paragraphs (a) and (c) of 
this section, as appropriate.
    (2) Provide the screening procedure in conformance with 
Sec. 700.3(p) when a screening procedure is used in connection with the 
reports requested by this part and is not already on file with the Food 
and Drug Administration.
    (3) Provide the name, title, and signature of the individual 
authorized to submit the report(s), and the name and address of the firm 
which he represents if it differs from that provided in paragraph (a) or 
(c) of this section.
    (e) The information requested under paragraph (a) of this section 
should be filed separately for each cosmetic product, except that a 
single report may be filed for two or more shades, flavors, or 
fragrances of a cosmetic product where only the proportions of these 
ingredients are varied, and such product is covered by a single cosmetic 
product ingredient statement under Sec. 720.4(e) of this chapter.
    (f) On the basis of a review of individual reports or patterns of 
experience disclosed as a result of a number of reports, the 
Commissioner of Food and Drugs may request as much additional 
information from persons submitting reports as the Commissioner deems 
appropriate. For this reason, every person participating in this program 
should retain for three years all correspondence and records pertaining 
to alleged cosmetic product injuries.

[39 FR 10062, Mar. 15, 1974, as amended at 46 FR 38074, July 24, 1981; 
51 FR 25687, July 16, 1986]



Sec. 730.5   Additions or amendments to reports.

    Additions or amendments to any experience report should be submitted 
by filing the appropriate amended form as soon as the need for such 
additions or amendments becomes apparent to the person submitting the 
original report.



Sec. 730.6   Notification to person submitting reports.

    Anyone desiring a receipt for information submitted should send it 
by registered mail requesting a return receipt.



Sec. 730.7   Confidentiality of reports.

    The availability for public disclosure of all data and information 
contained in, attached to, or included with Forms FD-2704, 2706, and 
amendments thereto, shall be handled in accordance with the provisions 
established in part 20 of this chapter. All such data and information 
are submitted voluntarily to the Food and Drug Administration and are 
thus subject to the specific provisions concerning data and information 
submitted voluntarily to the Food and Drug Administration in Sec. 20.111 
of this chapter, as well as to the exemptions in subpart D of part 20 of 
this chapter and

[[Page 200]]

the limitations on exemptions in subpart E of part 20 of this chapter.

[39 FR 44657, Dec. 24, 1974, as amended at 42 FR 15676, Mar. 22, 1977; 
46 FR 38074, July 24, 1981]



Sec. 730.8   Misbranding by reference to filing; filing does not constitute an admission.

    (a) The filing of an experience report does not in any way denote 
approval of the firm or the cosmetic product by the Food and Drug 
Administration. Any representation in labeling or advertising that 
creates an impression of official approval because of such filing will 
be considered misleading.
    (b) The filing of an experience report does not in any way 
constitute an admission by the person filing the report that the alleged 
experience was the result of an ingredient or ingredients in the 
cosmetic product, or of any other fact.



PARTS 741--799 [RESERVED]--Table of Contents






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.

    Authority: Secs. 201, 301, 502, 505, 601, 602, 701, 704 of the 
Federal Food, Drug, and Cosmetic Act (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/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 
Dockets Management Branch 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]



                      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

[[Page 201]]

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)(1) In addition to the warnings required by paragraphs (a)(1) and 
(b)(1) of this section, the label on each package of a cosmetic in a 
self-pressurized container in which the propellant consists in whole or 
in part of a fully halogenated chlorofluoroalkane (chlorofluorocarbon) 
shall bear the following warning:

    Warning--Contains a chlorofluorocarbon that may harm the public 
health and environment by reducing ozone in the upper atmosphere.

    (2) The warning required by paragraph (c)(1) of this section shall 
appear on an appropriate panel with such prominence and conspicuousness 
as to render it likely to be read and understood by ordinary individuals 
under normal conditions of purchase. The warning may appear on a firmly 
affixed tag, tape, card, or sticker or similar overlabeling attached to 
the package. The warning shall comply in all other respects with 
Sec. 740.2, e.g., type-size requirements.
    (3) The warning required by paragraph (c)(1) of this section is 
applicable only to self-pressurized containers that use a 
chlorofluorocarbon in whole or in part as a propellant to expel from the

[[Page 202]]

container liquid or solid material different from the propellant.

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



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, the effectiveness 
of Sec. 740.18 was stayed until further notice. The stay was effective 
Sept. 18, 1980.



PARTS 741--799 [RESERVED]--Table of Contents




[[Page 203]]



                              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.

  Material Approved for Incorporation by Reference
  Table of CFR Titles and Chapters
  Alphabetical List of Agencies Appearing in the CFR
  List of CFR Sections Affected

[[Page 205]]

........................................................................

            Material Approved for Incorporation by Reference

                      (Revised as of April 1, 1996)

  The Director of the Federal Register has approved under 5 U.S.C. 
552(a) and 1 CFR Part 51 the incorporation by reference of the following 
publications. This list contains only those incorporations by reference 
effective as of the revision date of this volume. Incorporations by 
reference found within a regulation are effective upon the effective 
date of that regulation. For more information on incorporation by 
reference, see the preliminary pages of this volume.


21 CFR CHAPTER I (PARTS 600 TO 799)

FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES


Cosmetic, Toiletry, and Fragrance Association, Inc.

  1133 15th St. NW., Washington, DC 20065.
Cosmetic, Toiletry, and Fragrance Association, 
  Inc., Cosmetic Ingredient Dictionary, Second 
  Ed., 1977.......................................       701.3(c)(2)(i).


National Academy of Sciences, National Research Council

  2101 Constitution Ave. NW., Washington, DC 20037.
Food Chemicals Codex, 2nd Ed., 1972...............              720.4(d)
Food Chemicals Codex, 2nd Ed., 1972, First 
  Supplement, 1974................................              701.3(c)
Food Chemicals Codex, 2nd Ed., 1972, Second 
  Supplement, 1975................................       701.3(c)(2)(iv)

  NOTE: The following materials are available through the Food and Drug 
  Administration at the addresses indicated.



Bureau of Biologics, Food and Drug Administration

  8800 Rockville Pike, Bethesda, MD 20205
Standard Methods for the Examination of Water and 
  Waste Water, 13th Ed............................                630.74


United States Pharmacopeial Covention, Inc.

  12601 Twinbrook Parkway, Rockville, MD 20852
United States Pharmacopeia (21st revision, 1985)..
  Test Procedures Using Membrane Filtration, p. 
  1159............................................             610.12(f)


                                                                    Chap.

[[Page 207]]



                    Table of CFR Titles and Chapters



                     (Revised as of March 29, 1996)

                      Title 1--General Provisions

         I  Administrative Committee of the Federal Register 
                (Parts 1--49)
        II  Office of the Federal Register (Parts 50--299)
        IV  Miscellaneous Agencies (Parts 400--500)

                          Title 2--[Reserved]

                        Title 3--The President

         I  Executive Office of the President (Parts 100--199)

                           Title 4--Accounts

         I  General Accounting Office (Parts 1--99)
        II  Federal Claims Collection Standards (General 
                Accounting Office--Department of Justice) (Parts 
                100--299)

                   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  Advisory Committee on Federal Pay (Parts 1400--1499)
         V  The International Organizations Employees Loyalty 
                Board (Parts 1500--1599)
        VI  Federal Retirement Thrift Investment Board (Parts 
                1600--1699)
       VII  Advisory Commission on Intergovernmental Relations 
                (Parts 1700--1799)
      VIII  Office of Special Counsel (Parts 1800--1899)
        IX  Appalachian Regional Commission (Parts 1900--1999)
        XI  Armed Forces Retirement Home (Part 2100)
       XIV  Federal Labor Relations Authority, General Counsel of 
                the Federal Labor Relations Authority and Federal 
                Service Impasses Panel (Parts 2400--2499)
        XV  Office of Administration, Executive Office of the 
                President (Parts 2500--2599)
       XVI  Office of Government Ethics (Parts 2600--2699)
       XXI  Department of the Treasury (Parts 3100--3199)
      XXII  Federal Deposit Insurance Corporation (Part 3202)
      XXVI  Department of Defense (Part 3601)

[[Page 208]]

       XXX  Farm Credit System Insurance Corporation (Parts 4000--
                4099)
      XXXI  Farm Credit Administration (Parts 4100--4199)
    XXXIII  Overseas Private Investment Corporation (Part 4301)
        XL  Interstate Commerce Commission (Part 5001)
       XLI  Commodity Futures Trading Commission (Part 5101)
      XLVI  Postal Rate Commission (Part 5601)
     XLVII  Federal Trade Commission (Part 5701)
    XLVIII  Nuclear Regulatory Commission (Part 5801)
       LII  Export-Import Bank of the United States (Part 6201)
      LIII  Department of Education (Parts 6300--6399)
       LIX  National Aeronautics and Space Administration (Part 
                6901)
        LX  United States Postal Service (Part 7001)
      LXII  Equal Employment Opportunity Commission (Part 7201)
     LXIII  Inter-American Foundation (Part 7301)
     LXXVI  Federal Retirement Thrift Investment Board (Part 8601)
    LXXVII  Office of Management and Budget (Part 8701)

                          Title 6--[Reserved]

                         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 Consumer 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)
      VIII  Grain Inspection, Packers and Stockyards 
                Administration (Federal Grain Inspection Service), 
                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)

[[Page 209]]

       XIV  Commodity Credit Corporation, Department of 
                Agriculture (Parts 1400--1499)
        XV  Foreign Agricultural Service, Department of 
                Agriculture (Parts 1500--1599)
       XVI  Rural Telephone Bank, Department of Agriculture (Parts 
                1600--1699)
      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)
       XXI  Foreign Economic Development Service, Department of 
                Agriculture (Parts 2100--2199)
      XXII  Office of International Cooperation and Development, 
                Department of Agriculture (Parts 2200--2299)
       XXV  Office of the General Sales Manager, 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, Department of Agriculture (Parts 
                2900--2999)
       XXX  Office of Finance and Management, Department of 
                Agriculture (Parts 3000--3099)
      XXXI  Office of Environmental Quality, Department of 
                Agriculture (Parts 3100--3199)
     XXXII  [Reserved]
    XXXIII  Office of Transportation, Department of Agriculture 
                (Parts 3300--3399)
     XXXIV  Cooperative State Research, Education, and Extension 
                Service, Department of Agriculture (Parts 3400--
                3499)
     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)
     XXXIX  Economic Analysis Staff, Department of Agriculture 
                (Parts 3900--3999)
        XL  Economics Management Staff, Department of Agriculture 
                (Parts 4000--4099)
       XLI  [Reserved]
      XLII  Rural Business-Cooperative Service and Rural Utilities 
                Service, Department of Agriculture (Parts 4200--
                4299)

                    Title 8--Aliens and Nationality

         I  Immigration and Naturalization Service, Department of 
                Justice (Parts 1--499)

[[Page 210]]

                 Title 9--Animals and Animal Products

         I  Animal and Plant Health Inspection Service, Department 
                of Agriculture (Parts 1--199)
        II  Grain Inspection, Packers and Stockyards 
                Administration (Packers and Stockyards Programs), 
                Department of Agriculture (Parts 200--299)
       III  Food Safety and Inspection Service, Meat and Poultry 
                Inspection, Department of Agriculture (Parts 300--
                399)

                           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)
        XI  United States Enrichment Corporation (Parts 1100--
                1199)
        XV  Office of the Federal Inspector for the Alaska Natural 
                Gas Transportation System (Parts 1500--1599)
      XVII  Defense Nuclear Facilities Safety Board (Parts 1700--
                1799)

                      Title 11--Federal Elections

         I  Federal Election Commission (Parts 1--9099)

                      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  Office of Thrift Supervision, Department of the 
                Treasury (Parts 500--599)
        VI  Farm Credit Administration (Parts 600--699)
       VII  National Credit Union Administration (Parts 700--799)
      VIII  Federal Financing Bank (Parts 800--899)
        IX  Federal Housing Finance Board (Parts 900--999)
        XI  Federal Financial Institutions Examination Council 
                (Parts 1100--1199)
       XIV  Farm Credit System Insurance Corporation (Parts 1400--
                1499)
        XV  Thrift Depositor Protection Oversight Board (Parts 
                1500--1599)
      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)

[[Page 211]]

                    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  Office of Commercial Space Transportation, Department 
                of Transportation (Parts 400--499)
         V  National Aeronautics and Space Administration (Parts 
                1200--1299)

                 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 Export Administration, Department of 
                Commerce (Parts 700--799)
      VIII  Bureau of Economic Analysis, Department of Commerce 
                (Parts 800--899)
        IX  National Oceanic and Atmospheric Administration, 
                Department of Commerce (Parts 900--999)
        XI  Technology Administration, Department of Commerce 
                (Parts 1100--1199)
       XII  United States Travel and Tourism Administration, 
                Department of Commerce (Parts 1200--1299)
      XIII  East-West Foreign Trade Board (Parts 1300--1399)
       XIV  Minority Business Development Agency (Parts 1400--
                1499)
            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)

                    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)

[[Page 212]]

        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  United States Customs Service, Department of the 
                Treasury (Parts 1--199)
        II  United States International Trade Commission (Parts 
                200--299)
       III  International Trade Administration, Department of 
                Commerce (Parts 300--399)

                     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  Employment Standards Administration, 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, 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, International 
                Development Cooperation Agency (Parts 200--299)

[[Page 213]]

       III  Peace Corps (Parts 300--399)
        IV  International Joint Commission, United States and 
                Canada (Parts 400--499)
         V  United States Information Agency (Parts 500--599)
        VI  United States Arms Control and Disarmament Agency 
                (Parts 600--699)
       VII  Overseas Private Investment Corporation, International 
                Development Cooperation Agency (Parts 700--799)
        IX  Foreign Service Grievance Board Regulations (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  Board for International Broadcasting (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)

                          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)
         V  Office of Assistant Secretary for Community Planning 
                and Development, Department of Housing and Urban 
                Development (Parts 500--599)

[[Page 214]]

        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 and Section 202 Direct Loan Program) 
                (Parts 800--899)
        IX  Office of Assistant Secretary for Public and Indian 
                Housing, Department of Housing and Urban 
                Development (Parts 900--999)
         X  Office of Assistant Secretary for Housing--Federal 
                Housing Commissioner, Department of Housing and 
                Urban Development (Interstate Land Sales 
                Registration Program) (Parts 1700--1799)
       XII  Office of Inspector General, Department of Housing and 
                Urban Development (Parts 2000--2099)
        XX  Office of Assistant Secretary for Housing--Federal 
                Housing Commissioner, Department of Housing and 
                Urban Development (Parts 3200--3699)
       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--799)
        VI  Office of the Assistant Secretary-Indian Affairs, 
                Department of the Interior (Part 1001)

                      Title 26--Internal Revenue

         I  Internal Revenue Service, Department of the Treasury 
                (Parts 1--799)

           Title 27--Alcohol, Tobacco Products and Firearms

         I  Bureau of Alcohol, Tobacco and Firearms, Department of 
                the Treasury (Parts 1--299)

                   Title 28--Judicial Administration

         I  Department of Justice (Parts 0--199)
       III  Federal Prison Industries, Inc., Department of Justice 
                (Parts 300--399)
         V  Bureau of Prisons, Department of Justice (Parts 500--
                599)

[[Page 215]]

        VI  Offices of Independent Counsel, Department of Justice 
                (Parts 600--699)
       VII  Office of Independent Counsel (Parts 700--799)

                            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 Programs, 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  Pension and Welfare Benefits Administration, 
                Department of Labor (Parts 2500--2599)
      XXVI  Pension Benefit Guaranty Corporation (Parts 2600--
                2699)
     XXVII  Federal Mine Safety and Health Review Commission 
                (Parts 2700--2799)

                      Title 30--Mineral Resources

         I  Mine Safety and Health Administration, Department of 
                Labor (Parts 1--199)
        II  Minerals Management Service, Department of the 
                Interior (Parts 200--299)
       III  Board of Surface Mining and Reclamation Appeals, 
                Department of the Interior (Parts 300--399)
        IV  Geological Survey, Department of the Interior (Parts 
                400--499)
        VI  Bureau of Mines, Department of the Interior (Parts 
                600--699)
       VII  Office of Surface Mining Reclamation and Enforcement, 
                Department of the Interior (Parts 700--999)

                 Title 31--Money and Finance: Treasury

            Subtitle A--Office of the Secretary of the Treasury 
                (Parts 0--50)
            Subtitle B--Regulations Relating to Money and Finance
         I  Monetary Offices, Department of the Treasury (Parts 
                51--199)
        II  Fiscal Service, Department of the Treasury (Parts 
                200--399)

[[Page 216]]

        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 International Investment, Department of the 
                Treasury (Parts 800--899)

                      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  Defense Logistics Agency (Parts 1200--1299)
       XVI  Selective Service System (Parts 1600--1699)
       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)
      XXIX  Presidential Commission on the Assignment of Women in 
                the Armed Forces (Part 2900)

               Title 33--Navigation and Navigable Waters

         I  Coast Guard, Department of Transportation (Parts 1--
                199)
        II  Corps of Engineers, Department of the Army (Parts 
                200--399)
        IV  Saint Lawrence Seaway Development Corporation, 
                Department of Transportation (Parts 400--499)

                          Title 34--Education

            Subtitle A--Office of the Secretary, Department of 
                Education (Parts 1--99)
            Subtitle B--Regulations of the Offices of the 
                Department of Education
         I  Office for Civil Rights, Department of Education 
                (Parts 100--199)
        II  Office of Elementary and Secondary Education, 
                Department of Education (Parts 200--299)
       III  Office of Special Education and Rehabilitative 
                Services, Department of Education (Parts 300--399)

[[Page 217]]

        IV  Office of Vocational and Adult Education, Department 
                of Education (Parts 400--499)
         V  Office of Bilingual Education and Minority Languages 
                Affairs, Department of Education (Parts 500--599)
        VI  Office of Postsecondary Education, Department of 
                Education (Parts 600--699)
       VII  Office of Educational Research and Improvement, 
                Department of Education (Parts 700--799)
        XI  National Institute for Literacy (Parts 1100-1199)
            Subtitle C--Regulations Relating to Education
       XII  National Council on Disability (Parts 1200--1299)

                        Title 35--Panama Canal

         I  Panama Canal Regulations (Parts 1--299)

             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)
       VII  Library of Congress (Parts 700--799)
      VIII  Advisory Council on Historic Preservation (Parts 800--
                899)
        IX  Pennsylvania Avenue Development Corporation (Parts 
                900--999)
        XI  Architectural and Transportation Barriers Compliance 
                Board (Parts 1100--1199)
       XII  National Archives and Records Administration (Parts 
                1200--1299)
       XIV  Assassination Records Review Board (Parts 1400-1499)

             Title 37--Patents, Trademarks, and Copyrights

         I  Patent and Trademark Office, Department of Commerce 
                (Parts 1--199)
        II  Copyright Office, Library of Congress (Parts 200--299)
        IV  Assistant Secretary for Technology Policy, Department 
                of Commerce (Parts 400--499)
         V  Under Secretary for Technology, Department of Commerce 
                (Parts 500--599)

           Title 38--Pensions, Bonuses, and Veterans' Relief

         I  Department of Veterans Affairs (Parts 0--99)

                       Title 39--Postal Service

         I  United States Postal Service (Parts 1--999)
       III  Postal Rate Commission (Parts 3000--3099)

[[Page 218]]

                  Title 40--Protection of Environment

         I  Environmental Protection Agency (Parts 1--799)
         V  Council on Environmental Quality (Parts 1500--1599)

          Title 41--Public Contracts and Property Management

            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, Department of Labor 
                (Parts 61-1--61-999)
            Subtitle C--Federal Property Management Regulations 
                System
       101  Federal Property Management Regulations (Parts 101-1--
                101-99)
       105  General Services Administration (Parts 105-1--105-999)
       109  Department of Energy Property Management Regulations 
                (Parts 109-1--109-99)
       114  Department of the Interior (Parts 114-1--114-99)
       115  Environmental Protection Agency (Parts 115-1--115-99)
       128  Department of Justice (Parts 128-1--128-99)
            Subtitle D--Other Provisions Relating to Property 
                Management [Reserved]
            Subtitle E--Federal Information Resources Management 
                Regulations System
       201  Federal Information Resources Management Regulation 
                (Parts 201-1--201-99)
            Subtitle F--Federal Travel Regulation System
       301  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 (Parts 303-1--303-2)
       304  Payment from a Non-Federal Source for Travel Expenses 
                (Parts 304-1--304-99)

                        Title 42--Public Health

         I  Public Health Service, Department of Health and Human 
                Services (Parts 1--199)
        IV  Health Care Financing Administration, Department of 
                Health and Human Services (Parts 400--499)
         V  Office of Inspector General-Health Care, Department of 
                Health and Human Services (Parts 1000--1999)

                   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 200--499)

[[Page 219]]

        II  Bureau of Land Management, Department of the Interior 
                (Parts 1000--9999)
       III  Utah Reclamation Mitigation and Conservation 
                Commission (Parts 10000--10005)

             Title 44--Emergency Management and Assistance

         I  Federal Emergency Management Agency (Parts 0--399)
        IV  Department of Commerce and Department of 
                Transportation (Parts 400--499)

                       Title 45--Public Welfare

            Subtitle A--Department of Health and Human Services, 
                General Administration (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)
         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  ACTION (Parts 1200--1299)
      XIII  Office of Human Development Services, 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 on Fine Arts (Parts 2100--2199)
      XXII  Christopher Columbus Quincentenary Jubilee Commission 
                (Parts 2200--2299)
     XXIII  Arctic Research Commission (Part 2301)
      XXIV  James Madison Memorial Fellowship Foundation (Parts 
                2400--2499)
       XXV  Corporation for National and Community Service (Parts 
                2500--2599)

[[Page 220]]

                          Title 46--Shipping

         I  Coast Guard, Department of Transportation (Parts 1--
                199)
        II  Maritime Administration, Department of Transportation 
                (Parts 200--399)
       III  Saint Lawrence Seaway Development Corporation (Great 
                Lakes Pilotage), Department of Transportation 
                (Parts 400--499)
        IV  Federal Maritime Commission (Parts 500--599)

                      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)

           Title 48--Federal Acquisition Regulations System

         1  Federal Acquisition Regulation (Parts 1--99)
         2  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  United States Information Agency (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)
        22  Small Business Administration (Parts 2200--2299)
        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)
        34  Department of Education Acquisition Regulation (Parts 
                3400--3499)

[[Page 221]]

        35  Panama Canal Commission (Parts 3500--3599)
        44  Federal Emergency Management Agency (Parts 4400--4499)
        51  Department of the Army Acquisition Regulations (Parts 
                5100--5199)
        52  Department of the Navy Acquisition Regulations (Parts 
                5200--5299)
        53  Department of the Air Force Federal Acquisition 
                Regulation Supplement (Parts 5300--5399)
        54  Defense Logistics Agency, Department of Defense (Part 
                5452)
        57  African Development Foundation (Parts 5700--5799)
        61  General Services Administration Board of Contract 
                Appeals (Parts 6100--6199)
        63  Department of Transportation Board of Contract Appeals 
                (Parts 6300--6399)
        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  Research and Special Programs Administration, 
                Department of Transportation (Parts 100--199)
        II  Federal Railroad Administration, Department of 
                Transportation (Parts 200--299)
       III  Federal Highway Administration, Department of 
                Transportation (Parts 300--399)
        IV  Coast Guard, Department of Transportation (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, Department of 
                Transportation (Parts 1000--1399)

                   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 Regulatory Agencies (Fishing and 
                Whaling) (Parts 300--399)

[[Page 222]]

        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)

                      CFR Index and Finding Aids

            Subject/Agency Index
            List of Agency Prepared Indexes
            Parallel Tables of Statutory Authorities and Rules
            List of CFR Titles, Chapters, Subchapters, and Parts
            Alphabetical List of Agencies Appearing in the CFR



[[Page 223]]





           Alphabetical List of Agencies Appearing in the CFR



                     (Revised as of March 29, 1996)

                                                  CFR Title, Subtitle or
                     Agency                               Chapter

ACTION                                            45, XII
Administrative Committee of the Federal Register  1, I
Advanced Research Projects Agency                 32, I
Advisory Commission on Intergovernmental          5, VII
     Relations
Advisory Committee on Federal Pay                 5, IV
Advisory Council on Historic Preservation         36, VIII
African Development Foundation                    22, XV
  Federal Acquisition Regulation                  48, 57
Agency for International Development              22, II
  Federal Acquisition Regulation                  48, 7
Agricultural Marketing Service                    7, I, IX, X, XI
Agricultural Research Service                     7, V
Agriculture Department
  Agricultural Marketing Service                  7, I, IX, X, XI
  Agricultural Research Service                   7, V
  Animal and Plant Health Inspection Service      7, III; 9, I
  Commodity Credit Corporation                    7, XIV
  Cooperative State Research, Education, and      7, XXXIV
       Extension Service
  Economic Analysis Staff                         7, XXXIX
  Economic Research Service                       7, XXXVII
  Economics Management Staff                      7, XL
  Energy, Office of                               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
  Finance and Management, Office of               7, XXX
  Food and Consumer Service                       7, II
  Food Safety and Inspection Service              9, III
  Foreign Agricultural Service                    7, XV
  Forest Service                                  36, II
  Grain Inspection, Packers and Stockyards        7, VIII; 9, II
       Administration
  Information Resources Management, Office of     7, XXVII
  Inspector General, Office of                    7, XXVI
  National Agricultural Library                   7, XLI
  National Agricultural Statistics Service        7, XXXVI
  Natural Resources Conservation Service          7, VI
  Operations, Office of                           7, XXVIII
  Rural Business-Cooperative Service              7, XVIII, XLII
  Rural Development Administration                7, XLII
  Rural Housing Service                           7, XVIII
  Rural Telephone Bank                            7, XVI
  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                              32, VII
  Federal Acquisition Regulation Supplement       48, 53
Alaska Natural Gas Transportation System, Office  10, XV
     of the Federal Inspector
Alcohol, Tobacco and Firearms, Bureau of          27, I
AMTRAK                                            49, VII

[[Page 224]]

American Battle Monuments Commission              36, IV
Animal and Plant Health Inspection Service        7, III; 9, I
Appalachian Regional Commission                   5, IX
Architectural and Transportation Barriers         36, XI
     Compliance Board
Arctic Research Commission                        45, XXIII
Arms Control and Disarmament Agency, United       22, VI
     States
Army Department                                   32, V
  Engineers, Corps of                             33, II; 36, III
  Federal Acquisition Regulation                  48, 51
Assassination Records Review Board                36, XIV
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
Board for International Broadcasting              22, XIII
Census Bureau                                     15, I
Central Intelligence Agency                       32, XIX
Child Support Enforcement, Office of              45, III
Children and Families, Administration for         45, II, III, IV, X
Christopher Columbus Quincentenary Jubilee        45, XXII
     Commission
Civil Rights, Commission on                       45, VII
Civil Rights, Office for                          34, I
Coast Guard                                       33, I; 46, I; 49, IV
Commerce Department                               44, IV
  Census Bureau                                   15, I`
  Economic Affairs, Under Secretary               37, V
  Economic Analysis, Bureau of                    15, VIII
  Economic Development Administration             13, III
  Emergency Management and Assistance             44, IV
  Export Administration, Bureau of                15, VII
  Federal Acquisition Regulation                  48, 13
  Fishery Conservation and Management             50, VI
  Foreign-Trade Zones Board                       15, IV
  International Trade Administration              15, III; 19, III
  National Institute of Standards and Technology  15, II
  National Marine Fisheries Service               50, II, IV
  National Oceanic and Atmospheric                15, IX; 50, II, III, IV, 
       Administration                             VI
  National Telecommunications and Information     15, XXIII; 47, III
       Administration
  National Weather Service                        15, IX
  Patent and Trademark Office                     37, I
  Productivity, Technology and Innovation,        37, IV
       Assistant Secretary for
  Secretary of Commerce, Office of                15, Subtitle A
  Technology, Under Secretary for                 37, V
  Technology Administration                       15, XI
  Technology Policy, Assistant Secretary for      37, IV
  Travel and Tourism Administration, United       15, XII
       States
Commercial Space Transportation, Office of        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 Product Safety Commission                16, II
Cooperative State Research, Education, and        7, XXXIV
     Extension Service
Copyright Office                                  37, II
Cost Accounting Standards Board                   48, 99
Council on Environmental Quality                  40, V
Customs Service, United States                    19, I
Defense Contract Audit Agency                     32, I
Defense Department                                5, XXVI; 32, Subtitle A
  Advanced Research Projects Agency               32, I
  Air Force Department                            32, VII

[[Page 225]]

  Army Department                                 32, V; 33, II; 36, III, 
                                                  48, 51
  Defense Intelligence Agency                     32, I
  Defense Logistics Agency                        32, I, XII; 48, 54
  Defense Mapping Agency                          32, I
  Engineers, Corps of                             33, II; 36, III
  Federal Acquisition Regulation                  48, 2
  Navy Department                                 32, VI; 48, 52
  Secretary of Defense, Office of                 32, I
Defense Contract Audit Agency                     32, I
Defense Intelligence Agency                       32, I
Defense Logistics Agency                          32, XII; 48, 54
Defense Mapping Agency                            32, I
Defense Nuclear Facilities Safety Board           10, XVII
Delaware River Basin Commission                   18, III
Drug Enforcement Administration                   21, II
East-West Foreign Trade Board                     15, XIII
Economic Affairs, Under Secretary                 37, V
Economic Analysis, Bureau of                      15, VIII
Economic Analysis Staff                           7, XXXIX
Economic Development Administration               13, III
Economics Management Staff                        7, XL
Economic Research Service                         7, XXXVII
Education, Department of                          5, LIII
  Bilingual Education and Minority Languages      34, V
       Affairs, Office 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
  Vocational and Adult Education, Office of       34, IV
Educational Research and Improvement, Office of   34, VII
Elementary and Secondary Education, Office of     34, II
Employees' Compensation Appeals Board             20, IV
Employees Loyalty Board                           5, V
Employment and Training Administration            20, V
Employment Standards Administration               20, VI
Endangered Species Committee                      50, IV
Energy, Department of                             10, II, III, X
  Federal Acquisition Regulation                  48, 9
  Federal Energy Regulatory Commission            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
Enrichment Corporation, United States             10, XI
Environmental Protection Agency                   40, I
  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
  Administration, Office of                       5, XV
  Environmental Quality, Council on               40, V
  Management and Budget, Office of                25, III, LXXVII; 48, 99
  National Drug Control Policy, Office of         21, III
  National Security Council                       32, XXI; 47, 2
  Presidential Documents                          3
  Science and Technology Policy, Office of        32, XXIV; 47, II
  Trade Representative, Office of the United      15, XX
       States
Export Administration, Bureau of                  15, VII
Export-Import Bank of the United States           5, LII; 12, IV
Family Assistance, Office of                      45, II

[[Page 226]]

Farm Credit Administration                        5, XXXI; 12, VI
Farm Credit System Insurance Corporation          5, XXX; 12, XIV
Farm Service Agency                               7, VII, XVIII
Farmers Home Administration                       7, XVIII
Federal Acquisition Regulation                    48, 1
Federal Aviation Administration                   14, I
Federal Claims Collection Standards               4, II
Federal Communications Commission                 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                       11, I
Federal Emergency Management Agency               44, I
  Federal Acquisition Regulation                  48, 44
Federal Employees Group Life Insurance Federal    48, 21
     Acquisition Regulation
Federal Employees Health Benefits Acquisition     48, 16
     Regulation
Federal Energy Regulatory Commission              18, I
Federal Financial Institutions Examination        12, XI
     Council
Federal Financing Bank                            12, VIII
Federal Highway Administration                    23, I, II; 49, III
Federal Home Loan Mortgage Corporation            1, IV
Federal Housing Enterprise Oversight Office       12, XVII
Federal Housing Finance Board                     12, IX
Federal Information Resources Management          41, Subtitle E, Ch. 201
     Regulations
Federal Inspector for the Alaska Natural Gas      10, XV
     Transportation System, Office of
Federal Labor Relations Authority, and General    5, XIV; 22, XIV
     Counsel of the Federal Labor Relations 
     Authority
Federal Law Enforcement Training Center           31, VII
Federal Maritime Commission                       46, IV
Federal Mediation and Conciliation Service        29, XII
Federal Mine Safety and Health Review Commission  29, XXVII
Federal Pay, Advisory Committee on                5, IV
Federal Prison Industries, Inc.                   28, III
Federal Procurement Policy Office                 48, 99
Federal Property Management Regulations           41, 101
Federal Property Management Regulations System    41, Subtitle C
Federal Railroad Administration                   49, II
Federal Register, Administrative Committee of     1, I
Federal Register, Office of                       1, II
Federal Reserve System                            12, II
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
Finance and Management, Office of                 7, XXX
Fine Arts, Commission on                          45, XXI
Fiscal Service                                    31, II
Fish and Wildlife Service, United States          50, I, IV
Fishery Conservation and Management               50, VI
Fishing and Whaling, International Regulatory     50, III
     Agencies
Food and Drug Administration                      21, I
Food and Consumer 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 Accounting Office                         4, I, II
General Services Administration
  Contract Appeals, Board of                      48, 61

[[Page 227]]

  Federal Acquisition Regulation                  48, 5
  Federal Information Resources Management        41, Subtitle E, Ch. 201
       Regulations
  Federal Property Management Regulations System  41, 101, 105
  Federal Travel Regulation System                41, Subtitle F
  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
  Travel Allowances                               41, 301
Geological Survey                                 30, IV
Government Ethics, Office of                      5, XVI
Government National Mortgage Association          24, III
Grain Inspection, Packers and Stockyards          7, VIII; 9, II
     Administration
Great Lakes Pilotage                              46, III
Harry S. Truman Scholarship Foundation            45, XVIII
Health and Human Services, Department of          45, Subtitle A
  Child Support Enforcement, Office of            45, III
  Children and Families, Administration for       45, II, III, IV, X
  Community Services, Office of                   45, X
  Family Assistance, Office of                    45, II
  Federal Acquisition Regulation                  48, 3
  Food and Drug Administration                    21, I
  Health Care Financing Administration            42, IV
  Human Development Services, Office of           45, XIII
  Inspector General (Health Care), Office of      42, V
  Public Health Service                           42, I
  Refugee Resettlement, Office of                 45, IV
Health Care Financing Administration              42, IV
Housing and Urban Development, Department of      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
  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
Human Development Services, Office of             45, XIII
Immigration and Naturalization Service            8, I
Independent Counsel, Office of                    28, VII
Indian Affairs, Bureau of                         25, I
Indian Affairs, Office of the Assistant           25, VI
     Secretary
Indian Arts and Crafts Board                      25, II
Information Agency, United States                 22, V
  Federal Acquisition Regulation                  48, 19
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
Institute of Peace, United States                 22, XVII
Inter-American Foundation                         5, LXIII; 22, X
Intergovernmental Relations, Advisory Commission  5, VII
     on
Interior Department
  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

[[Page 228]]

  Indian Affairs, Office of the Assistant         25, VI
       Secretary
  Indian Arts and Crafts Board                    25, II
  Land Management, Bureau of                      43, II
  Minerals Management Service                     30, II
  Mines, Bureau of                                30, VI
  National Indian Gaming Commission               25, III
  National Park Service                           36, I
  Reclamation, Bureau of                          43, I
  Secretary of the Interior, Office of            43, Subtitle A
  Surface Mining and Reclamation Appeals, Board   30, III
       of
  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, Agency for             22, II
  Federal Acquisition Regulation                  48, 7
International Development Cooperation Agency,     22, XII
     United States
  International Development, Agency for           22, II; 48, 7
  Overseas Private Investment Corporation         5, XXXIII; 22, VII
International Investment, Office of               31, VIII
International Joint Commission, United States     22, IV
     and Canada
International Organizations Employees Loyalty     5, V
     Board
International Regulatory Agencies (Fishing and    50, III
     Whaling)
International Trade Administration                15, III; 19, III
International Trade Commission, United States     19, II
Interstate Commerce Commission                    5, XL
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                                28, I
  Drug Enforcement Administration                 21, II
  Federal Acquisition Regulation                  48, 28
  Federal Claims Collection Standards             4, II
  Federal Prison Industries, Inc.                 28, III
  Foreign Claims Settlement Commission of the     45, V
       United States
  Immigration and Naturalization Service          8, I
  Offices of Independent Counsel                  28, VI
  Prisons, Bureau of                              28, V
  Property Management Regulations                 41, 128
Labor Department
  Benefits Review Board                           20, VII
  Employees' Compensation Appeals Board           20, IV
  Employment and Training Administration          20, V
  Employment Standards Administration             20, VI
  Federal Acquisition Regulation                  48, 29
  Federal Contract Compliance Programs, Office    41, 60
       of
  Federal Procurement Regulations System          41, 50
  Labor-Management Relations and Cooperative      29, II
       Programs, Bureau of
  Labor-Management Programs, Office of            29, IV
  Mine Safety and Health Administration           30, I
  Occupational Safety and Health Administration   29, XVII
  Pension and Welfare Benefits Administration     29, XXV
  Public Contracts                                41, 50
  Secretary of Labor, Office of                   29, Subtitle A
  Veterans' Employment and Training, Office of    41, 61; 20, IX
       the Assistant Secretary for
  Wage and Hour Division                          29, V
  Workers' Compensation Programs, Office of       20, I
Labor-Management Relations and Cooperative        29, II
     Programs, Bureau of
Labor-Management Programs, Office of              29, IV
Land Management, Bureau of                        43, II
Legal Services Corporation                        45, XVI
Library of Congress                               36, VII

[[Page 229]]

  Copyright Office                                37, II
Management and Budget, Office of                  5, III, LXXVII; 48, 99
Marine Mammal Commission                          50, V
Maritime Administration                           46, II
Merit Systems Protection Board                    5, II
Micronesian Status Negotiations, Office for       32, XXVII
Mine Safety and Health Administration             30, I
Minerals Management Service                       30, II
Mines, Bureau of                                  30, VI
Minority Business Development Agency              15, XIV
Miscellaneous Agencies                            1, IV
Monetary Offices                                  31, I
National Aeronautics and Space Administration     5, LIX; 14, V
  Federal Acquisition Regulation                  48, 18
National Agricultural Library                     7, XLI
National Agricultural Statistics Service          7, XXXVI
National Archives and Records Administration      36, XII
  Information Security Oversight Office           32, XX
National Bureau of Standards                      15, II
National Capital Planning Commission              1, IV
National Commission for Employment Policy         1, IV
National Commission on Libraries and Information  45, XVII
     Science
National and Community Service, Corporation for   45, XXV
National Council on Disability                    34, XII
National Credit Union Administration              12, VII
National Drug Control Policy, Office of           21, III
National Foundation on the Arts and the           45, XI
     Humanities
National Highway Traffic Safety Administration    23, II, III; 49, V
National Indian Gaming Commission                 25, III
National Institute for Literacy                   34, XI
National Institute of Standards and Technology    15, II
National Labor Relations Board                    29, I
National Marine Fisheries Service                 50, II, IV
National Mediation Board                          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                       45, VI
  Federal Acquisition Regulation                  48, 25
National Security Council                         32, XXI
National Security Council and Office of Science   47, II
     and Technology Policy
National Telecommunications and Information       15, XXIII; 47, III
     Administration
National Transportation Safety Board              49, VIII
National Weather Service                          15, IX
Natural Resources Conservation Service            7, VI
Navajo and Hopi Indian Relocation, Office of      25, IV
Navy Department                                   32, VI
  Federal Acquisition Regulation                  48, 52
Neighborhood Reinvestment Corporation             24, XXV
Nuclear Regulatory Commission                     5, XLVIII; 10, I
  Federal Acquisition Regulation                  48, 20
Occupational Safety and Health Administration     29, XVII
Occupational Safety and Health Review Commission  29, XX
Offices of Independent Counsel                    28, VI
Operations Office                                 7, XXVIII
Overseas Private Investment Corporation           5, XXXIII; 22, VII
Panama Canal Commission                           48, 35
Panama Canal Regulations                          35, I
Patent and Trademark Office                       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                                       22, III
Pennsylvania Avenue Development Corporation       36, IX

[[Page 230]]

Pension and Welfare Benefits Administration       29, XXV
Pension Benefit Guaranty Corporation              29, XXVI
Personnel Management, Office of                   5, I; 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
Postal Rate 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 Commission on the Assignment of      32, XXIX
     Women in the Armed Forces
Presidential Documents                            3
Prisons, Bureau of                                28, V
Productivity, Technology and Innovation,          37, IV
     Assistant Secretary
Public Contracts, Department of Labor             41, 50
Public and Indian Housing, Office of Assistant    24, IX
     Secretary for
Public Health Service                             42, I
Railroad Retirement Board                         20, II
Reclamation, Bureau of                            43, I
Refugee Resettlement, Office of                   45, IV
Regional Action Planning Commissions              13, V
Relocation Allowances                             41, 302
Research and Special Programs Administration      49, I
Rural Business-Cooperative Service                7, XVIII, XLII
Rural Development Administration                  7, XLII
Rural Housing Service                             7, XVIII
Rural Telephone Bank                              7, XVI
Rural Utilities Service                           7, XVII, XVIII, XLII
Saint Lawrence Seaway Development Corporation     33, IV; 46, III
Science and Technology Policy, Office of          32, XXIV
Science and Technology Policy, Office of, and     47, II
     National Security Council
Secret Service                                    31, IV
Securities and Exchange Commission                17, II
Selective Service System                          32, XVI
Small Business Administration                     13, I
  Federal Acquisition Regulation                  48, 22
Smithsonian Institution                           36, V
Social Security Administration                    20, III
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                                  22, I
  Federal Acquisition Regulation                  48, 6
Surface Mining and Reclamation Appeals, Board of  30, III
Surface Mining Reclamation and Enforcement,       30, VII
     Office of
Surface Transportation Board                      49, X
Susquehanna River Basin Commission                18, VIII
Technology Administration                         15, XI
Technology Policy, Assistant Secretary for        37, IV
Technology, Under Secretary for                   37, V
Tennessee Valley Authority                        18, XIII
Thrift Depositor Protection Oversight Board       12, XV
Thrift Supervision Office, Department of the      12, V
     Treasury
Trade Representative, United States, Office of    15, XX
Transportation, Department of
  Coast Guard                                     33, I; 46, I; 49, IV
  Commercial Space Transportation, Office of      14, III
  Contract Appeals, Board of                      48, 63
  Emergency Management and Assistance             44, IV
  Federal Acquisition Regulation                  48, 12
  Federal Aviation Administration                 14, I
  Federal Highway Administration                  23, I, II; 49, III
  Federal Railroad Administration                 49, II

[[Page 231]]

  Federal Transit Administration                  49, VI
  Maritime Administration                         46, II
  National Highway Traffic Safety Administration  23, II, III; 49, V
  Research and Special Programs Administration    49, I
  Saint Lawrence Seaway Development Corporation   33, IV; 46, III
  Secretary of Transportation, Office of          14, II; 49, Subtitle A
  Surface Transportation Board                    49, X
Transportation, Office of                         7, XXXIII
Travel Allowances                                 41, 301
Travel and Tourism Administration, United States  15, XII
Treasury Department                               5, XXI; 17, IV
  Alcohol, Tobacco and Firearms, Bureau of        27, I
  Community Development Financial Institutions    12, XVIII
       Fund
  Comptroller of the Currency                     12, I
  Customs Service, United States                  19, I
  Engraving and Printing, Bureau of               31, VI
  Federal Acquisition Regulation                  48, 10
  Federal Law Enforcement Training Center         31, VII
  Fiscal Service                                  31, II
  Foreign Assets Control, Office of               31, V
  Internal Revenue Service                        26, I
  International Investment, Office of             31, VIII
  Monetary Offices                                31, I
  Secret Service                                  31, IV
  Secretary of the Treasury, Office of            31, Subtitle A
  Thrift Supervision, Office of                   12, V
Truman, Harry S. Scholarship Foundation           45, XVIII
United States and Canada, International Joint     22, IV
     Commission
United States and Mexico, International Boundary  22, XI
     and Water Commission, United States Section
United States Enrichment Corporation              10, XI
Utah Reclamation Mitigation and Conservation      43, III
     Commission
Veterans Affairs Department                       38, I
  Federal Acquisition Regulation                  48, 8
Veterans' Employment and Training, Office of the  41, 61; 20, IX
     Assistant Secretary for
Vice President of the United States, Office of    32, XXVIII
Vocational and Adult Education, Office of         34, IV
Wage and Hour Division                            29, V
Water Resources Council                           18, VI
Workers' Compensation Programs, Office of         20, I
World Agricultural Outlook Board                  7, XXXVIII

[[Page 233]]





List of CFR Sections Affected


All changes in this volume of the Code of Federal Regulations which were 
made by documents published in the Federal Register since January 1, 
1986, 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 and parts as well as 
sections for revisions.
For the period before January 1, 1986, see the ``List of CFR Sections 
Affected, 1943-1963, 1964-1972, and 1973-1985'' published in seven 
separate volumes.

                                  1986

21 CFR
                                                                   51 FR
                                                                    Page
Chapter I
Mandatory compliance date 1-1-89...................................34085
601  Authority citation revised....................................15607
601.25  (d)(2) amended.............................................15607
610  Authority citation revised...............15607, 37450, 44453, 44906
610.9  (b) amended.................................................15607
610.11  Introductory text, (c) introductory text, (2), and (3) 
        amended....................................................15607
610.12  (a)(1)(i), (e)(2), (f), and (g) (2) and (8) revised; (h) 
        added......................................................44906
610.15  (a) introductory text amended..............................15607
610.18  (c) and (d) added; OMB number..............................44453
610.40  (b)(4), (d)(1)(v) and (2)(iv) amended......................15607
610.53  (c) table revised..........................................15607
    (c) table corrected............................................19750
    (c) table amended..............................................37450
620  Authority citation revised....................................15610
620.6  (h) amended.................................................15610
620.12  Introductory text amended..................................15610
620.14  (c) introductory text amended..............................15610
620.24  (c) introductory text amended..............................15610
620.35  (e) introductory text amended..............................15610
620.43  Amended....................................................15610
620.48  (a) introductory text and (2) amended......................15610
630  Authority citation revised....................................15610
630.5  (c) introductory text amended...............................15610
    (c) introductory text corrected................................18580
630.10  (a) revised................................................44454
630.12  (b) revised................................................44454
630.13  (b)(1) revised; (c) removed................................44454
630.16  (a)(6) amended.............................................15610
630.17  (e) introductory text amended..............................15610
630.36  (h) introductory text amended..............................15610
630.56  (f) introductory text amended..............................15610
630.66  (e) introductory text amended..............................15610
630.75  (d) introductory text amended..............................15610
630.86  (e) introductory text amended..............................15611
640.1  Amendments at 50 FR 4138 effective date deferred to 9-2-86 
                                                                    3773
640.3  (b) introductory text, (c) introductory text, (d), and (e) 
        amended....................................................15611

[[Page 234]]

640.10  Amendments at 50 FR 4138 effective date deferred to 9-2-86
                                                                    3773
640.20  Amendments at 50 FR 4139 effective date deferred to 9-2-86
                                                                    3773
640.30  Amendments at 50 FR 4139 effective date deferred to 9-2-86
                                                                    3773
640.50  Amendments at 50 FR 4139 effective date deferred to 9-2-86
                                                                    3773
640.101  (f) introductory text amended.............................15611
640.111  (g) introductory text amended.............................15611
650  Authority citation revised....................................15611
650.11  (c) introductory text amended..............................15611
660  Authority citation revised....................................15611
660.6  (a)(2) amended..............................................15611
660.22  Amended....................................................15611
660.29  (a) introductory text amended..............................15611
660.30--660.36 (Subpart D)  Revised; effective in part 10-7-88.....37450
660.36  (a) introductory text amended..............................15611
660.42  Amended....................................................15611
660.46  (a)(2) amended.............................................15611
660.52  Amended....................................................15611
660.53  Amended....................................................15611
660.54  Introductory text amended..................................15611
660.101  Introductory text amended.................................15611
660.102  Introductory text amended.................................39637
660.103  (f)(1) revised............................................39637
660.105  (a) introductory text amended.............................15611
    (a)(1) revised.................................................39637
680  Authority citation revised....................................15611
680.3  (e) and (f) added; OMB number...............................37607
680.4  (c)(1) introductory text amended............................15611
    Removed........................................................37607
680.21  Amended....................................................15611
680.26  Amended....................................................15611
720  Authority citation revised....................................11444
720.8  Revised.....................................................11444
730  Authority citation revised; section authority citations 
        removed....................................................25687
730.2  Revised.....................................................25687
730.3  Revised.....................................................25687
730.4  (a)(1) revised..............................................25687
740  Authority citation revised....................................20475
740.17  Revised; eff. 6-5-87.......................................20475

                                  1987

21 CFR
                                                                   52 FR
                                                                    Page
Chapter I
610  Authority citation revised....................................37450
610.53  (c) table amended..........................................37450
660.30-660.36 (Subpart D) Revised; eff. in part 10-7-88............37450
660.102  Introductory text amended.................................39637
660.103  (f)(1) revised............................................39637
660.105  (a)(1) revised............................................39637
680.3  (e) and (f) added; OMB number...............................37607
680.4  Removed.....................................................37607

                                  1988

21 CFR
                                                                   53 FR
                                                                    Page
Chapter I
Uniform compliance date 1-1-91.....................................44861
606  Authority citation revised......................................116
606.121  (h) revised.................................................116
606.122  (e) revised.................................................116
610  Authority citation revised......................................116
610.12  (g)(4)(i) revised..........................................12764
610.45  Added........................................................116
610.53  (c) table amended..........................................12764
640  Authority citation revised......................................116
640.2  (f) revised; OMB number.......................................116
640.5  (f) added.....................................................117
    (b) and (c) amended............................................12764
640.14  Revised......................................................117
640.23  (a) revised..................................................117
640.33  (a) revised..................................................117

[[Page 235]]

640.53  (a) revised..................................................117
640.67  Revised......................................................117
640.70  (a)(11) added................................................117
640.71  (a)(4) added.................................................117
640.72  (a)(2) revised; OMB number...................................117
660.20--660.28 (Subpart C)  Revised; eff. in part 4-19-89..........12764
660.29  Removed....................................................12764

                                  1989

21 CFR
                                                                   54 FR
                                                                    Page
Chapter I
600  Authority citation revised; sectional authority citations 
        removed....................................................39639
601  Authority citation revised; sectional and subpart authority 
        citations removed..........................................39639
606  Authority citation revised.............................24707, 39639
607  Authority citation revised....................................39639
610  Authority citation revised; sectional authority citations 
        removed....................................................39639
620  Authority citation revised; sectional authority citations 
        removed....................................................39639
630  Authority citation revised; sectional authority citations 
        removed....................................................39639
640  Authority citation revised; sectional authority citations 
        removed....................................................39639
650  Authority citation revised; sectional authority citations 
        removed....................................................39640
660  Authority citation revised; sectional and subpart authority 
        citations removed..........................................39640
680  Authority citation revised; sectional authority citations 
        removed....................................................39640
700  Authority citation revised....................................27342
    Authority citation revised; sectional authority citations 
removed............................................................39640
700.19  Added......................................................27342
701  Authority citation revised; sectional authority citations 
        removed....................................................39640
701.3  (c)(2)(iv) amended..........................................24900
710  Authority citation revised....................................39640
710.4  Authority citation removed..................................39640
720  Authority citation revised....................................39640
730  Authority citation revised....................................39640
740  Authority citation revised....................................39640
740.11  Authority citation removed.................................39640

                                  1990

21 CFR
                                                                   55 FR
                                                                    Page
Chapter I
Uniform compliance date 1-1-93.......................................276
600.3  (d) revised.................................................11014
600.10  (a) nomenclature change....................................11014
600.11  (f)(6) nomenclature change.................................11013
600.12  (b)(2) and (3) nomenclature change.........................11013
600.13  Nomenclature change........................................11013
600.14  (a) amended................................................11014
600.15  (b) nomenclature change....................................11013
600.22  (e) nomenclature change....................................11013
601.2  (a) nomenclature change.....................................11013
    (b) amended....................................................11014
601.3  (a) introductory text and (b) introductory text 
        nomenclature change........................................11013
601.4  (a) nomenclature change.....................................11013
601.6  (a)(2) nomenclature change..................................11013
601.9  (a) nomenclature change.....................................11013
601.12  (a) and (b) nomenclature change............................11013
601.21  Amended....................................................11014
601.25  (b)(2) amended.............................................11014
601.31  Nomenclature change........................................11013
601.33  Nomenclature change........................................11013
601.51  (b) nomenclature change....................................11013
606.20  (a) nomenclature change....................................11014

[[Page 236]]

606.100  (a) and (d)(3) nomenclature change........................11013
606.110  (b) nomenclature change...................................11013
606.121  (c)(13), (d) introductory text, (4), and (5) nomenclature 
        change.....................................................11014
606.170  (b) nomenclature change...................................11014
607.3  (e) nomenclature change.....................................11014
607.7  (b) and (c) nomenclature change.............................11014
607.22  (a) and (b) nomenclature change............................11014
607.25  (b)(2) nomenclature change.................................11013
607.37  (a) introductory text and (b) amended......................11014
607.40  (b) nomenclature change....................................11014
610.2  (a) nomenclature change.....................................11013
    (b) amended....................................................11014
610.9  (b) nomenclature change.....................................11014
610.11  (c)(2) and (3) nomenclature change.........................11013
610.12  (e)(2)(i) and (g)(4)(ii) nomenclature change...............11013
610.13  (a) revised; OMB control number............................28381
610.15  (a)(3) nomenclature change.................................11013
610.18  (c)(2) nomenclature change.................................11013
610.20  Introductory text nomenclature change......................11013
610.40  (a) and (e)(2) nomenclature change.........................11013
    (b)(4), (d)(1)(v) and (2)(iv) amended..........................11014
610.53  (d) nomenclature change....................................11014
610.61  (s) removed; (t) redesignated as (s).......................10423
    Technical correction...........................................14037
620.6  (h) introductory text nomenclature change...................11013
620.12  Introductory text amended..................................11015
620.13  (h) nomenclature change....................................11013
620.14  (c)(2) and (3) nomenclature change.........................11013
    (c) introductory text amended..................................11015
620.21  (b) nomenclature change....................................11013
620.22  Nomenclature change........................................11013
620.24  (c) introductory text, (1), and (3) nomenclature change....11013
620.31  (a)(1) nomenclature change.................................11013
620.32  Introductory text nomenclature change......................11013
620.35  (e) introductory text, (2), and (3) nomenclature change....11013
620.43  Nomenclature change........................................11013
620.44  (c) nomenclature change....................................11013
620.45  (b) introductory text, (1), (4), and (5) nomenclature 
        change.....................................................11013
620.48  (a) introductory text, (a)(2) and (b) nomenclature change 
                                                                   11013
630  Authority citation revised....................................47875
    Technical correction...........................................50279
630.1  (b) and (c) nomenclature change.............................11013
630.2  (c) nomenclature change.....................................11013
630.3  Introductory text and (a) nomenclature change...............11013
630.4  (e)(1) and (3) nomenclature change..........................11013
630.5  (c) introductory text and (4) nomenclature change...........11013
630.10  (a), (b)(2), (4), (5), and (6) nomenclature change.........11013
630.12  (a)(1) and (b) nomenclature change.........................11013
630.14  Nomenclature change........................................11013
630.17  (e) introductory text and (1) nomenclature change..........11013
630.30  (c)(1)(iii) nomenclature change............................11013
    (c)(1) introductory text revised...............................47875
630.31  Revised....................................................47875
630.33  Nomenclature change........................................11013
630.36  (h) introductory text and (1)(i) nomenclature change.......11013
630.50  (c)(1)(ii) nomenclature change.............................11013

[[Page 237]]

    (c)(1) introductory text revised...............................47875
630.53  Nomenclature change........................................11013
630.55  (a)(4) revised.............................................47876
630.56  (f) introductory text and (1) nomenclature change..........11013
630.60  (d)(3) and (e)(1)(ii) nomenclature change..................11013
    (e)(1) introductory text revised...............................47876
630.62  (a) revised................................................47876
630.63  Nomenclature change........................................11013
630.66  (e) introductory text, (1)(i), and (3) nomenclature change
                                                                   11013
630.70  (b) nomenclature change....................................11013
630.72  Nomenclature change........................................11013
630.74  (c) nomenclature change....................................11013
630.75  (d)(1), (i) and (2) nomenclature change....................11013
630.80--630.86 (Subpart I)  Removed................................47876
630.81  Nomenclature change........................................11013
630.83  Nomenclature change........................................11013
630.86  (e) introductory text, (1)(i), and (3) nomenclature change
                                                                   11013
640.2  (a) nomenclature change.....................................11013
640.3  (a)(1) nomenclature change..................................11013
640.4  (a)(1) nomenclature change..................................11013
640.6  Introductory text nomenclature change.......................11013
640.17  Nomenclature change........................................11013
640.21  (c) nomenclature change....................................11013
640.22  (c) nomenclature change....................................11013
640.25  (c) introductory text and (3) nomenclature change..........11013
640.55  Nomenclature change........................................11013
640.56  (c) introductory text and (2) nomenclature change..........11013
640.64  (c) introductory text nomenclature change..................11013
640.66  Nomenclature change........................................11013
640.71  (b)(3) nomenclature change.................................11013
640.73  Nomenclature change........................................11013
640.74  (a) and (b)(2) nomenclature change.........................11013
640.75  Removed....................................................10423
    Technical correction...........................................14037
640.82  (b) nomenclature change....................................11013
640.92  (b) nomenclature change....................................11013
640.101  (f) introductory text nomenclature change.................11013
640.104  (c) introductory text nomenclature change.................11013
640.111  (g) introductory text nomenclature change.................11013
640.112  (b) nomenclature change...................................11013
640.120 (Subpart L)  Added.........................................10423
    Technical correction...........................................14037
650.6  Introductory text, (a), and (c) nomenclature change.........11013
650.11  (c) introductory text, (1), and (5) nomenclature change....11013
660.3  Nomenclature change.........................................11013
660.5  Nomenclature change.........................................11013
660.6  (a)(2) introductory text and (iii), (b), (c)(1), (2), and 
        (3) nomenclature change....................................11013
660.33  Nomenclature change........................................11013
660.34  (d) nomenclature change....................................11013
660.36  (a)(1), (b), and (c) nomenclature change...................11013
    (a) introductory text amended..................................11015
660.42  Nomenclature change........................................11013
660.44  Nomenclature change........................................11013
660.46  (a)(2) introductory text and (iii), (b), (c)(1), (2), and 
        (3) nomenclature change....................................11013
    (a)(2)  Introductory text amended..............................11014
660.52  Amended....................................................11015
660.53  Nomenclature change........................................11014
660.54  Introductory text nomenclature change......................11014
660.55  (a)(3) nomenclature change.................................11014
660.101  Introductory text nomenclature change.....................11013
660.102  (b)(1) and (c)(7) nomenclature change.....................11013
660.103  (d) and (g)(2)(ii) nomenclature change....................11013
660.105  (a) introductory and (b) nomenclature change..............11013
680  Nomenclature change...........................................11014

[[Page 238]]

680.1  (b)(2)(iii), (3)(iv), (c), and (d)(1) nomenclature change 
                                                                   11014
680.3  (e) nomenclature change.....................................11013
680.11  Nomenclature change........................................11013
    Heading revised................................................11015
680.12  Nomenclature change........................................11013
680.21  Nomenclature change........................................11013
680.24  (e) nomenclature change....................................11013
680.26  Introductory text and (c) nomenclature change..............11013

                                  1991

21 CFR
                                                                   56 FR
                                                                    Page
Chapter I
620.1  Revised.....................................................63410
630.10--630.19 (Subpart B)  Revised................................21432
    Regulation at 56 FR 21432 effective date delayed in part.......23505
630.12  (a)(3) corrected...........................................27787
630.18  (a)(3) and (5) corrected...................................27787

                                  1992

21 CFR
                                                                   57 FR
                                                                    Page
Chapter I
601.40--601.46 (Subpart E)  Added..................................58959
    Technical correction...........................................61489
606.60  (c) amended................................................11263
    (c) corrected..................................................12862
606.121  (a) amended...............................................10814
610.41  Amended....................................................10814
620.1  Technical correction.........................................2135
630.4  (e)(3) amended..............................................10814
640.67  (a) amended................................................10814
720.1  Revised......................................................3129
720.2  Revised......................................................3129
720.3  Revised......................................................3129
720.4  (a) introductory text, (b) introductory text, (c)(13) 
        introductory text and (e) amended; (b)(5), (c)(12)(xi) and 
        (xii) removed; (c)(12)(iii), (iv), (v), (ix), (x) and (d) 
        revised; OMB number.........................................3129
720.5  Removed......................................................3130
    Technical correction............................................5210
720.6  Revised; OMB number..........................................3130
720.7  Revised......................................................3130
720.8  (a) amended..................................................3130
720.9  Revised......................................................3130

                                  1993

21 CFR
                                                                   57 FR
                                                                    Page
Chapter I
601  Technical correction...........................................4078
630.13  (b)(4) amended.............................................19609

                                  1994

21 CFR
                                                                   59 FR
                                                                    Page
Chapter I
600  Authority citation revised....................................54042
600.15  (b) amended................................................49351
600.80--600.90 (Subpart D)  Added..................................54042
606.65  (c) table amended..........................................23636
606.121  (c)(12)(i), (ii) and (iii) amended........................23636
610.9  (a) amended.................................................49351
610.11  Introductory text amended..................................49351
610.53  (d) amended................................................49351
630.10  (c)(3) amended.............................................49351
640.6  Introductory text amended...................................49351
640.21  (c) amended................................................49351
640.22  (c) amended................................................49351
640.64  (c) amended................................................49351
640.74  (a) amended................................................49351
660.28  (a)(1) table and (4) amended...............................23637

                                  1995

                       (No regulations published)

                                  1996

  (No regulations published from January 1, 1996 through April 1, 1996)

                                  1996

                  (Regulations published April 2, 1996)

21 CFR
                                                                   61 FR
                                                                    Page
730.3  Amended.....................................................14481

[[Page 239]]