[Title 21 CFR ]
[Code of Federal Regulations (annual edition) - April 1, 2003 Edition]
[From the U.S. Government Printing Office]



[[Page i]]



                    21


          Parts 600 to 799

                         Revised as of April 1, 2003

Food and Drugs





          Containing a codification of documents of general 
          applicability and future effect
          As of April 1, 2003
          With Ancillaries
          Published by
          Office of the Federal Register
          National Archives and Records
          Administration

A Special Edition of the Federal Register


                                      


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                     U.S. GOVERNMENT PRINTING OFFICE
                            WASHINGTON : 2003



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                            Table of Contents



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

  Title 21:
          Chapter I--Food and Drug Administration, Department 
          of Health and Human Services (Continued)                   3
  Finding Aids:
      Material Approved for Incorporation by Reference........     159
      Table of CFR Titles and Chapters........................     161
      Alphabetical List of Agencies Appearing in the CFR......     179
      List of CFR Sections Affected...........................     189



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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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                               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, 2003), 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.

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Many agencies have begun publishing numerous OMB control numbers as 
amendments 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, 2001, consult either the List of CFR Sections Affected, 1949-
1963, 1964-1972, 1973-1985, or 1986-2000, published in 11 separate 
volumes. For the period beginning January 1, 2001, 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) 741-6010.

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). 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.

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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 202-741-6000 
or write to the Director, Office of the Federal Register, National 
Archives and Records Administration, Washington, DC 20408 or e-mail 
info@fedreg.nara.gov.

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register. The NARA site also contains links to GPO Access.

                              Raymond A. Mosley,
                                    Director,
                          Office of the Federal Register.

April 1, 2003.



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                               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, 2003.

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[[Page 1]]



                        TITLE 21--FOOD AND DRUGS




                  (This book contains parts 600 to 799)

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

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

Cross References: Food Safety and Inspection Service, Department of 
  Agriculture: See 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.

  Alcohol and Tobacco Tax and Trade Bureau, 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)

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


  Editorial Note: For nomenclature changes to chapter I see 59 FR 14366, 
Mar. 28, 1994, and 66 FR 56035, Nov. 6, 2001.

                         SUBCHAPTER F--BIOLOGICS
Part                                                                Page
600             Biological products: general................           5
601             Licensing...................................          19
606             Current good manufacturing practice for 
                    blood and blood components..............          44
607             Establishment registration and product 
                    listing for manufacturers of human blood 
                    and blood products......................          56
610             General biological products standards.......          62
630             General requirements for blood, blood 
                    components, and blood derivatives.......          86
640             Additional standards for human blood and 
                    blood products..........................          87
660             Additional standards for diagnostic 
                    substances for laboratory tests.........         111
680             Additional standards for miscellaneous 
                    products................................         124
                         SUBCHAPTER G--COSMETICS
700             General.....................................         128
701             Cosmetic labeling...........................         134
710             Voluntary registration of cosmetic product 
                    establishments..........................         147
720             Voluntary filing of cosmetic product 
                    ingredient composition statements.......         148
740             Cosmetic product warning statements.........         152
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 biological product deviations by licenses 
          manufacturers.
600.15  Temperatures during shipment.

                   Subpart C--Establishment Inspection

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

               Subpart D--Reporting of Adverse Experiences

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

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371, 374; 
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 
containing some organic constituent or product other than a hormone or 
an

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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 or established in the 
biologics license application designed to insure the continued safety, 
purity, and potency of such products.
    (o) The word continued as applied to the safety, purity and potency 
of products is interpreted to apply to the dating period.
    (p) The word safety means the relative freedom from harmful effect 
to persons affected, directly or indirectly, by a product when prudently 
administered, taking into consideration the character of the product in 
relation to the condition of the recipient at the time.
    (q) The word sterility is interpreted to mean freedom from viable 
contaminating microorganisms, as determined by the tests 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; 
``Manufacturer'' also includes any legal person or entity who is an 
applicant for a license where the applicant assumes responsibility for 
compliance with the applicable product and establishment standards.
    (u) Manufacture means all steps in propagation or manufacture and 
preparation of products and includes but is not limited to filling, 
testing, labeling, packaging, and storage by the manufacturer.
    (v) Location includes all buildings, appurtenances, equipment and 
animals used, and personnel engaged by a manufacturer within a 
particular area designated by an address adequate for identification.
    (w) Establishment has the same meaning as ``facility'' in section 
351 of the Public Health Service Act and includes all locations.
    (x) Lot means that quantity of uniform material identified by the 
manufacturer as having been thoroughly mixed in a single vessel.
    (y) A filling refers to a group of final containers identical in all 
respects, which have been filled with the same product from the same 
bulk lot without any change that will affect the integrity of the 
filling assembly.

[[Page 7]]

    (z) Process refers to a manufacturing step that is performed on the 
product itself which may affect its safety, purity or potency, in 
contrast to such manufacturing steps which do not affect intrinsically 
the safety, purity or potency of the product.
    (aa) Selling agent or distributor means any person engaged in the 
unrestricted distribution, other than by sale at retail, of products 
subject to license.
    (bb) Container (referred to also as ``final container'') is the 
immediate unit, bottle, vial, ampule, tube, or other receptacle 
containing the product as distributed for sale, barter, or exchange.
    (cc) Package means the immediate carton, receptacle, or wrapper, 
including all labeling matter therein and thereon, and the contents of 
the one or more enclosed containers. If no package, as defined in the 
preceding sentence, is used, the container shall be deemed to be the 
package.
    (dd) Label means any written, printed, or graphic matter on the 
container or package or any such matter clearly visible through the 
immediate carton, receptacle, or wrapper.
    (ee) Radioactive biological product means a biological product which 
is labeled with a radionuclide or intended solely to be labeled with a 
radionuclide.
    (ff) Amendment is the submission of information to a pending license 
application or supplement, to revise or modify the application as 
originally submitted.
    (gg) Supplement is a request to the Director, Center for Biologics 
Evaluation and Research, to approve a change in an approved license 
application.
    (hh) Distributed means the biological product has left the control 
of the licensed manufacturer.
    (ii) Control means having responsibility for maintaining the 
continued safety, purity, and potency of the product and for compliance 
with applicable product and establishment standards, and for compliance 
with current good manufacturing practices.

[38 FR 32048, Nov. 20, 1973, as amended at 40 FR 31313, July 25, 1975; 
55 FR 11014, Mar. 26, 1990; 61 FR 24232, May 14, 1996; 62 FR 39901, July 
24, 1997; 64 FR 56449, Oct. 20, 1999; 65 FR 66634, Nov. 7, 2000]



                   Subpart B--Establishment Standards



Sec. 600.10  Personnel.

    (a) [Reserved]
    (b) Personnel. Personnel shall have capabilities commensurate with 
their assigned functions, a thorough understanding of the manufacturing 
operations which they perform, the necessary training and experience 
relating to individual products, and adequate information concerning the 
application of the pertinent provisions of this subchapter to their 
respective functions. Personnel shall include such professionally 
trained persons as are necessary to insure the competent performance of 
all manufacturing processes.
    (c) Restrictions on personnel--(1) Specific duties. Persons whose 
presence can affect adversely the safety and purity of a product shall 
be excluded from the room where the manufacture of a product is in 
progress.
    (2) Sterile operations. Personnel performing sterile operations 
shall wear clean or sterilized protective clothing and devices to the 
extent necessary to protect the product from contamination.
    (3) Pathogenic viruses and spore-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

[[Page 8]]

be replaced or covered by suitable laboratory clothing before entering a 
live vaccine processing unit. Persons caring for animals used in the 
manufacture of live vaccines shall be excluded from other animal 
quarters and from contact with other animals during the same working 
day.

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



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.

[[Page 9]]

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 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

[[Page 10]]

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 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

[[Page 11]]

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, 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

[[Page 12]]

prepared to a physician's prescription. Samples so retained shall be 
selected at random from either final container material, or from bulk 
and final containers, provided they include at least one final container 
as a final package, or package-equivalent of such filling of each lot of 
the product as intended for distribution. Such sample material shall be 
stored at temperatures and under conditions which will maintain the 
identity and integrity of the product. Samples retained as required in 
this section shall be in addition to samples of specific products 
required to be submitted to the Center for Biologics Evaluation and 
Research. 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 biological product deviations by licensed manufacturers.

    (a) Who must report under this section? (1) You, the manufacturer 
who holds the biological product license and who had control over the 
product when the deviation occurred, must report under this section. If 
you arrange for another person to perform a manufacturing, holding, or 
distribution step, while the product is in your control, that step is 
performed under your control. You must establish, maintain, and follow a 
procedure for receiving information from that person on all deviations, 
complaints, and adverse events concerning the affected product.
    (2) Exceptions:
    (i) Persons who manufacture only in vitro diagnostic products that 
are not subject to licensing under section 351 of the Public Health 
Service Act do not report biological product deviations for those 
products under this section but must report in accordance with part 803 
of this chapter;
    (ii) Persons who manufacture blood and blood components, including 
licensed manufacturers, unlicensed registered blood establishments, and 
transfusion services, do not report biological product deviations for 
those products under this section but must report under Sec. 606.171 of 
this chapter;
    (iii) Persons who manufacture Source Plasma or any other blood 
component and use that Source Plasma or any other blood component in the 
further manufacture of another licensed biological product must report:
    (A) Under Sec. 606.171 of this chapter, if a biological product 
deviation occurs during the manufacture of that Source Plasma or any 
other blood component; or
    (B) Under this section, if a biological product deviation occurs 
after the manufacture of that Source Plasma or any other blood 
component, and during manufacture of the licensed biological product.
    (b) What do I report under this section? You must report any event, 
and information relevant to the event, associated with the 
manufacturing, to include testing, processing, packing, labeling, or 
storage, or with the holding or distribution, of a licensed biological 
product, if that event meets all the following criteria:
    (1) Either:
    (i) Represents a deviation from current good manufacturing practice, 
applicable regulations, applicable standards, or established 
specifications that may affect the safety, purity, or potency of that 
product; or
    (ii) Represents an unexpected or unforeseeable event that may affect 
the safety, purity, or potency of that product; and
    (2) Occurs in your facility or another facility under contract with 
you; and
    (3) Involves a distributed biological product.
    (c) When do I report under this section? You should report a 
biological product deviation as soon as possible but you must report at 
a date not to exceed 45-calendar days from the date you, your agent, or 
another person who performs a manufacturing, holding, or distribution 
step under your control, acquire information reasonably suggesting that 
a reportable event has occurred.
    (d) How do I report under this section? You must report on Form FDA-
3486.
    (e) Where do I report under this section? You must send the 
completed

[[Page 13]]

Form FDA-3486 to the Director, Office of Compliance and Biologics 
Quality (HFM-600), Center for Biologics Evaluation and Research, 1401 
Rockville Pike, suite 200N, Rockville, MD 20852-1448, by either a paper 
or an electronic filing:
    (1) If you make a paper filing, you should identify on the envelope 
that a BPDR (biological product deviation report) is enclosed; or
    (2) If you make an electronic filing, you may submit the completed 
Form FDA-3486 electronically through CBER's website at www.fda.gov/cber.
    (f) How does this regulation affect other FDA regulations? This part 
supplements and does not supersede other provisions of the regulations 
in this chapter. All biological product deviations, whether or not they 
are required to be reported under this section, should be investigated 
in accordance with the applicable provisions of parts 211 and 820 of 
this chapter.

[65 FR 66634, Nov. 7, 2000]



Sec. 600.15  Temperatures during shipment.

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

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

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

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



                   Subpart C--Establishment Inspection



Sec. 600.20  Inspectors.

    Inspections shall be made by an officer of the Food and Drug 
Administration having special knowledge of the

[[Page 14]]

methods used in the manufacture and control of products and designated 
for such purposes by the Commissioner of Food and Drugs, or by any 
officer, agent, or employee of the Department of Health and Human 
Services specifically designated for such purpose by the Secretary.

[38 FR 32048, Nov. 20, 1973]



Sec. 600.21  Time of inspection.

    The inspection of an establishment for which a biologics license 
application is pending need not be made until the establishment is in 
operation and is manufacturing the complete product for which a 
biologics license is desired. 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; 64 
FR 56449, Oct. 20, 1999]



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. Any adverse event associated with the use of a 
biological product in humans, whether or not considered product related, 
including the following: An adverse event occurring in the course of the 
use of a biological product in professional practice; an adverse event 
occurring from overdose of the product whether accidental or 
intentional; an adverse event occurring from abuse of the product; an 
adverse event occurring from withdrawal of the product; and any failure 
of expected pharmacological action.
    Blood Component. As defined in Sec. 606.3(c) of this chapter.
    Disability. A substantial disruption of a person's ability to 
conduct normal life functions.
    Life-threatening adverse experience. Any adverse experience that 
places the

[[Page 15]]

patient, in the view of the initial reporter, at immediate risk of death 
from the adverse experience as it occurred, i.e., it does not include an 
adverse experience that, had it occurred in a more severe form, might 
have caused death.
    Serious adverse experience. Any adverse experience occurring at any 
dose that results in any of the following outcomes: Death, a life-
threatening adverse experience, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.
    Unexpected adverse experience: Any adverse experience that is not 
listed in the current labeling for the biological product. This includes 
events that may be symptomatically and pathophysiologically related to 
an event listed in the labeling, but differ from the event because of 
greater severity or specificity. For example, under this definition, 
hepatic necrosis would be unexpected (by virtue of greater severity) if 
the labeling only referred to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be 
unexpected (by virtue of greater specificity) if the labeling only 
listed cerebral vascular accidents. ``Unexpected,'' as used in this 
definition, refers to an adverse experience that has not been previously 
observed (i.e., included in the labeling) rather than from the 
perspective of such experience not being anticipated from the 
pharmacological properties of the pharmaceutical product.
    (b) Review of adverse experiences. Any person having a biologics 
license under Sec. 601.20 of this chapter 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. Licensed manufacturers 
are not required to resubmit to FDA adverse product experience reports 
forwarded to the licensed manufacturer by FDA; licensed manufacturers, 
however, must submit all followup information on such reports to FDA. 
Any person subject to the reporting requirements under paragraph (c) of 
this section shall also develop written procedures for the surveillance, 
receipt, evaluation, and reporting of postmarketing adverse experiences 
to FDA.
    (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)(i) Postmarketing 15-day ``Alert reports''. The licensed 
manufacturer shall report each adverse experience that is both serious 
and unexpected, whether foreign or domestic, as soon as possible but in 
no case later than 15 calendar days of initial receipt of the 
information by the licensed manufacturer.
    (ii) Postmarketing 15-day ``Alert reports''--followup. The licensed 
manufacturer shall promptly investigate all adverse experiences that are 
the subject of these postmarketing 15-day Alert reports and shall submit 
followup

[[Page 16]]

reports within 15 calendar days of receipt of new information or as 
requested by FDA. If additional information is not obtainable, records 
should be maintained of the unsuccessful steps taken to seek additional 
information. Postmarketing 15-day Alert reports and followups to them 
shall be submitted under separate cover.
    (iii) Submission of reports. The requirements of paragraphs 
(c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of 
postmarketing 15-day Alert reports, shall also apply to any person whose 
name appears on the label of a licensed biological product as a 
manufacturer, packer, distributor, shared manufacturer, joint 
manufacturer, or any other participant involved in divided 
manufacturing. To avoid unnecessary duplication in the submission to FDA 
of reports required by paragraphs (c)(1)(i) and (c)(1)(ii) of this 
section, obligations of persons other than the licensed manufacturer of 
the final biological product may be met by submission of all reports of 
serious adverse experiences to the licensed manufacturer of the final 
product. If a person elects to submit adverse experience reports to the 
licensed manufacturer of the final product rather than to FDA, the 
person shall submit each report to the licensed manufacturer of the 
final product within 5 calendar days of receipt of the report by the 
person, and the licensed manufacturer of the final product shall then 
comply with the requirements of this section. Under this circumstance, a 
person who elects to submit reports to the licensed manufacturer of the 
final product 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 of the final product;
    (B) The date the report was received by the person;
    (C) The date the report was submitted to the licensed manufacturer 
of the final product; and-
    (D) The name and address of the licensed manufacturer of the final 
product.
    (iv) Report identification. 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 biologics 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 biologics license) and each annual report 
within 60 days of the anniversary date of the issuance of the biologics 
license. Upon written notice, FDA may extend or reestablish the 
requirement that 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

[[Page 17]]

scientific literature, and from foreign marketing experience.
    (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.
    (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 paragraph (f)(3) of 
this section, the licensed manufacturer shall complete the reporting 
form designated by FDA for each report of an adverse experience (FDA 
Form 3500A, or, for vaccines, a VAERS form; foreign events including 
those associated with the use of vaccines, may be submitted either on an 
FDA Form 3500A or, if preferred, on a CIOMS I form).
    (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 experience that occurred in 
clinical trials if they were previously submitted as part of the 
biologics license application. If a report refers to more than one 
biological product marketed by a licensed manufacturer, the licensed 
manufacturer should submit the report to the biologics license 
application 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, hospitals, and 
geographical identifiers in

[[Page 18]]

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) Revocation of biologics 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 biologics license for such a product in accordance with the 
procedures of Sec. 601.5 of this chapter.
    (k) 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.
    (l) 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.

[59 FR 54042, Oct. 27, 1994, as amended at 62 FR 34168, June 25, 1997; 
62 FR 52252, Oct. 7, 1997; 63 FR 14612, Mar. 26, 1998; 64 FR 56449, Oct. 
20, 1999]



Sec. 600.81  Distribution reports.

    The licensed manufacturer shall submit information about the 
quantity of the product distributed under the biologics 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.

[59 FR 54042, Oct. 27, 1994, as amended at 64 FR 56449, Oct. 20, 1999]



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:

[[Page 19]]

    (1) An explanation why the licensed manufacturer's compliance with 
the requirement is unnecessary or cannot be achieved,
    (2) A description of an alternative submission that satisfies the 
purpose of the requirement, or
    (3) Other information justifying a waiver.
    (b) FDA may grant a waiver if it finds one of the following:
    (1) The 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.
601.2  Applications for biologics licenses; procedures for filing.
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 [Reserved]

                     Subpart C--Biologics Licensing

601.12  Changes to an approved application.
601.15  Foreign establishments and products: Samples for each 
          importation.
601.20  Biologics licenses; issuance and conditions.
601.21  Products under development.
601.22  Products in short supply; initial manufacturing at other than 
          licensed location.
601.25  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.
601.27  Pediatric studies.
601.28  Annual reports of postmarketing pediatric studies.
601.29  Guidance documents.

               Subpart D--Diagnostic Radiopharmaceuticals

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

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

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

                Subpart F--Confidentiality of Information

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

                    Subpart G--Postmarketing Studies

601.70  Annual progress reports of postmarketing studies.

 Subpart H--Approval of Biological Products When Human Efficacy Studies 
                       Are Not Ethical or Feasible

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

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

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

    Cross References: For U.S. Customs Service regulations relating to 
viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal 
Service regulations relating to the admissibility to the United States 
mails see parts 124 and 125 of the Domestic Mail

[[Page 20]]

Manual, that is incorporated by reference in 39 CFR part 111.



                      Subpart A--General Provisions



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

    (a) General. To obtain a biologics license under section 351 of the 
Public Health Service Act for any biological product, the manufacturer 
shall submit an application to the Director, Center for Biologics 
Evaluation and Research, on forms prescribed for such purposes, and 
shall submit data derived from nonclinical laboratory and clinical 
studies which demonstrate that the manufactured product meets prescribed 
requirements of safety, purity, and potency; with respect to each 
nonclinical laboratory study, either a statement that the study was 
conducted in compliance with the requirements set forth in part 58 of 
this chapter, or, if the study was not conducted in compliance with such 
regulations, a brief statement of the reason for the noncompliance; 
statements regarding each clinical investigation involving human 
subjects contained in the application, that it either was conducted in 
compliance with the requirements for institutional review set forth in 
part 56 of this chapter; or was not subject to such requirements in 
accordance with Sec. 56.104 or Sec. 56.105, and was conducted in 
compliance with requirements for informed consent set forth in part 50 
of this chapter. A full description of manufacturing methods; data 
establishing stability of the product through the dating period; 
sample(s) representative of the product for introduction or delivery for 
introduction into interstate commerce; summaries of results of tests 
performed on the lot(s) represented by the submitted sample(s); 
specimens of the labels, enclosures, and containers, and if applicable, 
any Medication Guide required under part 208 of this chapter proposed to 
be used for the product; and the address of each location involved in 
the manufacture of the biological product shall be listed in the 
biologics license application. The applicant shall also include a 
financial certification or disclosure statement(s) or both for clinical 
investigators as required by part 54 of this chapter. An application for 
a biologics license shall not be considered as filed until all pertinent 
information and data have been received from the manufacturer by the 
Center for Biologics Evaluation and Research. The applicant shall also 
include either a claim for categorical exclusion under Sec. 25.30 or 
Sec. 25.31 of this chapter or an environmental assessment under 
Sec. 25.40 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. The applicant, or 
the applicant's attorney, agent, or other authorized official shall sign 
the application. An application for any of the following specified 
categories of biological products subject to licensure shall be handled 
as set forth in paragraph (c) of this section:
    (1) Therapeutic DNA plasmid products;
    (2) Therapeutic synthetic peptide products of 40 or fewer amino 
acids;
    (3) Monoclonal antibody products for in vivo use; and
    (4) Therapeutic recombinant DNA-derived products.
    (b) Radioactive biological products. To obtain marketing approval 
for a radioactive biological product, as defined in Sec. 600.3(ee) of 
this chapter, the manufacturer of such product shall comply with the 
following:
    (1) An applicant for a radioactive coupled antibody, which means a 
product that consists of an antibody component coupled with a 
radionuclide component (or an antibody component intended solely to be 
coupled with a radionuclide) in which both components provide a 
pharmacological effect but the biological component determines the site 
of action, shall submit a biologics license application to the Director, 
Center for Biologics Evaluation and Research, Food and Drug 
Administration, except if, as determined by FDA, there are significant 
scientific issues associated with the radionuclide or other chemically 
synthesized component, in which case a new drug application shall be 
submitted to the Center for Drug Evaluation and Research, Food and Drug 
Administration;
    (2) An applicant for a radioactive biological product other than as 
described

[[Page 21]]

in paragraph (b)(1) of this section, shall submit a new drug application 
to the Center for Drug Evaluation and Research, Food and Drug 
Administration.
    (c)(1) To obtain marketing approval for a biological product subject 
to licensure which is a therapeutic DNA plasmid product, therapeutic 
synthetic peptide product of 40 or fewer amino acids, monoclonal 
antibody product for in vivo use, or therapeutic recombinant DNA-derived 
product, an applicant shall submit a biologics license application in 
accordance with paragraph (a) of this section except that the following 
sections in parts 600 through 680 of this chapter shall not be 
applicable to such products: Secs. 600.10(b) and (c), 600.11, 600.12, 
600.13, 610.11, 610.53, and 610.62 of this chapter.
    (2) To the extent that the requirements in this paragraph (c) 
conflict with other requirements in this subchapter (except for those 
products described in paragraph (b) of this section for which a new drug 
application is required), this paragraph (c) shall supersede other 
requirements.
    (d) Approval of a biologics license application or issuance of a 
biologics license shall constitute a determination that the 
establishment(s) and the product meet applicable requirements to ensure 
the continued safety, purity, and potency of such products. Applicable 
requirements for the maintenance of establishments for the manufacture 
of a product subject to this section shall include but not be limited to 
the good manufacturing practice requirements set forth in parts 210, 
211, 600, 606, and 820 of this chapter.
    (e) Any establishment and product license for a biological product 
issued under section 351 of the Public Health Service Act (42 U.S.C. 201 
et seq.) that has not been revoked or suspended as of December 20, 1999, 
shall constitute an approved biologics license application in effect 
under the same terms and conditions set forth in such product license 
and such portions of the establishment license relating to such product.

[64 FR 56450, Oct. 20, 1999]



Sec. 601.4  Issuance and denial of license.

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

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



Sec. 601.5  Revocation of license.

    (a) A biologics license shall be revoked upon application of the 
manufacturer giving notice of intention to discontinue the manufacture 
of all products manufactured under such license or to discontinue the 
manufacture of a particular product for which a license is held and 
waiving an opportunity for a hearing on the matter.
    (b)(1) The Commissioner shall notify the licensed manufacturer of 
the intention to revoke the biologics license, setting forth the grounds 
for, and offering an opportunity for a hearing on the proposed 
revocation if the Commissioner finds any of the following:
    (i) Authorized Food and Drug Administration employees after 
reasonable efforts have been unable to gain access to an establishment 
or a location for the purpose of carrying out the inspection required 
under Sec. 600.21 of this chapter,
    (ii) Manufacturing of products or of a product has been discontinued 
to an extent that a meaningful inspection or evaluation cannot be made,
    (iii) The manufacturer has failed to report a change as required by 
Sec. 601.12 of this chapter,
    (iv) The establishment or any location thereof, or the product for 
which the license has been issued, fails to conform to the applicable 
standards established in the license and in this

[[Page 22]]

chapter designed to ensure the continued safety, purity, and potency of 
the manufactured product,
    (v) The establishment or the manufacturing methods have been so 
changed as to require a new showing that the establishment or product 
meets the requirements established in this chapter in order to protect 
the public health, or
    (vi) The licensed product is not safe and effective for all of its 
intended uses or is misbranded with respect to any such use.
    (2) Except as provided in Sec. 601.6 of this chapter, or in cases 
involving willfulness, the notification required in this paragraph shall 
provide a reasonable period for the licensed manufacturer to demonstrate 
or achieve compliance with the requirements of this chapter, before 
proceedings will be instituted for the revocation of the license. If 
compliance is not demonstrated or achieved and the licensed manufacturer 
does not waive the opportunity for a hearing, the Commissioner shall 
issue a notice of opportunity for hearing on the matter under 
Sec. 12.21(b) of this chapter.

[64 FR 56451, Oct. 20, 1999]



Sec. 601.6   Suspension of license.

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

[64 FR 56451, Oct. 20, 1999]



Sec. 601.7  Procedure for hearings.

    (a) A notice of opportunity for hearing, notice of appearance and 
request for hearing, and grant or denial of hearing for a biological 
drug pursuant to this part, for which the exemption from the Federal 
Food, Drug, and Cosmetic Act in Sec. 310.4 of this chapter has been 
revoked, shall be subject to the provisions of Sec. 314.200 of this 
chapter except to the extent that the notice of opportunity for hearing 
on the matter issued pursuant to Sec. 12.21(b) of this chapter 
specifically provides otherwise.
    (b) Hearings pursuant to 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 requirements. A biologics license, previously 
suspended or revoked, may be reissued or reinstated upon a showing of 
compliance with requirements and upon such inspection and examination as 
may be considered necessary by the Director, Center for Biologics 
Evaluation and Research.
    (b) Exclusion of noncomplying location. A biologics license, 
excluding a location or locations that fail to comply with the 
requirements in this chapter, may be issued without further application 
and concurrently with the suspension or revocation of the license for 
noncompliance at the excluded location or locations.
    (c) Exclusion of noncomplying product(s). In the case of multiple 
products

[[Page 23]]

included under a single biologics license application, a biologics 
license may be issued, excluding the noncompliant product(s), without 
further application and concurrently with the suspension or revocation 
of the biologics license for a noncompliant product(s).

[64 FR 56451, Oct. 20, 1999]

Subpart B [Reserved]



                     Subpart C--Biologics Licensing



Sec. 601.12  Changes to an approved application.

    (a) General. As provided by this section, an applicant shall inform 
Food and Drug Administration (FDA) about each change in the product, 
production process, quality controls, equipment, facilities, responsible 
personnel, or labeling, established in the approved license 
application(s). Before distributing a product made using a change, an 
applicant shall demonstrate through appropriate validation and/or other 
clinical and/or non-clinical laboratory studies, the lack of adverse 
effect of the change on the identity, strength, quality, purity, or 
potency of the product as they may relate to the safety or effectiveness 
of the product.
    (b) Changes requiring supplement submission and approval prior to 
distribution of the product made using the change (major changes). (1) A 
supplement shall be submitted for any change in the product, production 
process, quality controls, equipment, facilities, or responsible 
personnel that has a substantial potential to have an adverse effect on 
the identity, strength, quality, purity, or potency of the product as 
they may relate to the safety or effectiveness of the product.
    (2) These changes include, but are not limited to:
    (i) Changes in the qualitative or quantitative formulation or other 
specifications as provided in the approved application or in the 
regulations;
    (ii) Changes requiring completion of an appropriate human study to 
demonstrate the equivalence of the identity, strength, quality, purity, 
or potency of the product as they may relate to the safety or 
effectiveness of the product;
    (iii) Changes in the virus or adventitious agent removal or 
inactivation method(s);
    (iv) Changes in the source material or cell line;
    (v) Establishment of a new master cell bank or seed; and
    (vi) Changes which may affect product sterility assurance, such as 
changes in product or component sterilization method(s), or an addition, 
deletion, or substitution of steps in an aseptic processing operation.
    (3) The applicant must obtain approval of the supplement from FDA 
prior to distribution of the product made using the change. Except for 
submissions under paragraph (e) of this section, the following shall be 
contained in the supplement:
    (i) A detailed description of the proposed change;
    (ii) The product(s) involved;
    (iii) The manufacturing site(s) or area(s) affected;
    (iv) A description of the methods used and studies performed to 
evaluate the effect of the change on the identity, strength, quality, 
purity, or potency of the product as they may relate to the safety or 
effectiveness of the product;
    (v) The data derived from such studies;
    (vi) Relevant validation protocols and data; and
    (vii) A reference list of relevant standard operating procedures 
(SOP's).
    (c) Changes requiring supplement submission at least 30 days prior 
to distribution of the product made using the change. (1) A supplement 
shall be submitted for any change in the product, production process, 
quality controls, equipment, facilities, or responsible personnel that 
has a moderate potential to have an adverse effect on the identity, 
strength, quality, purity, or potency of the product as they may relate 
to the safety or effectiveness of the product. The supplement shall be 
labeled ``Supplement--Changes Being Effected in 30 Days'' or, if 
applicable under paragraph (c)(5) of this section, ``Supplement--Changes 
Being Effected.''

[[Page 24]]

    (2) These changes include, but are not limited to:
    (i) Change in the site of testing from one facility to another;
    (ii) An increase or decrease in production scale during finishing 
steps that involves new or different equipment; and
    (iii) Replacement of equipment with that of similar, but not 
identical, design and operating principle that does not affect the 
process methodology or process operating parameters.
    (3) Pending approval of the supplement by FDA, and except as 
provided in paragraph (c)(5) of this section, distribution of the 
product made using the change may begin not less than 30 days after 
receipt of the supplement by FDA. The information listed in paragraph 
(b)(3)(i) through (b)(3)(vii) of this section shall be contained in the 
supplement.
    (4) If within 30 days following FDA's receipt of the supplement, FDA 
informs the applicant that either:
    (i) The change requires approval prior to distribution of the 
product in accordance with paragraph (b) of this section; or
    (ii) Any of the information required under paragraph (c)(3) of this 
section is missing; the applicant shall not distribute the product made 
using the change until FDA determines that compliance with this section 
is achieved.
    (5) In certain circumstances, FDA may determine that, based on 
experience with a particular type of change, the supplement for such 
change is usually complete and provides the proper information, and on 
particular assurances that the proposed change has been appropriately 
submitted, the product made using the change may be distributed 
immediately upon receipt of the supplement by FDA. These circumstances 
may include substantial similarity with a type of change regularly 
involving a ``Supplement--Changes Being Effected'' supplement or a 
situation in which the applicant presents evidence that the proposed 
change has been validated in accordance with an approved protocol for 
such change under paragraph (e) of this section.
    (d) Changes to be described in an annual report (minor changes). (1) 
Changes in the product, production process, quality controls, equipment, 
facilities, or responsible personnel that have a minimal potential to 
have an adverse effect on the identity, strength, quality, purity, or 
potency of the product as they may relate to the safety or effectiveness 
of the product shall be documented by the applicant in an annual report 
submitted each year within 60 days of the anniversary date of approval 
of the application. The Director, Center for Biologics Evaluation and 
Research, may approve a written request for an alternative date to 
combine annual reports for multiple approved applications into a single 
annual report submission.
    (2) These changes include, but are not limited to:
    (i) Any change made to comply with an official compendium that is 
consistent with FDA requirements;
    (ii) The deletion of an ingredient intended only to affect the color 
of the product except that a change intended only to affect Blood 
Grouping Reagents requires supplement submission and approval prior to 
distribution of the product made using the change in accordance with the 
requirements set forth in paragraph (b) of this section;
    (iii) An extension of an expiration date based upon full shelf-life 
data obtained from a protocol approved in the application;
    (iv) A change within the container and closure system for solid 
dosage forms, based upon a showing of equivalency to the approved system 
under a protocol approved in the application or published in an official 
compendium;
    (v) A change in the size of a container for a solid dosage form, 
without a change from one container and closure system to another;
    (vi) The addition by embossing, debossing, or engraving of a code 
imprint to a solid dosage form biological product other than a modified 
release dosage form, or a minor change in an existing code imprint; and
    (vii) The addition or deletion of an alternate analytical method.
    (3) The following information for each change shall be contained in 
the annual report:

[[Page 25]]

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

[[Page 26]]

    (4) Advertisements and promotional labeling. Advertisements and 
promotional labeling shall be submitted to the Center for Biologics 
Evaluation and Research in accordance with the requirements set forth in 
Sec. 314.81(b)(3)(i) of this chapter, except that Form FDA-2567 
(Transmittal of Labels and Circulars) or an equivalent form shall be 
used.
    (g) Failure to comply. In addition to other remedies available in 
law and regulations, in the event of repeated failure of the applicant 
to comply with this section, FDA may require that the applicant submit a 
supplement for any proposed change and obtain approval of the supplement 
by FDA prior to distribution of the product made using the change.
    (h) Administrative review. Under Sec. 10.75 of this chapter, an 
applicant may request internal FDA review of FDA employee decisions 
under this section.

[62 FR 39901, July 24, 1997, as amended at 63 FR 66399, Dec. 1, 1998. 
Redesignated at 65 FR 59718, Oct. 6, 2000.]



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

    Random samples of each importation, obtained by the District 
Director of Customs and forwarded to the Director, Center for Biologics 
Evaluation and Research, 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. Redesignated at 64 FR 26668, May 17, 1999. 
Further redesignated at 65 FR 59718, Oct. 6, 2000]



Sec. 601.20  Biologics licenses; issuance and conditions.

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

[64 FR 56451, Oct. 20, 1999]



Sec. 601.21  Products under development.

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

[[Page 27]]

Drug, and Cosmetic Act, as amended, and the regulations thereunder (21 
CFR parts 312 and 812).

[64 FR 56451, Oct. 20, 1999]



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

    A biologics license issued to a manufacturer and covering all 
locations of manufacture shall authorize persons other than such 
manufacturer to conduct at places other than such locations the initial, 
and partial manufacturing of a product for shipment solely to such 
manufacturer only to the extent that the names of such persons and 
places are registered with the Commissioner of Food and Drugs and it is 
found upon application of such manufacturer, that the product is in 
short supply due either to the peculiar growth requirements of the 
organism involved or to the scarcity of the animal required for 
manufacturing purposes, and such manufacturer has established with 
respect to such persons and places such procedures, inspections, tests 
or other arrangements as will ensure full compliance with the applicable 
regulations of this subchapter related to continued safety, purity, and 
potency. Such persons and places shall be subject to all regulations of 
this subchapter except Secs. 601.2 to 601.6, 601.9, 601.10, 601.20, 
601.21 to 601.33, and 610.60 to 610.65 of this chapter. For persons and 
places authorized under this section to conduct the initial and partial 
manufacturing of a product for shipment solely to a manufacturer of a 
product subject to licensure under Sec. 601.2(c), the following 
additional regulations shall not be applicable: Secs. 600.10(b) and (c), 
600.11, 600.12, 600.13, 610.11, and 610.53 of this chapter. Failure of 
such manufacturer to maintain such procedures, inspections, tests, or 
other arrangements, or failure of any person conducting such partial 
manufacturing to comply with applicable regulations shall constitute a 
ground for suspension or revocation of the authority conferred pursuant 
to this section on the same basis as provided in Secs. 601.6 to 601.8 
with respect to the suspension and the revocation of licenses.

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



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 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

[[Page 28]]

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.
    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.

[[Page 29]]

    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 licensed manufacturer, a statement 
signed by the authorized official of the licensed manufacturer shall be 
included, stating that to the best of his or her 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 licensed manufacturer, 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 available 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 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

[[Page 30]]

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 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

[[Page 31]]

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 biologics 
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; 62 FR 53538, Oct. 15, 1997; 64 FR 56452, Oct. 
20, 1999]



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 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

[[Page 32]]

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.
    (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 biologics 
license application 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

[[Page 33]]

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 licensed manufacturer for a 
biological product designated as requiring further study to justify 
continued marketing on an interim basis, under 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 
licensed manufacturer 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 biologics 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 biologics 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 biologics 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 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, as amended at 64 FR 56452, Oct. 20, 1999]



Sec. 601.27  Pediatric studies.

    (a) Required assessment. Except as provided in paragraphs (b), (c), 
and (d) of this section, each application for a new active ingredient, 
new indication, new dosage form, new dosing regimen, or new route of 
administration shall contain data that are adequate to assess the safety 
and effectiveness of the

[[Page 34]]

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

[[Page 35]]

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

[63 FR 66671, Dec. 2, 1998]



Sec. 601.28  Annual reports of postmarketing pediatric studies.

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

[65 FR 59718, Oct. 6, 2000, as amended at 65 FR 64618, Oct. 30, 2000]



Sec. 601.29  Guidance documents.

    (a) FDA has made available guidance documents under Sec. 10.115 of 
this chapter to help you comply with certain requirements of this part.
    (b) The Center for Biologics Evaluation and Research (CBER) 
maintains a list of guidance documents that apply to the center's 
regulations. The lists are maintained on the Internet and are published 
annually in the Federal Register. You may request a copy of the CBER 
list from the Office of Communication, Training, and Manufacturers 
Assistance (HFM-40), Center for Biologics Evaluation and Research, Food 
and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852-1448.

[65 FR 56480, Sept. 19, 2000]



               Subpart D--Diagnostic Radiopharmaceuticals

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



Sec. 601.30  Scope.

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

[[Page 36]]



Sec. 601.31  Definition.

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



Sec. 601.32  General factors relevant to safety and effectiveness.

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



Sec. 601.33  Indications.

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



Sec. 601.34  Evaluation of effectiveness.

    (a) The effectiveness of a diagnostic radiopharmaceutical is 
assessed by evaluating its ability to provide useful clinical 
information related to its proposed indications for use. The method of 
this evaluation varies depending upon the proposed indication(s) and may 
use one or more of the following criteria:
    (1) The claim of structure delineation is established by 
demonstrating in a defined clinical setting the ability to locate 
anatomical structures and to characterize their anatomy.
    (2) The claim of functional, physiological, or biochemical 
assessment is established by demonstrating in a defined clinical setting 
reliable measurement of function(s) or physiological, biochemical, or 
molecular process(es).
    (3) The claim of disease or pathology detection or assessment is 
established by demonstrating in a defined clinical setting that the 
diagnostic radiopharmaceutical has sufficient accuracy in identifying or 
characterizing the disease or pathology.
    (4) The claim of diagnostic or therapeutic patient management is 
established by demonstrating in a defined clinical setting that the test 
is useful in diagnostic or therapeutic patient management.
    (5) For a claim that does not fall within the indication categories 
identified in Sec. 601.33, the applicant or sponsor should consult FDA 
on how to establish the effectiveness of the diagnostic 
radiopharmaceutical for the claim.
    (b) The accuracy and usefulness of the diagnostic information is 
determined by comparison with a reliable assessment of actual clinical 
status. A reliable assessment of actual clinical status may be provided 
by a diagnostic standard or standards of demonstrated accuracy. In the 
absence of such diagnostic standard(s), the actual clinical status must 
be established in another manner, e.g., patient followup.



Sec. 601.35  Evaluation of safety.

    (a) Factors considered in the safety assessment of a diagnostic 
radiopharmaceutical include, among others, the following:
    (1) The radiation dose;
    (2) The pharmacology and toxicology of the radiopharmaceutical, 
including any radionuclide, carrier, or ligand;
    (3) The risks of an incorrect diagnostic determination;

[[Page 37]]

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



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

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



Sec. 601.40  Scope.

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



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

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

[[Page 38]]



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 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

[[Page 39]]

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 biologics licenses.

    (a) For purposes of this section the biological product file 
includes all data and information submitted with or incorporated by 
reference in any application for a biologics license, IND's incorporated 
into any such application, master files, and other related submissions. 
The availability for public disclosure of any record in the biological 
product file shall be handled in accordance with the provisions of this 
section.
    (b) The existence of a biological product file will not be disclosed 
by the Food and Drug Administration before a biologics license 
application has been approved unless it has previously been publicly 
disclosed or acknowledged. The Director of the Center for Biologics 
Evaluation and Research will maintain a list available for public 
disclosure of biological products for which a license application has 
been approved.
    (c) If the existence of a biological product file has not been 
publicly disclosed or acknowledged, no data or information in the 
biological product file is available for public disclosure.
    (d)(1) If the existence of a biological product file has been 
publicly disclosed or acknowledged before a license has been issued, no 
data or information contained in the file is available for public 
disclosure before such license is issued, but the Commissioner may, in 
his discretion, disclose a summary of such selected portions of the 
safety and effectiveness data as are appropriate for public 
consideration of a specific

[[Page 40]]

pending issue, e.g., at an open session of a Food and Drug 
Administration advisory committee or pursuant to an exchange of 
important regulatory information with a foreign government.
    (2) Notwithstanding paragraph (d)(1) of this section, FDA will make 
available to the public upon request the information in the IND that was 
required to be filed in Docket Number 95S-0158 in the Dockets Management 
Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 
1-23, Rockville, MD 20857, for investigations involving an exception 
from informed consent under Sec. 50.24 of this chapter. Persons wishing 
to request this information shall submit a request under the Freedom of 
Information Act.
    (e) After a license has been issued, the following data and 
information in the biological product file are immediately available for 
public disclosure unless extraordinary circumstances are shown:
    (1) All safety and effectiveness data and information.
    (2) A protocol for a test or study, unless it is shown to fall 
within the exemption established for trade secrets and confidential 
commercial or financial information in Sec. 20.61 of this chapter.
    (3) Adverse reaction reports, product experience reports, consumer 
complaints, and other similar data and information, after deletion of:
    (i) Names and any information that would identify the person using 
the product.
    (ii) Names and any information that would identify any third party 
involved with the report, such as a physician or hospital or other 
institution.
    (4) A list of all active ingredients and any inactive ingredients 
previously disclosed to the public, as defined in Sec. 20.81 of this 
chapter.
    (5) An assay method or other analytical method, unless it serves no 
regulatory or compliance purpose and it is shown to fall within the 
exemption established in Sec. 20.61 of this chapter.
    (6) All correspondence and written summaries of oral discussions 
relating to the biological product file, in accordance with the 
provisions of part 20 of this chapter.
    (7) All records showing the manufacturer's testing of a particular 
lot, after deletion of data or information that would show the volume of 
the drug produced, manufacturing procedures and controls, yield from raw 
materials, costs, or other material falling within Sec. 20.61 of this 
chapter.
    (8) All records showing the testing of and action on a particular 
lot by the Food and Drug Administration.
    (f) The following data and information in a biological product file 
are not available for public disclosure unless they have been previously 
disclosed to the public as defined in Sec. 20.81 of this chapter or they 
relate to a product or ingredient that has been abandoned and they no 
longer represent a trade secret or confidential commercial or financial 
information as defined in Sec. 20.61 of this chapter:
    (1) Manufacturing methods or processes, including quality control 
procedures.
    (2) Production, sales, distribution, and similar data and 
information, except that any compilation of such data and information 
aggregated and prepared in a way that does not reveal data or 
information which is not available for public disclosure under this 
provision is available for public disclosure.
    (3) Quantitative or semiquantitative formulas.
    (g) For purposes of this regulation, safety and effectiveness data 
include all studies and tests of a biological product on animals and 
humans and all studies and tests on the drug for identity, stability, 
purity, potency, and bioavailability.

[39 FR 44656, Dec. 24, 1974, as amended at 42 FR 15676, Mar. 22, 1977; 
49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 61 FR 51530, Oct. 
2, 1996; 64 FR 56452, Oct. 20, 1999]



                    Subpart G--Postmarketing Studies

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



Sec. 601.70  Annual progress reports of postmarketing studies.

    (a) General requirements. This section applies to all required 
postmarketing studies (e.g., accelerated approval clinical benefit 
studies, pediatric studies)

[[Page 41]]

and postmarketing studies that an applicant has committed, in writing, 
to conduct either at the time of approval of an application or a 
supplement to an application, or after approval of an application or a 
supplement. Postmarketing studies within the meaning of this section are 
those that concern:
    (1) Clinical safety;
    (2) Clinical efficacy;
    (3) Clinical pharmacology; and
    (4) Nonclinical toxicology.
    (b)What to report. Each applicant of a licensed biological product 
shall submit a report to FDA on the status of postmarketing studies for 
each approved product application. The status of these postmarketing 
studies shall be reported annually until FDA notifies the applicant, in 
writing, that the agency concurs with the applicant's determination that 
the study commitment has been fulfilled, or that the study is either no 
longer feasible or would no longer provide useful information. Each 
annual progress report shall be accompanied by a completed transmittal 
Form FDA-2252, and shall include all the information required under this 
section that the applicant received or otherwise obtained during the 
annual reporting interval which ends on the U.S. anniversary date. The 
report must provide the following information for each postmarketing 
study:
    (1) Applicant's name.
    (2) Product name. Include the approved product's proper name and the 
proprietary name, if any.
    (3) Biologics license application (BLA) and supplement number.
    (4) Date of U.S. approval of BLA.
    (5) Date of postmarketing study commitment.
    (6) Description of postmarketing study commitment. The description 
must include sufficient information to uniquely describe the study. This 
information may include the purpose of the study, the type of study, the 
patient population addressed by the study and the indication(s) and 
dosage(s) that are to be studied.
    (7) Schedule for completion and reporting of the postmarketing study 
commitment. The schedule should include the actual or projected dates 
for submission of the study protocol to FDA, completion of patient 
accrual or initiation of an animal study, completion of the study, 
submission of the final study report to FDA, and any additional 
milestones or submissions for which projected dates were specified as 
part of the commitment. In addition, it should include a revised 
schedule, as appropriate. If the schedule has been previously revised, 
provide both the original schedule and the most recent, previously 
submitted revision.
    (8) Current status of the postmarketing study commitment. The status 
of each postmarketing study should be categorized using one of the 
following terms that describes the study's status on the anniversary 
date of U.S. approval of the application or other agreed upon date:
    (i) Pending. The study has not been initiated, but does not meet the 
criterion for delayed.
    (ii) Ongoing. The study is proceeding according to or ahead of the 
original schedule described under paragraph (b)(7) of this section.
    (iii) Delayed. The study is behind the original schedule described 
under paragraph (b)(7) of this section.
    (iv) Terminated. The study was ended before completion but a final 
study report has not been submitted to FDA.
    (v) Submitted. The study has been completed or terminated and a 
final study report has been submitted to FDA.
    (9) Explanation of the study's status. Provide a brief description 
of the status of the study, including the patient accrual rate 
(expressed by providing the number of patients or subjects enrolled to 
date, and the total planned enrollment), and an explanation of the 
study's status identified under paragraph (b)(8) of this section. If the 
study has been completed, include the date the study was completed and 
the date the final study report was submitted to FDA, as applicable. 
Provide a revised schedule, as well as the reason(s) for the revision, 
if the schedule under paragraph (b)(7) of this section has changed since 
the previous report.
    (c) When to report. Annual progress reports for postmarketing study 
commitments entered into by applicants shall be reported to FDA within 
60 days

[[Page 42]]

of the anniversary date of the U.S. approval of the application for the 
product.
    (d) Where to report. Submit two copies of the annual progress report 
of postmarketing studies to the Food and Drug Administration, Center for 
Biologics Evaluations and Research, Document Control Center (HFM-99), 
1401 Rockville Pike, Rockville, MD 20852-1448.
    (e) Public disclosure of information. Except for the information 
described in this paragraph, FDA may publicly disclose any information 
concerning a postmarketing study, within the meaning of this section, if 
the agency determines that the information is necessary to identify an 
applicant or to establish the status of the study including the reasons, 
if any, for failure to conduct, complete, and report the study. Under 
this section, FDA will not publicly disclose trade secrets, as defined 
in Sec. 20.61 of this chapter, or information, described in Sec. 20.63 
of this chapter, the disclosure of which would constitute an unwarranted 
invasion of personal privacy.



 Subpart H--Approval of Biological Products When Human Efficacy Studies 
                       Are Not Ethical or Feasible

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



Sec. 601.90  Scope.

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



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

    (a) FDA may grant marketing approval for a biological product for 
which safety has been established and for which the requirements of 
Sec. 601.90 are met based on adequate and well-controlled animal studies 
when the results of those animal studies establish that the biological 
product is reasonably likely to produce clinical benefit in humans. In 
assessing the sufficiency of animal data, the agency may take into 
account other data, including human data, available to the agency. FDA 
will rely on the evidence from studies in animals to provide substantial 
evidence of the effectiveness of these products only when:
    (1) There is a reasonably well-understood pathophysiological 
mechanism of the toxicity of the substance and its prevention or 
substantial reduction by the product;
    (2) The effect is demonstrated in more than one animal species 
expected to react with a response predictive for humans, unless the 
effect is demonstrated in a single animal species that represents a 
sufficiently well-characterized animal model for predicting the response 
in humans;
    (3) The animal study endpoint is clearly related to the desired 
benefit in humans, generally the enhancement of survival or prevention 
of major morbidity; and
    (4) The data or information on the kinetics and pharmacodynamics of 
the product or other relevant data or information, in animals and 
humans, allows selection of an effective dose in humans.
    (b) Approval under this subpart will be subject to three 
requirements:
    (1) Postmarketing studies. The applicant must conduct postmarketing 
studies, such as field studies, to verify

[[Page 43]]

and describe the biological product's clinical benefit and to assess its 
safety when used as indicated when such studies are feasible and 
ethical. Such postmarketing studies would not be feasible until an 
exigency arises. When such studies are feasible, the applicant must 
conduct such studies with due diligence. Applicants must include as part 
of their application a plan or approach to postmarketing study 
commitments in the event such studies become ethical and feasible.
    (2) Approval with restrictions to ensure safe use. If FDA concludes 
that a biological product shown to be effective under this subpart can 
be safely used only if distribution or use is restricted, FDA will 
require such postmarketing restrictions as are needed to ensure safe use 
of the biological product, commensurate with the specific safety 
concerns presented by the biological product, such as:
    (i) Distribution restricted to certain facilities or health care 
practitioners with special training or experience;
    (ii) Distribution conditioned on the performance of specified 
medical procedures, including medical followup; and
    (iii) Distribution conditioned on specified recordkeeping 
requirements.
    (3) Information to be provided to patient recipients. For biological 
products or specific indications approved under this subpart, applicants 
must prepare, as part of their proposed labeling, labeling to be 
provided to patient recipients. The patient labeling must explain that, 
for ethical or feasibility reasons, the biological product's approval 
was based on efficacy studies conducted in animals alone and must give 
the biological product's indication(s), directions for use (dosage and 
administration), contraindications, a description of any reasonably 
foreseeable risks, adverse reactions, anticipated benefits, drug 
interactions, and any other relevant information required by FDA at the 
time of approval. The patient labeling must be available with the 
product to be provided to patients prior to administration or dispensing 
of the biological product for the use approved under this subpart, if 
possible.



Sec. 601.92  Withdrawal procedures.

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

[[Page 44]]

    (e) Procedures for hearings. Hearings held under this section will 
be conducted in accordance with the provisions of part 15 of this 
chapter, with the following modifications:
    (1) An advisory committee duly constituted under part 14 of this 
chapter will be present at the hearing. The committee will be asked to 
review the issues involved and to provide advice and recommendations to 
the Commissioner of Food and Drugs.
    (2) The presiding officer, the advisory committee members, up to 
three representatives of the applicant, and up to three representatives 
of CBER may question any person during or at the conclusion of the 
person's presentation. No other person attending the hearing may 
question a person making a presentation. The presiding officer may, as a 
matter of discretion, permit questions to be submitted to the presiding 
officer for response by a person making a presentation.
    (f) Judicial review. The Commissioner of Food and Drugs' decision 
constitutes final agency action from which the applicant may petition 
for judicial review. Before requesting an order from a court for a stay 
of action pending review, an applicant must first submit a petition for 
a stay of action under Sec. 10.35 of this chapter.



Sec. 601.93  Postmarketing safety reporting.

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



Sec. 601.94  Promotional materials.

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



601.95  Termination of requirements.

    If FDA determines after approval under this subpart that the 
requirements established in Secs. 601.91(b)(2), 601.92, and 601.93 are 
no longer necessary for the safe and effective use of a biological 
product, FDA will so notify the applicant. Ordinarily, for biological 
products approved under Sec. 601.91, these requirements will no longer 
apply when FDA determines that the postmarketing study verifies and 
describes the biological product's clinical benefit. For biological 
products approved under Sec. 601.91, the restrictions would no longer 
apply when FDA determines that safe use of the biological product can be 
ensured through appropriate labeling. FDA also retains the discretion to 
remove specific postapproval requirements upon review of a petition 
submitted by the sponsor in accordance with Sec. 10.30 of this chapter.



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




                      Subpart A--General Provisions

Sec.
606.3  Definitions.

                  Subpart B--Organization and Personnel

606.20  Personnel.

                     Subpart C--Plant and Facilities

606.40  Facilities.

                          Subpart D--Equipment

606.60  Equipment.
606.65  Supplies and reagents.

Subpart E [Reserved]

               Subpart F--Production and Process Controls

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

[[Page 45]]

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

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

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



                      Subpart A--General Provisions



Sec. 606.3  Definitions.

    As used in this part:
    (a) Blood means 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's blood separated by 
physical or mechanical means.
    (d) Plasma for further manufacturing means that liquid portion of 
blood separated and used as material to prepare another product.
    (e) Plasmapheresis means the procedure in which blood is removed 
from the donor, the plasma is separated from the formed elements and at 
least the red blood cells are returned to the donor.
    (f) Plateletpheresis means the procedure in which blood is removed 
from a donor, a platelet concentrate is separated, and the remaining 
formed elements are returned to the donor along with a portion of the 
residual plasma.
    (g) Leukapheresis means the procedure in which blood is removed from 
the donor, a leukocyte concentrate is separated, and the remaining 
formed elements and residual plasma are returned to the donor.
    (h) Facilities means any area used for the collection, processing, 
compatibility testing, storage or distribution of blood and blood 
components.
    (i) Processing means any procedure employed after collection and 
before 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 procedures performed to 
establish the matching of a donor's blood or blood components with that 
of a potential recipient.
    (k) Distributed means:
    (1) The blood or blood components have left the control of the 
licensed manufacturer, unlicensed registered blood establishment, or 
transfusion service; or
    (2) The licensed manufacturer has provided Source Plasma or any 
other blood component for use in the manufacture of a licensed 
biological product.
    (l) Control means having responsibility for maintaining the 
continued safety, purity, and potency of the product and for compliance 
with applicable product and establishment standards, and for compliance 
with current good manufacturing practices.

[40 FR 53532, Nov. 18, 1975, as amended at 64 FR 45370, Aug. 19, 1999; 
65 FR 66635, Nov. 7, 2000; 66 FR 1835, Jan. 10, 2001; 66 FR 40889, Aug. 
6, 2001]



                  Subpart B--Organization and Personnel



Sec. 606.20  Personnel.

    (a) [Reserved]
    (b) The personnel responsible for the collection, processing, 
compatibility testing, storage or distribution of blood or blood 
components shall be adequate in number, educational background, training 
and experience, including professional training as necessary, or 
combination thereof, to assure competent performance of their assigned 
functions, and to ensure that the final

[[Page 46]]

product has the safety, purity, potency, identity and effectiveness it 
purports or is represented to possess. All personnel shall have 
capabilities commensurate with their assigned functions, a thorough 
understanding of the procedures or control operations they perform, the 
necessary training or experience, and adequate information concerning 
the application of pertinent provisions of this part to their respective 
functions.
    (c) Persons whose presence can adversely affect the safety and 
purity of the products shall be excluded from areas where the 
collection, processing, compatibility testing, storage or distribution 
of blood or blood components is conducted.

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



                     Subpart C--Plant and Facilities



Sec. 606.40  Facilities.

    Facilities shall be maintained in a clean and orderly manner, and 
shall be of suitable size, construction and location to facilitate 
adequate cleaning, maintenance and proper operations. The facilities 
shall:
    (a) Provide adequate space for the following when applicable:
    (1) Private and accurate examinations of individuals to determine 
their 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 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.

[[Page 47]]

 
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.
    (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.

[[Page 48]]

    (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 transfusion and further manufacturing purposes. Such 
procedures shall be available to the personnel for use in the areas 
where the procedures are performed. 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 manufacturing.
    (8) Pretransfusion testing, where applicable, including precautions 
to be taken to identify accurately the recipient blood samples and 
crossmatched donor units.
    (9) Procedures for investigating adverse donor and recipient 
reactions.
    (10) Storage temperatures and methods of controlling storage 
temperatures for all blood products and reagents as prescribed in 
Secs. 600.15 and 610.53 of this chapter.
    (11) Length of expiration dates, if any, assigned for all final 
products as prescribed in Sec. 610.53 of this chapter.
    (12) Criteria for determining whether returned blood is suitable for 
reissue.
    (13) Procedures used for relating a unit of blood or blood component 
from the donor to its final disposition.
    (14) Quality control procedures for supplies and reagents employed 
in blood collection, processing and pretransfusion testing.
    (15) Schedules and procedures for equipment maintenance and 
calibration.
    (16) Labeling procedures, including safeguards to avoid labeling 
mixups.
    (17) Procedures of plasmapheresis, plateletpheresis, and 
leukapheresis, if performed, including precautions to be taken to ensure 
reinfusion of a donor's own cells.
    (18) Procedures for preparing recovered plasma, if performed, 
including details of separation, pooling, labeling, storage, and 
distribution.
    (19) Procedures in accordance with Sec. 610.46 of this chapter to 
look at prior donations of Whole Blood, blood components, Source Plasma 
and Source Leukocytes from a donor who has donated blood and 
subsequently tests repeatedly reactive for antibody to human 
immunodeficiency virus (HIV) or otherwise is determined to be unsuitable 
when tested in accordance with Sec. 610.45 of this chapter. Procedures 
to quarantine in-house Whole Blood, blood components, Source Plasma and

[[Page 49]]

Source Leukocytes intended for further manufacture into injectable 
products that were obtained from such donors; procedures to notify 
consignees regarding the need to quarantine such products; procedures to 
determine the suitability for release of such products from quarantine; 
procedures to notify consignees of Whole Blood, blood components, Source 
Plasma and Source Leukocytes from such donors of the results of the 
antibody testing of such donors; and procedures in accordance with 
Sec. 610.47 of this chapter to notify attending physicians so that 
transfusion recipients are informed that they may have received Whole 
Blood and, blood components at increased risk for transmitting human 
immunodeficiency virus.
    (20) Procedures for donor deferral as prescribed in Sec. 610.41 of 
this chapter; and procedures for donor notification and autologous donor 
referring physician notification, including procedures for the 
appropriate followup if the initial attempt at notification fails, as 
prescribed in Sec. 630.6 of this chapter.
    (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 organizations, as long 
as such specific procedures are consistent with, and at least as 
stringent as, the requirements contained in this part.
    (1) American Association of Blood Banks.
    (2) American National Red Cross.
    (3) Other organizations or individual blood banks, subject to 
approval by the Director, Center for Biologics Evaluation and Research.

[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55 
FR 11013, Mar. 26, 1990; 61 FR 47422, Sept. 9, 1996; 64 FR 45370, Aug. 
19, 1999; 66 FR 31176, June 11, 2001]



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.

[[Page 50]]

    (3) All necessary checks in labeling procedures shall be utilized to 
prevent errors in translating test results to container labels.
    (c) All labeling shall be clear and legible.

[50 FR 35469, Aug. 30, 1985]



Sec. 606.121  Container label.

    (a) The container label requirements are designed to facilitate the 
use of a uniform container label for blood and blood components (except 
Source Plasma) by all blood establishments.
    (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) ``Rx only.''
    (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:
    (1) The Rh blood group shall be printed as follows:
    (i) Rh positive: Use black print on white background.

[[Page 51]]

    (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 or in solid black.
    (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 approved for use by the 
Director, Center for Biologics Evaluation and Research.
    (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 as applicable: ``Caution: For Manufacturing Use 
Only''; or ``Caution: For Use in Manufacturing Noninjectable Products 
Only.'' If the recovered plasma has a reactive screening test for 
evidence of infection due to a communicable disease agent(s) under 
Sec. 610.40 of this chapter, or is collected from a donor with a 
previous record of a reactive screening test for evidence of infection 
due to a communicable disease agent(s) under Sec. 610.40 of this 
chapter, the recovered plasma must be labeled as required under 
Sec. 610.40(h)(2)(ii)(E) of this chapter.
    (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) [Reserved]
    (h) The following additional information shall appear on the label 
for blood or blood components shipped in an emergency, prior to 
completion of 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, and 640.5 
(a), (b), or (c) of this chapter completed before shipment.

[[Page 52]]

    (3) Indication of any tests prescribed under Secs. 610.40, 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; 63 FR 16685, Apr. 6, 1998; 64 FR 45371, Aug. 19, 1999; 66 FR 
31162, June 11, 2001; 67 FR 4907, Feb. 1, 2002]

    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 infectious 
agents is present. Careful donor selection and available laboratory 
tests do not eliminate the hazard.''
    (g) The names of cryoprotective agents and other additives that may 
still be present in the product.
    (h) The names and results of all tests performed when necessary for 
safe and effective use.
    (i) The use of the product, indications, contradications, side 
effects and hazards, dosage and administration recommendations.
    (j) [Reserved]
    (k) For Red Blood Cells, the 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:
    (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:

[[Page 53]]

    (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 between 30 and 37  deg.C.
    (5) Instructions to store at room temperature after thawing and to 
begin administration as soon as possible but no more than 4 hours after 
entering the container or after pooling and within 6 hours after 
thawing.
    (6) A statement that 0.9 percent Sodium Chloride Injection U.S.P. is 
the preferred diluent.
    (7) Adequate instructions for pooling to ensure complete removal of 
all concentrated material from each container.
    (8) The statement: ``Good patient management requires monitoring 
treatment responses to Cryoprecipitated AHF transfusions with periodic 
plasma factor VIII or fibrinogen assays in hemophilia A and 
hypofibrinogenemic recipients, respectively.''

[50 FR 35470, Aug. 30, 1985, as amended at 53 FR 116, Jan. 5, 1988; 64 
FR 45371, Aug. 19, 1999]

    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 or plasma samples less than 3 
days old for all pretransfusion testing if the recipient has been 
pregnant or transfused within the previous 3 months.
    (c) Procedures to demonstrate incompatibility between the donor's 
cell type and the recipient's serum or plasma type.
    (d) A provision that, if the unit of donor's blood has not been 
screened by a method that will demonstrate agglutinating, coating and 
hemolytic antibodies, the recipient's cells shall be tested with the 
donor's serum (minor crossmatch) by a method that will so demonstrate.
    (e) Procedures to expedite transfusion in life-threatening 
emergencies. Records of all such incidents shall be maintained, 
including complete documentation justifying the emergency action, which 
shall be signed by a physician.

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

[[Page 54]]



                     Subpart I--Records and Reports



Sec. 606.160  Records.

    (a)(1) Records shall be maintained concurrently with the performance 
of each significant step in the collection, processing, compatibility 
testing, storage and distribution of each unit of blood and blood 
components so that all steps can be clearly traced. All records shall be 
legible and indelible, and shall identify the person performing the 
work, include dates of the various entries, show test results as well as 
the interpretation of the results, show the expiration date assigned to 
specific products, and be as detailed as necessary to provide a complete 
history of the work performed.
    (2) Appropriate records shall be available from which to determine 
lot numbers of supplies and reagents used for specific lots or units of 
the final product.
    (b) Records shall be maintained that include, but are not limited 
to, the following when applicable:
    (1) Donor records:
    (i) Donor selection, including medical interview and examination and 
where applicable, informed consent.
    (ii) Permanent and temporary deferrals for health reasons including 
reason(s) for deferral.
    (iii) Donor adverse reaction complaints and reports, including 
results of all investigations and followup.
    (iv) Therapeutic bleedings, including signed requests from attending 
physicians, the donor's disease and disposition of units.
    (v) Immunization, including informed consent, identification of the 
antigen, dosage and route of administration.
    (vi) Blood collection, including identification of the phlebotomist.
    (vii) Records to relate the donor with the unit number of each 
previous donation from that donor.
    (viii) Records of quarantine, notification, testing, and disposition 
performed pursuant to Secs. 610.46 and 610.47 of this chapter.
    (ix) Records of notification of donors deferred or determined not to 
be suitable for donation, including appropriate followup if the initial 
attempt at notification fails, performed under Sec. 630.6 of this 
chapter.
    (x) The donor's address provided at the time of donation where the 
donor may be contacted within 8 weeks after donation.
    (xi) Records of notification of the referring physician of a 
deferred autologous donor, including appropriate followup if the initial 
notification attempt fails, performed under Sec. 630.6 of this chapter.
    (2) Processing records:
    (i) Blood processing, including results and interpretation of all 
tests and retests.
    (ii) Component preparation, including all relevant dates and times.
    (iii) Separation and pooling of recovered plasma.
    (iv) Centrifugation and pooling of source plasma.
    (v) Labeling, including initials of the person(s) performing the 
procedure.
    (3) Storage and distribution records:
    (i) Distribution and disposition, as appropriate, of blood and blood 
products.
    (ii) Visual inspection of whole blood and red blood cells during 
storage and immediately before distribution.
    (iii) Storage temperature, including initialed temperature recorder 
charts.
    (iv) Reissue, including records of proper temperature maintenance.
    (v) Emergency release of blood, including signature of requesting 
physician obtained before or after release.
    (4) Compatibility test records:
    (i) Results of all compatibility tests, including crossmatching, 
testing of patient samples, antibody screening and identification.
    (ii) Results of confirmatory testing.
    (5) Quality control records:
    (i) Calibration and standardization of equipment.
    (ii) Performance checks of equipment and reagents.
    (iii) Periodic check on sterile technique.
    (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:

[[Page 55]]

    (i) Sterilization of supplies and reagents prepared within the 
facility, including date, time interval, temperature and mode.
    (ii) Responsible personnel.
    (iii) Biological product deviations.
    (iv) Maintenance records for equipment and general physical plant.
    (v) Supplies and reagents, including name of manufacturer or 
supplier, lot numbers, expiration date and date of receipt.
    (vi) Disposition of rejected supplies and reagents used in the 
collection, processing and compatibility testing of blood and blood 
components.
    (c) A donor number shall be assigned to each accepted donor, which 
relates the unit of blood collected to that donor, to his medical 
record, to any component or blood product from that donor's unit of 
blood, and to all records describing the history and ultimate 
disposition of these products.
    (d) Records shall be retained for such interval beyond the 
expiration date for the blood or blood component as necessary to 
facilitate the reporting of any unfavorable clinical reactions. 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.

[40 FR 53532, Nov. 18, 1975, as amended at 61 FR 47422, Sept. 9, 1996; 
64 FR 45371, Aug. 19, 1999; 65 FR 66635, Nov. 7, 2000; 66 FR 31176, June 
11, 2001]



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

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



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

    (a) Who must report under this section? You, a licensed manufacturer 
of blood and blood components, including

[[Page 56]]

Source Plasma; an unlicensed registered blood establishment; or a 
transfusion service who had control over the product when the deviation 
occurred, must report under this section. If you arrange for another 
person to perform a manufacturing, holding, or distribution step, while 
the product is in your control, that step is performed under your 
control. You must establish, maintain, and follow a procedure for 
receiving information from that person on all deviations, complaints, 
and adverse events concerning the affected product.
    (b) What do I report under this section? You must report any event, 
and information relevant to the event, associated with the 
manufacturing, to include testing, processing, packing, labeling, or 
storage, or with the holding or distribution, of both licensed and 
unlicensed blood or blood components, including Source Plasma, if that 
event meets all the following criteria:
    (1) Either:
    (i) Represents a deviation from current good manufacturing practice, 
applicable regulations, applicable standards, or established 
specifications that may affect the safety, purity, or potency of that 
product; or
    (ii) Represents an unexpected or unforeseeable event that may affect 
the safety, purity, or potency of that product; and
    (2) Occurs in your facility or another facility under contract with 
you; and
    (3) Involves distributed blood or blood components.
    (c) When do I report under this section? You should report a 
biological product deviation as soon as possible but you must report at 
a date not to exceed 45-calendar days from the date you, your agent, or 
another person who performs a manufacturing, holding, or distribution 
step under your control, acquire information reasonably suggesting that 
a reportable event has occurred.
    (d) How do I report under this section? You must report on Form FDA-
3486.
    (e) Where do I report under this section? You must send the 
completed Form FDA-3486 to the Director, Office of Compliance and 
Biologics Quality (HFM-600), 1401 Rockville Pike, suite 200N, Rockville 
MD, 20852-1448 by either a paper or electronic filing:
    (1) If you make a paper filing, you should identify on the envelope 
that a BPDR (biological product deviation report) is enclosed; or
    (2) If you make an electronic filing, you may submit the completed 
Form FDA-3486 electronically through CBER's website at www.fda.gov/cber.
    (f) How does this regulation affect other FDA regulations? This part 
supplements and does not supersede other provisions of the regulations 
in this chapter. All biological product deviations, whether or not they 
are required to be reported under this section, should be investigated 
in accordance with the applicable provisions of parts 211, 606, and 820 
of this chapter.

[65 FR 66635, Nov. 7, 2000]



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.
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.

[[Page 57]]

     Subpart C--Procedures for Foreign Blood Product Establishments

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

                          Subpart D--Exemptions

607.65  Exemptions for blood product establishments.

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

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



                      Subpart A--General Provisions



Sec. 607.3  Definitions.

    (a) The term act means the Federal Food, Drug, and Cosmetic Act 
approved June 25, 1938 (52 Stat. 1040 et seq., as amended, 21 U.S.C. 
301-392).
    (b) Blood and blood product means a drug which consists of human 
whole blood, plasma, or serum or any product derived from human whole 
blood, plasma, or serum, hereinafter referred to as ``blood product.'' 
For the purposes of this part only, blood and blood product also means 
those products that meet the definition of a device under the Federal 
Food, Drug, and Cosmetic Act and that are licensed under section 351 of 
the Public Health Service Act.
    (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 under the investigational use provisions of part 312 of 
this chapter, but does not include internal or interplant transfer of a 
bulk product substance between registered establishments within the same 
parent, subsidiary, and/or affiliate company. For foreign 
establishments, the term ``commercial distribution'' shall have the same 
meaning except that the term shall not include distribution of any blood 
or blood product that is neither imported nor offered for import into 
the United States.
    (f) Any material change includes but is not limited to any change in 
the name of the blood product, in the quantity or identity of the active 
ingredient(s) or in the quantity or identity of the inactive 
ingredient(s) where quantitative listing of all ingredients is required 
pursuant to Sec. 607.31(a)(2) and any significant change in the labeling 
of a blood product. Changes that are not significant include changes in 
arrangement or printing or changes of an editorial nature.
    (g) Bulk product substance means any substance that is represented 
for use in a blood product and when used in the manufacturing of a blood 
product becomes an active ingredient or a finished dosage form of such 
product.
    (h) Advertising and labeling include the promotional material 
described in Sec. 202.1(l) (1) and (2) of this chapter, respectively.
    (i) The definitions and interpretations contained in sections 201 
and 510 of the act shall be applicable to such terms when used in this 
part 607.
    (j) United States agent means a person residing or maintaining a 
place of business in the United States whom a foreign establishment 
designates as its agent. This definition excludes mailboxes, answering 
machines or services, or other places where an individual acting as the 
foreign establishment's agent is not physically present.

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

[[Page 58]]



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. 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 (HFM-375), 
1401 Rockville Pike, suite 200N, Rockville, MD 20852-1448, 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 (HFM-375), 1401 Rockville Pike, suite 200N, 
Rockville, MD 20852-1448.

[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 55 
FR 11014, Mar. 26, 1990; 66 FR 59158, Nov. 27, 2001]



     Subpart B--Procedures for Domestic Blood Product Establishments



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

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

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



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

    The owner or operator of an establishment entering into an operation 
defined in Sec. 607.3(d) shall register such establishment within 5 days 
after the beginning of such operation and submit a list of every blood 
product in commercial distribution at the time. If the owner or operator 
of the establishment has not previously entered into such operation 
(defined in Sec. 607.3(d) of this chapter) for which a license is 
required, registration shall follow within 5 days after the submission 
of a biologics license application in order to manufacture blood 
products. Owners or operators of all establishments so engaged shall 
register annually between November 15 and December 31 and shall update 
their blood product listing information every June and December.

[40 FR 52788, Nov. 12, 1975, as amended at 64 FR 56453, Oct. 20, 1999]



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 (HFM-
375), 1401 Rockville Pike, suite 200N, Rockville, MD 20852-1448, or from 
Food and Drug Administration district offices.

[[Page 59]]

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 under Sec. 607.35. The completed form shall 
be mailed to the preceding 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.

[66 FR 59158, Nov. 27, 2001]



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 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 the 
parent establishment. An establishment not owned, operated, or 
controlled by another firm or establishment is its own parent 
establishment.

[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 55 
FR 11013, Mar. 26, 1990; 66 FR 59158, Nov. 27, 2001]



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 
FDA-2830 (Blood Establishment Registration and Product Listing) as an 
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.

[40 FR 52788, Nov. 12, 1975, as amended at 66 FR 59158, Nov. 27, 2001]



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

[[Page 60]]

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

[66 FR 59158, Nov. 27, 2001]



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

    (a) The Director of the Center for Biologics Evaluation and Research 
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 to the location shown for 
the registering establishment, and a copy will be sent to the reporting 
official if at another address. 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; 66 
FR 59159, Nov. 27, 2001]



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 under section 510(f) of the act, at the Department of Health 
and Human Services, Food and Drug Administration, Office of 
Communication, Training and Manufacturers' Assistance (HFM-40), Center 
for Biologics Evaluation and Research, 1401 Rockville Pike, suite 200N, 
Rockville, MD 20852-1448. In addition, for domestic firms, the same 
information will be available for inspection at each of the Food and 
Drug Administration district offices 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 registered establishment will be provided. The following 
information submitted under the blood

[[Page 61]]

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.
    (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 Communication, Training and Manufacturers' Assistance (HFM-
40), Center for Biologics Evaluation and Research, 1401 Rockville Pike, 
suite 200N, Rockville, MD 20852-1448.

[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 55 
FR 11014, Mar. 26, 1990; 66 FR 59159, Nov. 27, 2001]



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

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

[[Page 62]]

such an action shall be considered to be equivalent to providing the 
same information or documents to the foreign establishment.
    (3) The foreign establishment or the United States agent shall 
report changes in the United States agent's name, address, or phone 
number to FDA within 10-business days of the change.

[66 FR 59159, Nov. 27, 2001]



                          Subpart D--Exemptions



Sec. 607.65  Exemptions for blood product establishments.

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

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



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.

[[Page 63]]

         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--Testing Requirements for Communicable Disease Agents

610.40  Test requirements.
610.41  Donor deferral.
610.42  Restrictions on use for further manufacture of medical devices.
610.44  Use of reference panels by manufacturers of test kits.
610.46  ``Lookback'' requirements.
610.47  ``Lookback'' notification requirements for transfusion services.

                  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 and address of distributor.
610.65  Products for export.

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

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

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



                     Subpart A--Release Requirements



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

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



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

    (a) 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.

[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; 67 FR 
9587, Mar. 4, 2002]

[[Page 64]]



                      Subpart B--General Provisions



Sec. 610.9  Equivalent methods and processes.

    Modification of any particular test method or manufacturing process 
or the conditions under which it is conducted as required in this part 
or in the additional standards for specific biological products in parts 
620 through 680 of this chapter shall be permitted only under the 
following conditions:
    (a) The applicant presents evidence, in the form of a license 
application, or a supplement to the application submitted in accordance 
with Sec. 601.12(b) or (c), demonstrating that the modification will 
provide assurances of the safety, purity, potency, and effectiveness of 
the biological product equal to or greater than the assurances provided 
by the method or process specified in the general standards or 
additional standards for the biological product; and
    (b) Approval of the modification is received in writing from the 
Director, Center for Biologics Evaluation and Research, Food and Drug 
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448.

[62 FR 39903, July 24, 1997]



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 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

[[Page 65]]

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--(1) The test prescribed in this section need not be 
performed for Whole Blood, Red Blood Cells, Cryoprecipitated AHF, 
Platelets, Plasma, or Cellular Therapy Products.
    (2) [Reserved]

[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; 63 FR 
19403, Apr. 20, 1998; 63 FR 41718, Aug. 5, 1998]

    Effective Date Note: At 68 FR 10160, Mar. 4, 2003, Sec. 610.11 was 
amended by adding paragraph (g)(2), effective May 5, 2003. For the 
convenience of the user the added text follows:

Sec. 610.11  General safety.

                                * * * * *

    (g) * * *
    (2) For products other than those identified in paragraph (g)(1) of 
this section, a manufacturer may request from the Director, Center for 
Biologics Evaluation and Research, an exemption from the general safety 
test. The manufacturer must submit information as part of a biologics 
license application submission or supplement to an approved biologics 
license application establishing that because of the mode of 
administration, the method of preparation, or the special nature of the 
product a test of general safety is unnecessary to assure the safety, 
purity, and potency of the product or cannot be performed. The request 
must include alternate procedures, if any, to be performed. The 
Director, Center for Biologics Evaluation and Research, upon finding 
that the manufacturer's request justifies an exemption, may exempt the 
product from the general safety test subject to any condition necessary 
to assure the safety, purity, and potency of the product.



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 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

[[Page 66]]

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 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 
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 
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

[[Page 67]]

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 (C6H12O6[middot]H2)O)...........  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 7.10.2.
 

    (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 (C6H12O6[middot]H2O)............  2.5 gm.
Purified water...........................  1,000.0 ml.
pH after sterilization 7.30.2.
 

    (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 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

[[Page 68]]

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 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.

[[Page 69]]

    (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 (23d Revision, 1995), section entitled 
``Test Procedures Using Membrane Filtration,'' pp. 1689 to 1690, which 
is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 
CFR part 51. Copies are available from the United States Pharmacopeial 
Convention, Inc., 12601 Twinbrook Pkwy., Rockville, MD 20852, or 
available for inspection at the Center for Drug Evaluation and 
Research's Division of Medical Library, 5600 Fishers Lane, rm. 11B-40, 
Rockville, MD, or at the Office of the Federal Register, 800 North 
Capitol St. NW., suite 700, Washington, DC, 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\1/2\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.
    (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,

[[Page 70]]

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 7.1 0.1, 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.

[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; 62 FR 48175, Sept. 15, 1997; 67 FR 9587, Mar. 4, 2002]



Sec. 610.13  Purity.

    Products shall be free of extraneous material except that which is 
unavoidable in the manufacturing process described in the approved 
biologics license application. In addition, products shall be tested as 
provided in paragraphs (a) and (b) of this section.
    (a)(1) Test for residual moisture. Each lot of dried product shall 
be tested for residual moisture and shall meet and not exceed 
established limits as specified by an approved method on file in the 
biologics license application. The test for residual moisture may be 
exempted by the Director, Center for Biologics Evaluation and Research, 
when deemed not necessary for the continued safety, purity, and potency 
of the product.
    (2) Records. Appropriate records for residual moisture under 
paragraph (a)(1) of this section shall be prepared and maintained as 
required by the applicable provisions of Secs. 211.188 and 211.194 of 
this chapter.

[[Page 71]]

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

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



Sec. 610.14  Identity.

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



Sec. 610.15  Constituent materials.

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

[[Page 72]]

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

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



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

    The presence of Group A streptococcus organisms and derivatives of

[[Page 73]]

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]



                          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 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

[[Page 74]]

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 
1  deg.C and the remaining plates and tubes shall be 
incubated anaerobically at 36  deg.C 1  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 300x. 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.

[38 FR 32056, Nov. 20, 1973, as amended at 63 FR 16685, Apr. 6, 1998]



     Subpart E--Testing Requirements for Communicable Disease Agents



Sec. 610.40  Test requirements.

    (a) Human blood and blood components. Except as specified in 
paragraphs (c) and (d) of this section, you, an establishment that 
collects blood or blood components, must test each donation of human 
blood or blood component intended for use in preparing a product, 
including donations intended as a component of, or used to prepare, a 
medical device, for evidence of infection due to the following 
communicable disease agents:
    (1) Human immunodeficiency virus, type 1;
    (2) Human immunodeficiency virus, type 2;
    (3) Hepatitis B virus;
    (4) Hepatitis C virus;
    (5) Human T-lymphotropic virus, type I; and
    (6) Human T-lymphotropic virus, type II.
    (b) Testing using one or more approved screening tests. To test for 
evidence of infection due to communicable disease agents designated in 
paragraph (a) of this section, you must use screening tests that the 
Food and Drug Administration (FDA) has approved for such use, in 
accordance with the manufacturer's instructions. You must perform one or 
more such tests as necessary to reduce adequately and appropriately the 
risk of transmission of communicable disease.
    (c) Exceptions to testing for allogeneic transfusion or further 
manufacturing use--(1) Dedicated donations. (i) You must test donations 
of human blood and blood components from a donor whose donations are 
dedicated to and used solely by a single identified recipient under 
paragraphs (a), (b), and (e) of this section; except that, if the donor 
makes multiple donations for a single identified recipient, you may 
perform such testing only on the first donation in each 30-day period. 
If an untested dedicated donation is made available for any use other 
than transfusion to the single, identified recipient, then this 
exemption from the testing required under this section no longer 
applies.
    (ii) Each donation must be labeled as required under Sec. 606.121 of 
this chapter and with a label entitled ``INTENDED RECIPIENT INFORMATION 
LABEL'' containing the name and identifying information of the 
recipient. Each donation must also have the following label, as 
appropriate:

[[Page 75]]



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

    (2) Source Plasma. You are not required to test donations of Source 
Plasma for evidence of infection due to the communicable disease agents 
listed in paragraphs (a)(5) and (a)(6) of this section.
    (3) Medical device. (i) You are not required to test donations of 
human blood or blood components intended solely as a component of, or 
used to prepare, a medical device for evidence of infection due to the 
communicable disease agents listed in paragraphs (a)(5) and (a)(6) of 
this section unless the final device contains viable leukocytes.
    (ii) Donations of human blood and blood components intended solely 
as a component of, or used to prepare, a medical device must be labeled 
``Caution: For Further Manufacturing Use as a Component of, or to 
Prepare, a Medical Device.''
    (4) Samples. You are not required to test samples of blood, blood 
components, plasma, or sera if used or distributed for clinical 
laboratory testing or research purposes and not intended for 
administration to humans or in the manufacture of a product.
    (d) Autologous donations. You, an establishment that collects human 
blood or blood components from autologous donors, or you, an 
establishment that is a consignee of a collecting establishment, are not 
required to test donations of human blood or blood components from 
autologous donors for evidence of infection due to communicable disease 
agents listed in paragraph (a) of this section or by a serological test 
for syphilis under paragraph (i) of this section, except:
    (1) If you allow any autologous donation to be used for allogeneic 
transfusion, you must assure that all autologous donations are tested 
under this section.
    (2) If you ship autologous donations to another establishment that 
allows autologous donations to be used for allogeneic transfusion, you 
must assure that all autologous donations shipped to that establishment 
are tested under this section.
    (3) If you ship autologous donations to another establishment that 
does not allow autologous donations to be used for allogeneic 
transfusion, you must assure that, at a minimum, the first donation in 
each 30-day period is tested under this section.
    (4) Each autologous donation must be labeled as required under 
Sec. 606.121 of this chapter and with the following label, as 
appropriate:

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

    (e) Further testing. You must further test each donation, including 
autologous donations, found to be reactive by a screening test performed 
under paragraphs (a) and (b) of this section, whenever a supplemental 
(additional, more specific) test has been approved for such use by FDA, 
except:
    (1) For autologous donations, you must further test under this 
paragraph, at a minimum, the first reactive donation in each 30-day 
period; or
    (2) If you have a record for that donor of a positive result on a 
supplemental (additional, more specific) test approved for such use by 
FDA, you do not have to further test an autologous donation.
    (f) Testing responsibility. Required testing under this section, 
must be performed by a laboratory registered in accordance with part 607 
of this chapter and either certified to perform such testing on human 
specimens under the

[[Page 76]]

Clinical Laboratory Improvement Amendments of 1988 (42 U.S.C. 263a) 
under 42 CFR part 493 or has met equivalent requirements as determined 
by the Health Care Financing Administration in accordance with those 
provisions.
    (g) Release or shipment prior to testing. Human blood or blood 
components that are required to be tested for evidence of infection due 
to communicable disease agents designated in paragraphs (a) and (i) of 
this section may be released or shipped prior to completion of testing 
in the following circumstances provided that you label the blood or 
blood components under Sec. 606.121(h) of this chapter, you complete the 
tests for evidence of infection due to communicable disease agents as 
soon as possible after release or shipment, and that you provide the 
results promptly to the consignee:
    (1) Only in appropriately documented medical emergency situations; 
or
    (2) For further manufacturing use as approved in writing by FDA.
    (h) Restrictions on shipment or use--(1) Reactive screening test. 
You must not ship or use human blood or blood components that have a 
reactive screening test for evidence of infection due to a communicable 
disease agent(s) designated in paragraphs (a) and (i) of this section or 
that are collected from a donor with a previous record of a reactive 
screening test for evidence of infection due to a communicable disease 
agent(s) designated in paragraphs (a) and (i) of this section, except as 
provided in paragraphs (h)(2)(i) through (h)(2)(vii) of this section.
    (2) Exceptions. (i) You may ship or use blood or blood components 
intended for autologous use, including reactive donations, as described 
in paragraph (d) of this section.
    (ii) You must not ship or use human blood or blood components that 
have a reactive screening test for evidence of infection due to a 
communicable disease agent(s) designated in paragraph (a) of this 
section or that are collected from a donor deferred under Sec. 610.41(a) 
unless you meet the following conditions:
    (A) Except for autologous donations, you must obtain from FDA 
written approval for the shipment or use;
    (B) You must appropriately label such blood or blood components as 
required under Sec. 606.121, or Sec. 640.70 of this chapter, and with 
the ``BIOHAZARD'' legend;
[GRAPHIC] [TIFF OMITTED] TR11JN01.000

    (C) Except for autologous donations, you must label such human blood 
and blood components as reactive for the appropriate screening test for 
evidence of infection due to the identified communicable disease 
agent(s);
    (D) If the blood or blood components are intended for further 
manufacturing use into injectable products, you must include a statement 
on the container label indicating the exempted use specifically approved 
by FDA.
    (E) Each blood or blood component with a reactive screening test and 
intended solely as a component of, or used to prepare a medical device, 
must be labeled with the following label, as appropriate:

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

    (iii) The restrictions on shipment or use do not apply to samples of 
blood, blood components, plasma, or sera if used or distributed for 
clinical laboratory testing or research purposes, and

[[Page 77]]

not intended for administration in humans or in the manufacture of a 
product.
    (iv) You may use human blood or blood components from a donor with a 
previous record of a reactive screening test(s) for evidence of 
infection due to a communicable disease agent(s) designated in paragraph 
(a) of this section, if:
    (A) At the time of donation, the donor is shown or was previously 
shown to be suitable by a requalification method or process found 
acceptable for such purposes by FDA under Sec. 610.41(b); and
    (B) tests performed under paragraphs (a) and (b) of this section are 
nonreactive.
    (v) Anti-HBc reactive donations, otherwise nonreactive when tested 
as required under this section, may be used for further manufacturing 
into plasma derivatives without prior FDA approval or a ``BIOHAZARD'' 
legend as required under paragraphs (h)(2)(ii)(A) and (h)(2)(ii)(B) of 
this section.
    (vi) You may use human blood or blood components, excluding Source 
Plasma, that test reactive by a screening test for syphilis as required 
under paragraph (i) of this section if, consistent with Sec. 640.5 of 
this chapter, the donation is further tested by an adequate and 
appropriate test which demonstrates that the reactive screening test is 
a biological false positive. You must label the blood or blood 
components with both test results.
    (vii) You may use Source Plasma from a donor who tests reactive by a 
screening test for syphilis as required under Sec. 610.40(i) of this 
chapter, if the donor meets the requirements of Sec. 640.65(b)(2) of 
this chapter.
    (i) Syphilis testing. In addition to the testing otherwise required 
under this section, you must test by a serological test for syphilis 
under Secs. 640.5(a), 640.14, 640.23(a), 640.33(a), 640.53(a), and 
640.65(b)(2) of this chapter.

[66 FR 31162, June 11, 2001]



Sec. 610.41  Donor deferral.

    (a) You, an establishment that collects human blood or blood 
components, must defer donors testing reactive by a screening test for 
evidence of infection due to a communicable disease agent(s) listed in 
Sec. 610.40(a) or reactive for a serological test for syphilis under 
Sec. 610.40(i), from future donations of human blood and blood 
components, except:
    (1) You are not required to defer a donor who tests reactive for 
anti-HBc or anti-HTLV, types I or II, on only one occasion. When a 
supplemental (additional, more specific) test for anti-HBc or anti-HTLV, 
types I and II, has been approved for use under Sec. 610.40(e) by FDA, 
such a donor must be deferred;
    (2) A deferred donor who tests reactive for evidence of infection 
due to a communicable disease agent(s) listed in Sec. 610.40(a) may 
serve as a donor for blood or blood components shipped or used under 
Sec. 610.40(h)(2)(ii);
    (3) A deferred donor who showed evidence of infection due to 
hepatitis B surface antigen (HBsAg) when previously tested under 
Sec. 610.40(a), (b), and (e) subsequently may donate Source Plasma for 
use in the preparation of Hepatitis B Immune Globulin (Human) provided 
the current donation tests nonreactive for HBsAg and the donor is 
otherwise determined to be suitable;
    (4) A deferred donor, who otherwise is determined to be suitable for 
donation and tests reactive for anti-HBc or for evidence of infection 
due to HTLV, types I and II, may serve as a donor of Source Plasma;
    (5) A deferred donor who tests reactive for a communicable disease 
agent(s) described under Sec. 610.40(a) or reactive with a serological 
test for syphilis under Sec. 610.40(i), may serve as an autologous donor 
under Sec. 610.40(d).
    (b) A deferred donor subsequently may be found to be suitable as a 
donor of blood or blood components by a requalification method or 
process found acceptable for such purposes by FDA. Such a donor is 
considered no longer deferred.

[66 FR 31164, June 11, 2001]



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

    (a) In addition to labeling requirements in subchapter H of this 
chapter, when a medical device contains human blood or a blood component 
as a component of the final device, and the human blood or blood 
component was found to be reactive by a screening test

[[Page 78]]

performed under Sec. 610.40(a) and (b) or reactive for syphilis under 
Sec. 610.40(i), then you must include in the device labeling a statement 
of warning indicating that the product was manufactured from a donation 
found to be reactive by a screening test for evidence of infection due 
to the identified communicable disease agent(s).
    (b) FDA may approve an exception or alternative to the statement of 
warning required in paragraph (a) of this section based on evidence that 
the reactivity of the human blood or blood component in the medical 
device presents no significant health risk through use of the medical 
device.

[66 FR 31164, June 11, 2001]



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

    (a) When available and appropriate to verify acceptable sensitivity 
and specificity, you, a manufacturer of test kits, must use a reference 
panel you obtain from FDA or from an FDA designated source to test lots 
of the following products. You must test each lot of the following 
products, unless FDA informs you that less frequent testing is 
appropriate, based on your consistent prior production of products of 
acceptable sensitivity and specificity:
    (1) A test kit approved for use in testing donations of human blood 
and blood components for evidence of infection due to communicable 
disease agents listed in Sec. 610.40(a); and
    (2) Human immunodeficiency virus (HIV) test kit approved for use in 
the diagnosis, prognosis, or monitoring of this communicable disease 
agent.
    (b) You must not distribute a lot that is found to be not acceptable 
for sensitivity and specificity under Sec. 610.44(a). FDA may approve an 
exception or alternative to this requirement. Applicants must submit 
such requests in writing. However, in limited circumstances, such 
requests may be made orally and permission may be given orally by FDA. 
Oral requests and approvals must be promptly followed by written 
requests and written approvals.

[66 FR 31164, June 11, 2001]



Sec. 610.46  ``Lookback'' requirements.

    (a) Quarantine and notification. (1) All blood and plasma 
establishments are required to take appropriate action when a donor of 
Whole Blood, blood components, Source Plasma and Source Leukocytes tests 
repeatedly reactive for antibody to human immunodeficiency virus (HIV), 
or otherwise is determined to be unsuitable when tested in accordance 
with Sec. 610.45. For Whole Blood, blood components, Source Plasma and 
Source Leukocytes collected from that donor within the 5 years prior to 
the repeatedly reactive test, if intended for transfusion, or collected 
within the 6 months prior to the repeatedly reactive test, if intended 
for further manufacture into injectable products, except those products 
exempt from quarantine in accordance with Sec. 610.46(c), the blood 
establishment shall promptly, within 72 hours:
    (i) Quarantine all such Whole Blood, blood components, Source Plasma 
and Source Leukocytes from previous collections held at that 
establishment; and
    (ii) Notify consignees of the repeatedly reactive HIV screening test 
results so that all Whole Blood, blood components, Source Plasma and 
Source Leukocytes from previous collections they hold are quarantined.
    (2) Consignees notified in accordance with paragraph (a)(1)(ii) of 
this section shall quarantine Whole Blood, blood components, Source 
Plasma and Source Leukocytes held at that establishment except as 
provided in paragraph (c) of this section.
    (b) Further testing and notification of consignees of results. Blood 
establishments that have collected Whole Blood, blood components, Source 
Plasma or Source Leukocytes from a donor as described in paragraph (a) 
of this section shall perform a licensed, more specific test for HIV on 
the donor's blood, and in the case of distributed products, further 
shall notify the consignee(s) of the results of this test, within 30 
calendar days after the donor's repeatedly reactive test. Pending the 
availability of a licensed, more specific test for HIV-2, a second, 
different screening test for antibody to HIV-2 shall be used along with 
a licensed, more specific test for HIV-1.

[[Page 79]]

    (c) Exemption from quarantine. Products intended for transfusion 
need not be held in quarantine if a determination has been made that the 
Whole Blood, blood components, Source Plasma or Source Leukocytes was 
collected more than 12 months prior to the donor's most recent negative 
antibody screening test when tested in accordance with Sec. 610.45. 
Pooled Source Plasma and Source Leukocytes are exempt from quarantine.
    (d) Release from quarantine. Whole Blood, blood components, Source 
Plasma and Source Leukocytes intended for transfusion or further 
manufacture which have been quarantined under paragraph (a) of this 
section may be released if the donor is subsequently tested for antibody 
to HIV as provided in paragraph (b) of this section and the test result 
is negative, absent other informative test results.
    (e) Actions under this section do not constitute a product recall as 
defined in Sec. 7.3(g) of this chapter.

[61 FR 47423, Sept. 9, 1996]



Sec. 610.47  ``Lookback'' notification requirements for transfusion services.

    (a) Transfusion services that are not subject to the Health Care 
Financing Administration's regulations on conditions of Medicare 
participation for hospitals (42 CFR part 482) are required to take 
appropriate action in accordance with paragraphs (b) and (c) of this 
section when a recipient has received Whole Blood or blood components 
from a donor determined to be unsuitable when tested for human 
immunodeficiency virus (HIV) infection in accordance with Sec. 610.45 
and the results of the additional tests as provided for in 
Sec. 610.46(b) are positive.
    (b) Notification of recipients of prior transfusion. If the 
transfusion service has administered Whole Blood or blood components as 
described in paragraph (a) of this section, the transfusion service 
shall notify the recipient's attending physician (physician of record) 
and ask him or her to inform the recipient of the need for HIV testing 
and counseling. If the physician is unavailable or declines to notify 
the recipient, the transfusion service shall notify the recipient and 
inform the recipient of the need for HIV testing and counseling. The 
notification process shall include a minimum of three attempts to notify 
the recipient and be completed within a maximum 8 weeks of receipt of 
the result of the licensed, more specific test for HIV. The transfusion 
service is responsible for notification, including basic explanations to 
the recipient and referral for counseling, and shall document the 
notification or attempts to notify the attending physician or the 
recipient, pursuant to Sec. 606.160 of this chapter.
    (c) Notification to legal representative or relative. If the 
transfusion recipient has been adjudged incompetent by a State court, 
the transfusion service or physician must notify a legal representative 
designated in accordance with State law. If the transfusion recipient is 
competent, but State law permits a legal representative or relative to 
receive the information on the recipient's behalf, the transfusion 
service or physician must notify the recipient or his or her legal 
representative or relative. If the transfusion recipient is deceased, 
the transfusion service or physician must continue the notification 
process and inform the deceased recipient's legal representative or 
relative. Reasons for notifying the recipient's relative or legal 
representative on his or her behalf shall be documented pursuant to 
Sec. 606.160 of this chapter.

[61 FR 47423, Sept. 9, 1996]



                  Subpart F--Dating Period Limitations



Sec. 610.50  Date of manufacture.

    The date of manufacture shall be determined as follows:
    (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]

[[Page 80]]



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.

----------------------------------------------------------------------------------------------------------------
                 A                              B                        C                         D
----------------------------------------------------------------------------------------------------------------
                                                                                          Dating period after
                                      Manufacturer's storage  Manufacturer's storage    leaving manufacturer's
              Product                  period 1 to 5  deg.C     period 0  deg.C or     storage when stored at 2
                                        (unless otherwise         colder (unless          to 8  deg.C (unless
                                             stated)             otherwise stated)         otherwise stated)
----------------------------------------------------------------------------------------------------------------
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  deg.C.
                                     Not applicable.........  ......do..............  (c) 10 years, if in a
                                                                                       hermetically sealed metal
                                                                                       container and provided
                                                                                       labeling recommends
                                                                                       storage between 2 and 8
                                                                                       deg.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  deg.C or
                                                                                       colder.
    4. Powders and tablets.........  ......do...............  ......do..............  5 years (from date of
                                                                                       manufacture), provided
                                                                                       labeling recommends
                                                                                       storage at 30  deg.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.
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.

[[Page 81]]

 
Antivenin (Crotalidae) Polyvalent..  ......do...............  ......do..............  5 years with an initial 10
                                                                                       percent excess of
                                                                                       potency, provided
                                                                                       labeling recommends
                                                                                       storage at 37  deg. 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  deg.C or
                                                                                       colder.
Cryoprecipitated AFH...............  ......do...............  ......do..............  12 months from the date of
                                                                                       collection of source
                                                                                       blood, provided labeling
                                                                                       recommends storage at -18
                                                                                        deg.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
                                                                                       deg.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.
    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        Not applicable........  3 years.
                                      deg.C.

[[Page 82]]

 
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  deg.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  deg.C or  Not applicable.
                                                               colder).
    2. Final container.............  Not applicable.........  3 years (-20  deg.C or  2 years.
                                                               colder).
Meningococcal Polysaccharide
 Vaccine Group C:
    1. Final bulk powder...........  ......do...............  2 years (-20  deg.C or  Not applicable.
                                                               colder).
    2. Final container.............  ......do...............  3 years (-20  deg.C or  2 years.
                                                               colder).
Meningococcal Polysaccharide
 Vaccine Groups A and C combined:
    1. Final bulk powder...........  ......do...............  2 years (-20  deg.C or  Not applicable.
                                                               colder).
    2. Final container.............  ......do...............  3 years (-20  deg.C or  2 years.
                                                               colder).
Meningococcal Polysaccharide
 Vaccine Groups A, C, Y, and W135
 combined:
    1. Final bulk power............  ......do...............  2 years (-20  deg.C or  Not applicable.
                                                               colder).
    2. Final container.............  ......do...............  3 years (-20  deg.C or  2 years.
                                                               colder).
Mumps Skin Test Antigen............  6 months...............  Not applicable........  18 months.
Mumps Virus Vaccine Live...........  Not applicable.........  1 year (-20  deg.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  deg.C or
                                                                                       colder).
    2. Liquid Plasma...............  ......do...............  ......do..............  (a) 26 days from date of
                                                                                       collection of source
                                                                                       blood (between 1 and 6
                                                                                       deg.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  deg.C).
    3. Plasma......................  ......do...............  ......do..............  5 years from date of
                                                                                       collection of source
                                                                                       blood (-18  deg.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  deg.C or between 1
                                                                                       and 6  deg.C). 5 days if
                                                                                       certain approved
                                                                                       containers are used (20
                                                                                       to 24  deg.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).
    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  deg.C).
Platelets..........................  Not applicable.........  ......do..............  72 hours from time of
                                                                                       collection of source
                                                                                       blood, provided labeling
                                                                                       recommends storage at 20
                                                                                       to 24  deg.C or between 1
                                                                                       and 6  deg.C. 5 days if
                                                                                       certain approved
                                                                                       containers are used (20
                                                                                       to 24  deg.C).

[[Page 83]]

 
Pneumococcal Vaccine Polyvalent:
    1. Final bulk powder...........  ......do...............  24 months after         Not applicable.
                                                               potency assay (-20
                                                               deg.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  deg.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  deg.C
                                                                                       and container has been
                                                                                       unopened.
Poliovirus Vaccine Live Oral Type
 I:
    1. Frozen......................  ......do...............  1 year (-10  deg.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  deg.C
                                                                                       and container has been
                                                                                       unopened.
Poliovirus Vaccine Live Oral Type
 II:
    1. Frozen......................  ......do...............  1 year (-10  deg.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  deg.C
                                                                                       and container has been
                                                                                       unopened.
Poliovirus Vaccine Live Oral Type
 III:
    1. Frozen......................  ......do...............  1 year (-10  deg.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  deg.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  deg.C or
                                                                                       colder).
ACD Red Blood Cells................  ......do...............  ......do..............  (a) 21 days from date of
                                                                                       collection of source
                                                                                       blood, provided labeling
                                                                                       recommends storage
                                                                                       between 1 and 6  deg.C
                                                                                       and the hermetic seal is
                                                                                       not broken during
                                                                                       processing.
                                                                                      (b) 24 hours after plasma
                                                                                       removal, provided
                                                                                       labeling recommends
                                                                                       storage between 1 and 6
                                                                                       deg.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  deg.C
                                                                                       and the hermetic seal is
                                                                                       not broken during
                                                                                       processing.
                                                                                      (b) 24 hours after plasma
                                                                                       removal, provided
                                                                                       labeling recommends
                                                                                       storage between 1 and 6
                                                                                       deg.C and the hermetic
                                                                                       seal is broken during
                                                                                       processing.

[[Page 84]]

 
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  deg.C
                                                                                       and the hermetic seal is
                                                                                       not broken during
                                                                                       processing.
                                                                                      (b) 24 hours after plasma
                                                                                       removal, provided
                                                                                       labeling recommends
                                                                                       storage between 1 and 6
                                                                                       deg.C and the hermetic
                                                                                       seal is broken during
                                                                                       processing.
Red Blood Cells Deglycerolized.....  ......do...............  ......do..............  24 hours after removal
                                                                                       from storage at -65
                                                                                       deg.C or colder, provided
                                                                                       labeling recommends
                                                                                       storage between 1 and 6
                                                                                       deg.C.
Red Blood Cells Frozen.............  ......do...............  ......do..............  3 years from date of
                                                                                       collection of source
                                                                                       blood, provided labeling
                                                                                       recommends storage at -65
                                                                                        deg.C or colder.
Rubella and Mumps Virus Vaccine      ......do...............  1 year (-20  deg.C or   1 year.
 Live.                                                         colder).
Rubella Virus Vaccine Live.........  ......do...............  ......do..............      Do.
Skin Test Antigens for Cellular      6 months...............  Not applicable........      Do.
 Hypersensitivity.
Smallpox Vaccine:
    1. Liquid......................  Not applicable.........  9 months (-10  deg.C    3 months, provided
                                                               or colder, if product   labeling recommends
                                                               is maintained as        storage at 0  deg.C or
                                                               glycerinated or         colder.
                                                               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  deg.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  deg.C; do not                                recommends storage at a
     puncture device.                 refrigerate).                                    temperature not to exceed
                                                                                       30  deg.C. Do not
                                                                                       refrigerate.
    3. Old on multiple puncture      ......do...............  ......do..............      Do.
     device.
Typhoid Vaccine....................  1 year.................  ......do..............  18 months.
ACD Whole Blood....................  Not applicable.........  ......do..............  21 days from date of
                                                                                       collection, provided
                                                                                       labeling recommends
                                                                                       storage between 1 and 6
                                                                                       deg.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
                                                                                       deg.C.
Heparin Whole Blood................  ......do...............  ......do..............  48 hours from date of
                                                                                       collection, provided
                                                                                       labeling recommends
                                                                                       storage between 1 and 6
                                                                                       deg.C.
Yellow Fever Vaccine...............  ......do...............  1 year (-20  deg.C or   1 year, provided labeling
                                                               colder).                recommends storage at 5
                                                                                       deg.C or colder.
----------------------------------------------------------------------------------------------------------------


[[Page 85]]

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

[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; 62 FR 15110, Mar. 31, 1997; 64 FR 56453, Oct. 20, 1999]



                      Subpart G--Labeling Standards



Sec. 610.60  Container label.

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

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



Sec. 610.61  Package label.

    The following items shall appear on the label affixed to each 
package containing a product:
    (a) The proper name of the product;
    (b) The name, address, and license number of manufacturer;
    (c) The lot number or other lot identification;
    (d) The expiration date;
    (e) The preservative used and its concentration, or if no 
preservative is used and the absence of a preservative is a safety 
factor, the words ``no preservative'';
    (f) The number of containers, if more than one;
    (g) The amount of product in the container expressed as (1) the 
number of doses, (2) volume, (3) units of potency, (4) weight, (5) 
equivalent volume (for dried product to be reconstituted), or (6) such 
combination of the foregoing as needed for an accurate description of 
the contents, whichever is applicable;
    (h) The recommended storage temperature;
    (i) The words ``Shake Well'', ``Do not Freeze'' or the equivalent, 
as well as other instructions, when indicated by the character of the 
product;
    (j) The recommended individual dose if the enclosed container(s) is 
a multiple-dose container;
    (k) The route of administration recommended, or reference to such 
directions in an enclosed circular;
    (l) Known sensitizing substances, or reference to an enclosed 
circular containing appropriate information;
    (m) The type and calculated amount of antibiotics added during 
manufacture;

[[Page 86]]

    (n) The inactive ingredients when a safety factor, or reference to 
an enclosed circular containing appropriate information;
    (o) The adjuvant, if present;
    (p) The source of the product when a factor in safe administration;
    (q) The identity of each microorganism used in manufacture, and, 
where applicable, the production medium and the method of inactivation, 
or reference to an enclosed circular containing appropriate information;
    (r) Minimum potency of product expressed in terms of official 
standard of potency or, if potency is a factor and no U.S. standard of 
potency has been prescribed, the words ``No U.S. standard of potency.''
    (s) The statement: `` `Rx only' '' for prescription biologicals.

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



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

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



Sec. 610.63   Divided manufacturing responsibility to be shown.

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

[64 FR 56453, Oct. 20, 1999]



Sec. 610.64  Name and address of distributor.

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

[61 FR 57330, Nov. 6, 1996]



Sec. 610.65  Products for export.

    Labels on packages or containers of products for export may be 
adapted to meet specific requirements of the regulations of the country 
to which the product is to be exported provided that in all such cases 
the minimum label requirements prescribed in Sec. 610.60 are observed.



PART 630--GENERAL REQUIREMENTS FOR BLOOD, BLOOD COMPONENTS, AND BLOOD DERIVATIVES--Table of Contents




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

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



Sec. 630.6  Donor notification.

    (a) Notification of donors. You, an establishment that collects 
blood or blood components, must make reasonable attempts to notify any 
donor, including an autologous donor, who has been deferred based on the 
results of tests for evidence of infection with a communicable disease 
agent(s) as required by Sec. 610.41 of this chapter; or who has been 
determined not to be suitable as a donor based on suitability criteria 
under Sec. 640.3 or Sec. 640.63 of this

[[Page 87]]

chapter. You must attempt to obtain the results of supplemental testing 
required under Sec. 610.40(e) of this chapter prior to notifying a donor 
of the deferral. If notification occurs prior to receipt of such 
results, you must also notify a deferred donor of the results of the 
supplemental testing. You must notify a donor as described in paragraph 
(b) of this section.
    (b) Content of notification. You must provide the following 
information to a donor deferred or determined not to be suitable as a 
donor as described in paragraph (a) of this section:
    (1) That the donor is deferred or determined not to be suitable for 
donation and the reason for that decision;
    (2) Where appropriate, the types of donation of blood or blood 
components that the donor should not donate in the future;
    (3) Where applicable, the results of tests for evidence of infection 
due to communicable disease agent(s) that were a basis for deferral 
under Sec. 610.41 of this chapter, including results of supplemental 
(i.e., additional, more specific) tests as required in Sec. 610.40(e) of 
this chapter; and,
    (4) Where appropriate, information concerning medical followup and 
counseling.
    (c) Time period for notification. You must make reasonable attempts 
to notify the donor within 8 weeks after determining that the donor is 
deferred or determined not to be suitable for donation as described in 
paragraph (a) of this section. You must document that you have 
successfully notified the donor or when you are unsuccessful that you 
have made reasonable attempts to notify the donor.
    (d) Autologous donors. (1) You also must provide the following 
information to the referring physician of an autologous donor who is 
deferred based on the results of tests for evidence of infection with a 
communicable disease agent(s) as described in paragraph (a) of this 
section:
    (i) Information that the autologous donor is deferred based on the 
results of tests for evidence of infection due to communicable disease 
agent(s), as required under Sec. 610.41 of this chapter, and the reason 
for that decision;
    (ii) Where appropriate, the types of donation of blood or blood 
components that the autologous donor should not donate in the future; 
and
    (iii) The results of tests for evidence of infection due to 
communicable disease agent(s), that were a basis for deferral under 
Sec. 610.41 of this chapter, including results of supplemental (i.e., 
additional, more specific) tests as required in Sec. 610.40(e) of this 
chapter.
    (2) You must make reasonable attempts to notify the autologous 
donor's referring physician within 8 weeks after determining that the 
autologous donor is deferred as described in paragraph (a) of this 
section. You must document that you have successfully notified the 
autologous donor's referring physician or when you are unsuccessful that 
you have made reasonable attempts to notify the physician.



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  Segments for testing.
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.

[[Page 88]]

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.

                        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 [Reserved]

                    Subpart L--Alternative Procedures

640.120  Alternative procedures.

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

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

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



                         Subpart A--Whole Blood



Sec. 640.1  Whole Blood.

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

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



Sec. 640.2  General requirements.

    (a) Manufacturing responsibility. All manufacturing of Whole Blood, 
including donor examination, blood collection, laboratory tests, 
labeling, storage and issue, shall be done under the supervision and 
control of the same licensed establishment except that the Director, 
Center for Biologics Evaluation and Research, may approve arrangements, 
upon joint request of two or more licensed establishments, which he 
finds are of such a nature as to assure compliance otherwise with the 
provisions of this subchapter.
    (b) Blood container. The blood container shall not be entered prior 
to issue for any purpose except for blood collection or when the method 
of processing requires use of a different container. The container shall 
be uncolored and transparent to permit visual inspection of the contents 
and any closure shall be such as will maintain 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.
    (c) Reissue of blood. Blood that has been removed from storage 
controlled by a licensed establishment shall not be reissued by a 
licensed establishment

[[Page 89]]

unless the following conditions are observed:
    (1) The container has a tamper-proof seal when originally issued and 
this seal remains unbroken;
    (2) A segment is properly attached and has not been removed, except 
that blood lacking a properly attached segment may be reissued in an 
emergency provided it is accompanied by instructions for sampling and 
for use within 6 hours after entering the container for sampling;
    (3) The blood has been stored continuously at 1 to 6  deg.C and 
shipped between 1 and 10  deg.C;
    (4) The blood is held for observation until a significant inspection 
consistent with the requirements of Sec. 640.5(e) can be made.

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



Sec. 640.3  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 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) of this section and for autologous donations, 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) For allogeneic donors, a blood hemoglobin level which shall be 
demonstrated to be no less than 12.5 grams (g) of hemoglobin per 100 
milliliters (mL) of blood; or a hematocrit value of 38 percent, and for 
autologous donors, a blood hemoglobin level which shall be demonstrated 
to be no less than 11.0 g of hemoglobin per 100 mL of blood or a 
hematocrit value of 33 percent.
    (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 after the 11th birthday;
    (2) A history of close contact within 12 months of donation with an 
individual having viral hepatitis;
    (3) A history of having received within 12 months of donation, human 
blood or any derivative of human blood which the Food and Drug 
Administration has advised the blood establishment is a possible source 
of viral hepatitis.

[[Page 90]]

    (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) [Reserved]
    (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; 64 FR 45371, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 
40889, Aug. 6, 2001]



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 the employees who collect blood when a physician is not 
present on the premises.
    (b) The donor center. The pertinent requirements of Secs. 600.10 and 
600.11 of this chapter shall apply at both the blood establishment and 
at any other place where the bleeding is performed.
    (c) Blood containers. Blood containers and donor sets shall be 
pyrogen-free, sterile and identified by lot number. The amount of 
anticoagulant required for the quantity of blood to be collected shall 
be in the blood container when it is sterilized. In addition, all 
container and donor set surfaces that come in contact with blood used in 
the processing of Heparin Whole Blood shall be water repellent.
    (d) The anticoagulant solution. The anticoagulant solution shall be 
sterile and pyrogen-free. Anticoagulant solutions shall be compounded 
and used according to a formula approved by the Director, Center for 
Biologics Evaluation and Research.
    (e) Donor identification. Each unit of blood shall be so marked or 
identified by number or other symbol as to relate it to the individual 
donor whose identity shall be established to the extent necessary for 
compliance with Sec. 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) Samples and segments for laboratory tests. Samples and segments 
for laboratory tests shall meet the following standards:
    (1) One or more segments shall be provided with each unit of blood 
when issued or reissued except as provided in Sec.  640.2(c)(2) and all 
segments shall be from the donor who is the source of the unit of blood.
    (2) All samples for laboratory tests performed by the manufacturer 
and all segments accompanying a unit of blood shall be collected at the 
time of filling the original blood container.
    (3) All containers for all samples shall bear the donor's 
identification before collecting the samples.
    (4) All segments accompanying a unit of blood shall be attached to 
the whole blood container before blood collection, in a tamperproof 
manner that will conspicuously indicate removal and reattachment.
    (5) Segments for compatibility testing shall contain blood mixed 
with the appropriate anticoagulant.
    (h) Storage. 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 and 6  deg.C unless it must be transported from 
the donor clinic to the processing

[[Page 91]]

laboratory. In the latter case, the blood shall be placed in temporary 
storage having sufficient refrigeration capacity to cool the blood 
continuously toward a range between 1 and 6  deg.C until it arrives at 
the processing laboratory, where it shall be stored at a temperature 
between 1 and 6  deg.C. Blood from which Platelets is to be prepared 
shall be held in an environment maintained at a temperature range 20 to 
24  deg.C until the platelets are separated. The red blood cells shall 
be placed in storage at a temperature between 1 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; 64 FR 45372, Aug. 19, 1999; 66 FR 
1836, Jan. 10, 2001; 66 FR 40889, Aug. 6, 2001]



Sec. 640.5  Testing the blood.

    All laboratory tests shall be made on a 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 
sample. The label shall indicate the extent of typing and the results of 
all tests performed. If the test, using Anti-D Blood Grouping Reagent, 
is positive, the container may be labeled ``Rh Positive.'' If the test 
is negative, the results shall be confirmed by further testing which 
shall include tests for the ``weak D (formerly D\u\).'' Blood may be 
labeled ``Rh Negative'' if further testing is negative. Units testing 
positive after additional more specific testing shall be labeled as ``Rh 
Positive.'' Only Anti-Rh Blood Grouping Reagents licensed under, or that 
otherwise meet the requirements of, this subchapter shall be used, and 
the technique used shall be that for which the reagent is specifically 
designed to be effective.
    (d) Sterility test. Whole Blood intended for transfusion shall not 
be tested for sterility by a method that entails entering the final 
container before the blood is used for transfusion.
    (e) Inspection. Whole Blood shall be inspected visually during 
storage and immediately prior to issue. If the color or physical 
appearance is abnormal or there is any indication or suspicion of 
microbial contamination the unit of Whole Blood shall not be issued for 
transfusion.
    (f) Test for communicable disease agents. Whole Blood shall be 
tested for evidence of infection due to communicable disease agents as 
required under Sec. 610.40 of this chapter.

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



Sec. 640.6  Modifications of Whole Blood.

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

[[Page 92]]

the plasma is being frozen for removal of the antihemophilic factor.

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



                       Subpart B--Red Blood Cells



Sec. 640.10  Red Blood Cells.

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

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



Sec. 640.11  General requirements.

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

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



Sec. 640.12  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.
    (b) Source blood may also be derived from Whole Blood manufactured 
in accordance with applicable provisions of this subchapter.

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



Sec. 640.14  Testing the blood.

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

[53 FR 117, Jan. 5, 1988, as amended at 66 FR 31165, June 11, 2001]



Sec. 640.15  Segments for testing.

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

[66 FR 40890, Aug. 6, 2001]



Sec. 640.16  Processing.

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

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

[[Page 93]]



Sec. 640.17  Modifications for specific products.

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

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



                          Subpart C--Platelets



Sec. 640.20  Platelets.

    (a) Proper name and definition. The proper name of this product 
shall be Platelets. The product is defined as platelets collected from 
one unit of blood and resuspended in an appropriate volume of original 
plasma, as prescribed in Sec. 640.24(d).
    (b) Source. The source material for Platelets 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 biologics license application or a supplement to the 
biologics license application, 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; 64 
FR 56453, Oct. 20, 1999]



Sec. 640.22  Collection of source material.

    (a) Whole blood used as the source of Platelets shall be collected 
as prescribed in Sec. 640.4.
    (b) 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 biologics license application or a supplement to a 
biologics license application, and must have the written approval of the 
Director, Center for Biologics Evaluation and Research, Food and Drug 
Administration.
    (d) The phlebotomy shall be performed by a single uninterrupted 
venipuncture with minimal damage to, and minimal manipulation of, the 
donor's tissue.

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



Sec. 640.23  Testing the blood.

    (a) Blood from which plasma is separated for the preparation of 
Platelets shall be tested as prescribed in Sec. 610.40 of this chapter 
and Sec. 640.5 (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; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, 
2001; 66 FR 31165, June 11, 2001]



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.

[[Page 94]]

    (b) Immediately after collection, the whole blood or plasma shall be 
held in storage between 20 and 24  deg.C unless it must be transported 
from the collection center to the processing laboratory. During such 
transport, all reasonable methods shall be used to maintain the 
temperature as close as possible to a range between 20 and 24  deg.C 
until it arrives at the processing laboratory where it shall be held 
between 20 and 24  deg.C until the platelets are separated. The platelet 
concentrate shall be separated within 4 hours or within the timeframe 
specified in the directions for use for the blood collecting, 
processing, and storage system.
    (c) The time and speed of centrifugation must have been demonstrated 
to produce an unclumped product, without visible hemolysis, that yields 
a count of not less than 5.5x10\10\ platelets per unit in at least 75 
percent of the units tested.
    (d) The volume of original plasma used for resuspension of the 
platelets shall be determined by the maintenance of a pH of not less 
than 6.0 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 to 24  deg.C.
    (2) 1 to 6  deg.C.
    (e) Final containers used for Platelets shall be colorless and 
transparent to permit visual inspection of the contents; any closure 
shall maintain a hermetic seal and prevent contamination of the 
contents. The container material shall not interact with the contents, 
under the customary conditions of storage and use, in such a manner as 
to have an adverse effect upon the safety, purity, potency, or efficacy 
of the product. At the time of filling, the final container shall be 
marked or identified by number so as to relate it to the donor.

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



Sec. 640.25  General requirements.

    (a) Storage. Immediately after resuspension, Platelets shall be 
placed in storage at the selected temperature range. If stored at 20 to 
24  deg.C, a continuous gentle agitation of the platelet concentrate 
shall be maintained throughout the storage period. Agitation is optional 
if stored at a temperature between 1 and 6  deg.C.
    (b) Quality control testing. Each month four units prepared from 
different donors shall be tested at the end of the storage period as 
follows:
    (1) Platelet count.
    (2) pH of not less than 6.0 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 of the 
Clinical Laboratories Improvement Amendments of 1988 (CLIA) (42 U.S.C. 
263a) and is qualified to perform platelet counts. Such arrangements 
must be approved by the Director, Center for Biologics Evaluation and 
Research, Food and Drug Administration. Such testing shall not be 
considered as divided manufacturing, as described in Sec. 610.63 of this 
chapter, provided the following conditions are met:
    (1) The results of each test are received within 10 days of the 
preparation of the platelet concentrate, and are maintained by the 
establishment licensed for Platelets so that they may be reviewed by an 
authorized representative of the Food and Drug Administration.
    (2) The licensed Platelets manufacturer has obtained a written 
agreement that the testing laboratory will permit an authorized 
representative of the Food and Drug Administration to inspect its 
testing procedures and facilities during reasonable business hours.

[[Page 95]]

    (3) The testing laboratory will participate in any proficiency 
testing programs undertaken by the Center for Biologics Evaluation and 
Research, Food and Drug Administration.

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



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.

[42 FR 59878, Nov. 22, 1977, as amended at 64 FR 45372, Aug. 19, 1999]



Sec. 640.32  Collection of source material.

    (a) Whole blood shall be collected, transported, and stored as 
prescribed in Sec. 640.4. When whole blood is intended for Plasma, Fresh 
Frozen Plasma, and Liquid Plasma, it shall be maintained at a 
temperature between 1 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 a temperature between 1 and 6  deg.C 
immediately after the plasma is separated.
    (b) Plasma obtained by plasmapheresis shall be collected as 
prescribed in 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; 64 FR 45372, Aug. 19, 1999]



Sec. 640.33  Testing the blood.

    (a) Blood from which plasma is separated shall be tested as 
prescribed in Sec. 610.40 of this chapter and Sec. 640.5 (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; 66 FR 31165, June 
11, 2001]



Sec. 640.34  Processing.

    (a) Plasma. Plasma shall be separated from the red blood cells and 
shall be stored at -18  deg.C or colder within 6 hours after transfer to 
the final container or within the timeframe specified in the directions 
for use for the blood collecting, processing, and storage system unless 
the product is to be stored as Liquid Plasma.
    (b) Fresh Frozen Plasma. Fresh frozen plasma shall be prepared from 
blood collected by a single uninterrupted

[[Page 96]]

venipuncture with minimal damage to and minimal manipulation of the 
donor's tissue. The plasma shall be separated from the red blood cells, 
and placed in a freezer within 8 hours or within the timeframe specified 
in the directions for use for the blood collecting, processing, and 
storage system, and stored at -18  deg.C or colder.
    (c) Liquid Plasma. Liquid Plasma shall be separated from the red 
blood cells and shall be stored at a temperature of 1 to 6  deg.C within 
4 hours after filling the final container or within the timeframe 
specified in the directions for use for the blood collecting, 
processing, and storage system.
    (d) Platelet Rich Plasma. Platelet rich plasma shall be prepared 
from blood collected by a single uninterrupted venipuncture with minimal 
damage to and manipulation of the donor's tissue. The plasma shall be 
separated from the red blood cells by centrifugation within 4 hours 
after completion of the phlebotomy or within the timeframe specified in 
the directions for use for the blood collecting, processing, and storage 
system. The time and speed of the centrifugation shall have been shown 
to produce a product with at least 250,000 platelets per microliter. The 
plasma shall be stored at a temperature between 20 and 24  deg.C 
immediately after filling the final container. A gentle and continuous 
agitation of the product shall be maintained throughout the storage 
period, if stored at a temperature of 20 to 24  deg.C.
    (e) Modifications of Plasma. It is possible to separate Platelets 
and/or Cryoprecipitated AHF from Plasma. When these components are to be 
separated, the plasma shall be collected as described in Sec. 640.32 for 
Plasma.
    (1) Platelets shall be separated as prescribed in subpart C of part 
640, prior to freezing the plasma. The remaining plasma may be labeled 
as ``Fresh Frozen Plasma,'' if frozen within 6 hours after filling the 
final container or within the timeframe specified in the directions for 
use for the blood collecting, processing, and storage system.
    (2) Cryoprecipitated AHF shall be removed as prescribed in subpart F 
of part 640. The remaining plasma shall be labeled ``Plasma, 
Cryoprecipitate Reduced.''
    (3) Plasma remaining after both Platelets and Cryoprecipitated AHF 
have been removed may be labeled ``Plasma, Cryoprecipitate Reduced.''
    (f) The final container. (1) The final container shall have no color 
added to the plastic and shall be transparent to permit visual 
inspection of the contents; any closure shall maintain a hermetic seal 
and prevent contamination of the contents.
    (2) The final container material shall not interact with the 
contents, under the customary conditions of storage and use, in such a 
manner as to have an adverse effect upon the safety, purity, potency, 
and effectiveness of the product.
    (3) Prior to filling, the final container shall be identified by 
number so as to relate it to the donor.
    (g) The final product. (1) The final product shall be inspected 
immediately after separation of the plasma and shall not be issued for 
transfusion if there is (i) any abnormality in color or physical 
appearance, or (ii) any indication of contamination.
    (2) With the exception of Platelet Rich Plasma and Liquid Plasma the 
final product shall be inspected for evidence of thawing or breakage at 
the time of issuance, however, the containers need not be stored in a 
manner that shows evidence of thawing if records of continuous 
monitoring of the storage temperature establish that the temperature 
remained at -18  deg.C or colder. If continuous monitoring of the 
product is not available, the final product shall be stored in a manner 
that will show evidence of thawing and shall not be issued if there is 
any evidence of thawing.
    (3) No preservative shall be added to the final product.

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

Subpart E [Reserved]

[[Page 97]]



                       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.

[42 FR 21774, Apr. 29, 1977, as amended at 64 FR 45373, Aug. 19, 1999]



Sec. 640.52  Collection of source material.

    (a) Whole blood used as a source of Cryoprecipitated AHF shall be 
collected as prescribed in Sec. 640.4. Whole blood from which both 
Platelets and Cryoprecipitated AHF is derived shall be maintained as 
required under Sec. 640.24 until the platelets are removed.
    (b) If plasmapheresis is used, the procedure for collection shall be 
as prescribed in 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; 64 
FR 45373, Aug. 19, 1999]



Sec. 640.53  Testing the blood.

    (a) Blood from which plasma is separated for the preparation of 
Cryoprecipitated AHF shall be tested as prescribed in Sec. 610.40 of 
this chapter and Sec. 640.5 (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; 66 FR 31165, June 11, 2001]



Sec. 640.54  Processing.

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

[[Page 98]]

of filling, the final container shall be identified by a number so as to 
relate it to the donor.

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



Sec. 640.55  U.S. Standard preparation.

    A U.S. Standard Antihemophilic Factor (Factor VIII) preparation may 
be obtained from the Center for Biologics Evaluation and Research, 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 Amendments of 1988 (CLIA) (42 U.S.C. 263a) and 
is qualified to perform potency tests for antihemophilic factor. Such 
arrangements must be approved by the Director, Center for Biologics 
Evaluation and Research, Food and Drug Administration. Such testing 
shall not be considered as divided manufacturing, as described in 
Sec. 610.63 of this chapter, provided the following conditions are met:
    (1) The establishment licensed for Cryoprecipitated AHF has obtained 
a written agreement that the testing laboratory will permit an 
authorized representative of the Food and Drug Administration to inspect 
its testing procedures and facilities during reasonable business hours.
    (2) The testing laboratory will participate in any proficiency 
testing programs undertaken by the Center for Biologics Evaluation and 
Research, Food and Drug Administration.
    (d) If the average potency level of antihemophilic factor in the 
containers tested is less than 80 units of antihemophilic factor per 
container, immediate corrective actions shall be taken and a record 
maintained of such action.

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



                        Subpart G--Source Plasma



Sec. 640.60  Source Plasma.

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

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



Sec. 640.61  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 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.

[66 FR 1837, Jan. 10, 2001]

[[Page 99]]



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 or a hematocrit level of 38 
percent;
    (4) A normal pulse rate;
    (5) A total serum or total plasma protein of no less than 6.0 grams 
per 100 milliliters of blood;
    (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 after the 11th 
birthday;
    (12) Freedom from a history of close contact within 12 months of 
donation with an individual having viral hepatitis;
    (13) Freedom from a history of having received, within 12 months, 
human blood or any derivative of human blood which the Food and Drug 
Administration has advised the blood establishment is a possible source 
of viral hepatitis, except for specific immunization performed in 
accordance with Sec. 640.66.
    (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 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;

[[Page 100]]

    (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; 64 FR 45373, Aug. 19, 1999; 66 FR 
1837, Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001]



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 biologics license application for Source Plasma.
    (1) Anticoagulant citrate dextrose solution (ACD).

Tri-sodium citrate                         22.0 grams.
 (Na3C6H5O7[middot]2H2O).
Citric acid (C6H8O7[middot]H2O)..........  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                         26.3 grams.
 (Na3C6H5O7[middot]2H2O).
Citric acid (C6H8O7[middot]H2O)..........  3.27 grams.
Dextrose (C6H12O6H2O)....................  25.5 grams.
Monobasic sodium phosphate                 2.22 grams.
 (NaH2PO4[middot]H2O).
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                         40 grams.
 (Na3C6H5O7[middot]2H2O).
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; 63 FR 
16685, Apr. 6, 1998; 64 FR 56453, Oct. 20, 1999]



Sec. 640.65  Plasmapheresis.

    (a) Procedure-general. The plasmapheresis procedure is a procedure 
in which, during a single visit to the establishment, blood is removed 
from a donor, the plasma separated from the formed elements, and at 
least the red blood cells returned to the donor. This procedure shall be 
described in detail in the biologics license application.
    (b) Procedures-specific requirements. The plasmapheresis procedure 
shall meet the following requirements:
    (1)(i) 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 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

[[Page 101]]

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 manual plasmapheresis procedure or in any 2-day 
period shall not exceed 1,000 milliliters unless the donor's weight is 
175 pounds or greater, in which case the amount of whole blood, not 
including anticoagulant, removed from the donor during a manual 
plasmapheresis procedure or in any 2-day period shall not exceed 1,200 
milliliters.
    (5) The amount of whole blood, not including anticoagulant, removed 
from a donor during a manual plasmapheresis procedure within a 7-day 
period shall not exceed 2,000 milliliters unless the donor's weight is 
175 pounds or greater, in which case the amount of whole blood, not 
including anticoagulant, removed from a donor during a manual 
plasmapheresis procedure within a 7-day period shall not exceed 2,400 
milliliters.
    (6) No more than 500 milliliters of whole blood shall be removed 
from a donor at one time, unless the donor's weight is 175 pounds or 
greater, in

[[Page 102]]

which case no more than 600 milliliters of whole blood shall be removed 
from the donor at one time.
    (7) The plasma shall be separated from the red blood cells 
immediately after blood collection. The maximum feasible volume of red 
blood cells shall be returned to the donor before another unit is 
collected.
    (8) The volume of plasma collected during an automated 
plasmapheresis collection procedure shall be consistent with the volumes 
specifically approved by the Director, Center for Biologics Evaluation 
and Research, and collection shall not occur less than 2 days apart or 
more frequently than twice in a 7-day period.

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



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.

    Each unit of Source Plasma shall be tested for evidence of infection 
due to communicable disease agents as required under Sec. 610.40 of this 
chapter.

[66 FR 31165, June 11, 2001]



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 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

[[Page 103]]

manufacture of Source Plasma intended for manufacturing into injectable 
products.
    (2) The pooling of plasma from two or more donors by the 
manufacturer of Source Plasma intended for manufacturing into 
noninjectable products is permitted: Provided, That the plasma from two 
or more donors is pooled after the plasma has been removed from the red 
blood cells, and after the red blood cell containers are sealed.
    (b) Storage. Immediately after filling, plasma intended for 
manufacturing into injectable products shall be stored at a temperature 
not warmer than -20  deg.C, except for plasma collected as provided in 
Sec. 640.74. Plasma intended for manufacturing into noninjectable 
products may be stored at temperatures appropriate for the intended use 
of the final product, provided these temperatures are included in the 
Source Plasma license application.
    (c) Inspection. Source Plasma intended for manufacturing into 
injectable products shall be inspected for evidence of thawing at the 
time of issuance, except that inspection of individual plasma containers 
need not be made if the records of continuous monitoring of the storage 
temperature establish that the temperature remained at -20  deg.C or 
colder. If there is evidence that the storage temperature has not been 
maintained at -20  deg.C or colder, the plasma may be relabeled and 
issued as provided in Sec. 640.76(a).
    (d) Samples. If samples are provided, they shall meet the following 
standards:
    (1) Prior to filling, all samples shall be marked or identified so 
as to relate them directly to the donor of that unit of plasma.
    (2) All samples shall be filled at the time the final product is 
prepared by the person who prepares the final product.
    (3) All samples shall be representative of the contents of the final 
product or be collected from the donor at the time of filling the 
collection container.
    (4) All samples shall be collected in a manner that does not 
contaminate the contents of the final container.

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



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. If the Source Plasma 
has a reactive screening test for evidence of infection due to a 
communicable disease agent(s) under Sec. 610.40 of this chapter, or is 
collected from a donor with a previous record of a reactive screening 
test for evidence of infection due to a communicable disease agent(s) 
under Sec. 610.40 of this chapter, the Source Plasma must be labeled 
under Sec. 610.40(h)(2)(ii)(E) of this chapter.
    (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

[[Page 104]]

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.
    (8) The test for hepatitis B surface antigen used for the results, 
or the statement ``Nonreactive for HBs Ag 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; 63 FR 
16685, Apr. 6, 1998; 66 FR 31165, June 11, 2001]



Sec. 640.71  Manufacturing responsibility.

    (a) All steps in the manufacturing of Source Plasma, including donor 
examination, blood collection, plasmapheresis, laboratory testing, 
labeling, storage, and issuing shall be performed by personnel of the 
establishment licensed to manufacture Source Plasma, except that the 
following tests may be performed by personnel of an establishment 
licensed for blood and blood derivatives under section 351(a) of the 
Public Health Service Act, or by a clinical laboratory that meets the 
standards of the Clinical Laboratories Improvement Amendments of 1988 
(CLIA) (42 U.S.C. 263a): Provided, The establishment or clinical 
laboratory is qualified to perform the assigned test(s).
    (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 biologics licenses for Source Plasma: Provided, That
    (1) The results of such tests are maintained by the licensed 
manufacturer of the Source Plasma whereby such results may be reviewed 
by a licensed physician as required in Sec. 640.65(b)(2) of this chapter 
and by an authorized representative of the Food and Drug Administration.
    (2) The Source Plasma manufacturer has obtained a written agreement 
that the testing laboratory will permit authorized representatives of 
the Food and Drug Administration to inspect its testing procedures and 
facilities during reasonable business hours.
    (3) The testing laboratory will participate in any proficiency 
testing programs undertaken by the Center for Biologics Evaluation and 
Research, Food and Drug Administration.

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



Sec. 640.72  Records.

    (a) In addition to the recordkeeping requirements of this 
subchapter, the following records shall be maintained:
    (1) Documentation shall be available to ensure that the shipping 
temperature requirements of Sec. 600.15 of this title and of 
Sec. 640.74(b)(2) are being met for Source Plasma intended for 
manufacture into injectable products.

[[Page 105]]

    (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.
    (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.

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



Sec. 640.73  Reporting of fatal donor reactions.

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

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



Sec. 640.74  Modification of Source Plasma.

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

[[Page 106]]

    (5) Source Plasma Liquid shall be inspected immediately prior to 
issuance. If the color or physical appearance is abnormal, or there is 
any indication or suspicion of microbial contamination, the unit of 
Source Plasma Liquid shall not be issued.

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



Sec. 640.76  Products stored or shipped at unacceptable temperatures.

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

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



                       Subpart H--Albumin (Human)



Sec. 640.80  Albumin (Human).

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

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

[[Page 107]]



Sec. 640.81  Processing.

    (a) Date of manufacture. The date of manufacture shall be the date 
of final sterile filtration of a uniform pool of bulk solution.
    (b) Processing method. The processing method shall not affect the 
integrity of the product, and shall have been shown to yield 
consistently a product which is safe for intravenous injection.
    (c) Microbial contamination. All processing steps shall be conducted 
in a manner to minimize the risk of contamination from microorganisms, 
pyrogens, or other impurities. Preservatives to inhibit growth of 
microorganisms shall not be used during processing.
    (d) Storage of bulk fraction. Bulk concentrate to be held more than 
1 week prior to further processing shall be stored in clearly identified 
closed vessels at a temperature of -5  deg.C or colder. Any other bulk 
form of the product, exclusive of the sterile bulk solution, to be held 
more than 1 week prior to further processing shall be stored in clearly 
identified closed vessels at a temperature of 5  deg.C or colder. Any 
bulk fraction to be held one week or less prior to further processing 
shall be stored in clearly identified closed vessels at a temperature of 
5  deg.C or colder.
    (e) Heat treatment. Heating of the final containers of Albumin 
(Human) shall begin within 24 hours after completion of filling. Heat 
treatment shall be conducted so that the solution is heated continuously 
for not less than 10, or more than 11 hours, at an attained temperature 
of 600.5  deg.C.
    (f) Stabilizer. Either 0.080.016 millimole sodium 
caprylate, or 0.080.016 millimole sodium acetyltryptophanate 
and 0.080.016 millimole sodium caprylate per gram of protein 
shall be present as a stabilizer(s). Calculations of the stabilizer 
concentration may employ the labeled value for the protein concentration 
of the product as referred to in Sec. 640.84(d).
    (g) Incubation. All final containers of Albumin (Human) shall be 
incubated at 20 to 35  deg.C for at least 14 days following the heat 
treatment prescribed in paragraph (e) of this section. At the end of 
this incubation period, each final container shall be examined and all 
containers showing any indication of turbidity or microbial 
contamination shall not be issued. The contents of turbid final 
containers shall be examined microscopically and tested for sterility. 
If growth occurs, organisms shall be identified as to genus, and the 
material from such containers shall not be used for further 
manufacturing.

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



Sec. 640.82  Tests on final product.

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

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



Sec. 640.83  General requirements.

    (a) Preservative. The final product shall not contain a 
preservative.

[[Page 108]]

    (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, the container and package labels shall 
contain the following information:
    (a) The osmotic equivalent in terms of plasma, and the sodium 
concentration in terms of a value or a range in milliequivalents per 
liter;
    (b) The cautionary statement placed in a prominent position on the 
label, ``Do Not Use if Turbid. Do Not Begin Administration More Than 4 
Hours After the Container Has Been Entered.'';
    (c) The need for additional fluids when 20 percent or 25 percent 
albumin is administered to a patient with marked dehydration;
    (d) The protein concentration, expressed as a 4 percent, 5 percent, 
20 percent, or 25 percent solution.

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



               Subpart I--Plasma Protein Fraction (Human)

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



Sec. 640.90  Plasma Protein Fraction (Human).

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

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



Sec. 640.91  Processing.

    (a) Date of manufacture. The date of manufacture shall be the date 
of final sterile filtration of a uniform pool of bulk solution.
    (b) Processing method. The processing method shall not affect the 
integrity of the product, and shall have been shown to yield 
consistently a product which:
    (1) After the heating prescribed in paragraph (e) of this section 
does not show an increase in the components with electrophoretic 
mobility similar to that of alpha globulin that amounts to more than 5 
percent of the total protein.
    (2) Contains less than 5 percent protein with a sedimentation 
coefficient greater than 7.0 S.
    (3) Is safe for intravenous injection.
    (c) Microbial contamination. All processing steps shall be conducted 
in a manner to minimize the risk of contamination from microorganisms, 
pyrogens, or other impurities. Preservatives to inhibit growth of 
microorganisms shall not be used during processing.
    (d) Storage of bulk fraction. Bulk concentrate to be held more than 
1 week prior to further processing shall be stored in clearly identified 
closed vessels at a temperature of -5  deg.C or colder. Any other bulk 
form of the product (exclusive of the sterile bulk solution) to be held 
more than 1 week prior to further processing, shall be stored in clearly 
identified closed vessels at a temperature of 5  deg.C or colder. Any 
bulk fraction to be held one week or less prior to further processing 
shall be stored in clearly identified closed vessels at a temperature of 
5  deg.C or colder.
    (e) Heat treatment. Heating of the final containers of Plasma 
Protein Fraction (Human) shall begin within 24

[[Page 109]]

hours after completion of filling. Heat treatment shall be conducted so 
that the solution is heated continuously for not less than 10 or more 
than 11 hours at an attained temperature of 600.5  deg.C.
    (f) Stabilizer. Either 0.080.016 millimole sodium 
caprylate, or 0.080.016 millimole sodium acetyltryptophanate 
and 0.080.016 millimole sodium caprylate per gram of protein 
shall be present as a stabilizer(s). Calculations of the stabilizer 
concentration may employ the labeled value 5 percent for the protein 
concentration of the product.
    (g) Incubation. All final containers of Plasma Protein Fraction 
(Human) shall be incubated at 20 to 35  deg.C for at least 14 days 
following the heat treatment prescribed in paragraph (e) of this 
section. At the end of this incubation period, each final container 
shall be examined and all containers showing any indication of turbidity 
or microbial contamination shall not be issued. The contents of turbid 
final containers shall be examined microscopically and tested for 
sterility. If growth occurs, the types of organisms shall be identified 
as to genus and the material from such containers shall not be used for 
further manufacturing.

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



Sec. 640.92  Tests on final product.

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

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



Sec. 640.93  General requirements.

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



Sec. 640.94  Labeling.

    In addition to the labeling requirements of 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 
concentration in terms of a value or a range in milliequivalents per 
liter.
    (b) The cautionary statement placed in a prominent position on the 
label, ``Do Not Use if Turbid. Do Not Begin Administration More than 4 
Hours After the Container Has Been Entered.''

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

[[Page 110]]



                   Subpart J--Immune Globulin (Human)



Sec. 640.100  Immune Globulin (Human).

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

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



Sec. 640.101  General requirements.

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

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



Sec. 640.102  Manufacture of Immune Globulin (Human).

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

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



Sec. 640.103  The final product.

    (a) Final solution. The final product shall be a 16.5 
1.5 percent solution of

[[Page 111]]

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

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



Sec. 640.104  Potency.

    (a) Antibody levels and tests. Each lot of final product shall 
contain at least the minimum levels of antibodies for diphtheria, 
measles, and for at least one type of poliomyelitis. In the event the 
final bulk solution is stored at a temperature above 5  deg.C the 
antibody level tests shall be performed after such storage with a sample 
of the stored material.
    (b) Minimum levels. The minimum antibody levels are as follows:
    (1) No less than 2 units of diphtheria antitoxin per ml.
    (2) A measles neutralizing antibody level that, when compared with 
that of a reference material designated by the Center for Biologics 
Evaluation and Research (CBER), Food and Drug Administration, as 
indicated in paragraph (c) of this section, demonstrates adequate 
potency. The Director, CBER, shall notify manufacturers when a new 
reference material will be used and will advise manufacturers of an 
appropriate antibody level taking into account a comparison of the new 
reference material to the previous reference material.
    (3) A poliomyelitis Type 1, Type 2, or Type 3 neutralizing antibody 
level that, when compared with that of a reference material designated 
by the Center for Biologics Evaluation and Research, Food and Drug 
Administration, as indicated in paragraph (c) of this section, 
demonstrates adequate potency. The Director, CBER, shall notify 
manufacturers when a new reference material will be used and will advise 
manufacturers of an appropriate antibody level taking into account a 
comparison of the new reference material to the previous reference 
material.
    (c) Reference materials. The following reference materials shall be 
obtained from the Center for Biologics Evaluation and Research:
    (1) Reference Immune Globulin for correlation of measles antibody 
titers.
    (2) Reference Immune Globulin for correlation of poliomyelitis 
antibody titers, Types 1, 2, and 3.

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

Subpart K [Reserved]



                    Subpart L--Alternative Procedures



Sec. 640.120  Alternative procedures.

    (a) The Director, Center for Biologics Evaluation and Research, may 
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 shall ordinarily be in writing. Licensed establishments 
shall submit such requests in accordance with Sec. 601.12 of this 
chapter. 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 promptly followed by written requests and written 
approvals.
    (b) FDA will publish a list of approved alternative procedures and 
exceptions periodically in the Federal Register.

[55 FR 10423, Mar. 21, 1990, as amended at 62 FR 39903, July 24, 1997]



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 112]]

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.
660.43  Potency test.
660.44  Specificity.
660.45  Labeling.
660.46  Samples; protocols; official release.

                     Subpart F--Anti-Human Globulin

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

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

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



           Subpart A--Antibody to Hepatitis B Surface Antigen



Sec. 660.1  Antibody to Hepatitis B Surface Antigen.

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

[40 FR 29711, July 15, 1975]



Sec. 660.2  General requirements.

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

[[Page 113]]

    (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 (\125\I) shall be the day of labeling the antibody with the 
radionuclide.
    (f) Retention samples. Each manufacturer shall retain representative 
samples of the product in accordance with Sec. 600.13 of this chapter 
except for that which has been iodinated with radioactive iodine. 
Retention samples of Antibody to Hepatitis B Surface Antigen iodinated 
with \125\I shall consist of a minimum of two complete finished packages 
of each lot of the diagnostic test kit and shall be retained for a 
period of at least 90 days from the date of manufacture.

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



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 \125\I means a sample from each filling of 
each lot packaged as for distribution, including all ancillary reagents 
and materials; and a sample of product iodinated with \125\I means a 
sample from each lot of diagnostic test kits in a finished package, 
including all ancillary reagents and materials.
    (2) Unless the Director, Center for Biologics Evaluation and 
Research, determines that the reliability and consistency of the 
finished product can be assured with a smaller quantity of sample or no 
sample and specifically reduces or eliminates the required quantity of 
sample, each manufacturer shall submit the following samples to the 
Director, Center for Biologics Evaluation and Research (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

[[Page 114]]

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 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.

[53 FR 12764, Apr. 19, 1988, as amended at 65 FR 77499, Dec. 12, 2000]



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.
    (2) Only that material that has been fully processed, thoroughly 
mixed in a single vessel, and filtered shall constitute a lot.
    (3) A lot may be subdivided into sublots. If lots are to be 
subdivided, the manufacturer shall include this information in the 
biologics license application. The manufacturer shall describe the test 
specifications to verify that each sublot is identical to other sublots 
of the lot.

[[Page 115]]

    (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 biologics license application.
    (e) Date of manufacture. The date of manufacture shall be the date 
the manufacturer begins the last entire group of potency tests.

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



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.

[53 FR 12764, Apr. 19, 1988, as amended at 67 FR 9587, Mar. 4, 2002]



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-Kp\a\, Anti-Kp\b\, Anti-Js\a\, Anti-Js\b\, 
Anti-Fy\b\, Anti-N, Anti-Le\a\, Anti-Le\b\, Anti-Lu\a\, Anti-Lu\b\, 
Anti-Di\a\, Anti-M\g\, Anti-Jk\b\, Anti-Co\b\, Anti-Wr\a\, and Anti-
Xg\a\, at least 2+ reaction with undiluted reagent.
    (b) Products recommended for slide tests or microplate techniques. 
Blood Grouping Reagent recommended for slide test methods or microplate 
techniques shall produce clearly positive macroscopic results when both 
undiluted reagent and reagent diluted with an equal volume of diluent 
are tested by all methods recommended in the manufacturer's package 
insert using red blood cells showing heterozygous or diminished 
expression of the corresponding antigen. The dilution shall be made with 
an equal volume of compatible serum or approved diluent.
    (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

[[Page 116]]

cells representing heterozygous or diminished expression of the 
corresponding antigen.

[53 FR 12764, Apr. 19, 1988, as amended at 67 FR 9587, Mar. 4, 2002]



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.

[53 FR 12764, Apr. 19, 1988, as amended at 67 FR 9587, Mar. 4, 2002]



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 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.

[[Page 117]]

    (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; 67 
FR 9587, Mar. 4, 2002]



                   Subpart D--Reagent Red Blood Cells

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



Sec. 660.30  Reagent Red Blood Cells.

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

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



Sec. 660.31  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

[[Page 118]]

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 
biologics license application. Group O Reagent Red Blood Cells used in 
the detection or identification of unexpected antibodies shall include 
at least the following common antigens in each lot of the product: D, C, 
E, c, e, K, k, 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; 64 
FR 56454, Oct. 20, 1999]



Sec. 660.34  Processing.

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

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

[[Page 119]]



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 
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.

[52 FR 37450, Oct. 7, 1987, as amended at 67 FR 9587, Mar. 4, 2002]

[[Page 120]]



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.

[52 FR 37450, Oct. 7, 1987, as amended at 55 FR 11013 and 11015, Mar. 
26, 1990; 67 FR 9587, Mar. 4, 2002]



                 Subpart E--Hepatitis B Surface Antigen

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



Sec. 660.40  Hepatitis B Surface Antigen.

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



Sec. 660.41  Processing.

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

[[Page 121]]

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. 660.43  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 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.

[[Page 122]]

    (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).
    (b) Source. The source of this product shall be either serum from 
animals immunized with one or more human serum globulins or protein-rich 
fluids derived from stable immunoglobulin-secreting cell lines 
maintained either in tissue cultures or in secondary hosts.

[50 FR 5579, Feb. 11, 1985, as amended at 65 FR 77499, Dec. 12, 2000]



Sec. 660.51  Processing.

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

[[Page 123]]

    (c) Date of manufacture. The date of manufacture shall be the date 
the manufacturer begins the last entire group of potency tests.

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



Sec. 660.52  Reference preparations.

    Reference Anti-Human Globulin preparations shall be obtained from 
the 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.

[50 FR 5579, Feb. 11, 1985, as amended at 50 FR 16474, Apr. 26, 1985; 51 
FR 15611, Apr. 25, 1986; 55 FR 11015, Mar. 26, 1990; 67 FR 9587, Mar. 4, 
2002]



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.

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



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.

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



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.

[[Page 124]]

    (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 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.

[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; 67 FR 9587, Mar. 4, 
2002]



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




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

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

[[Page 125]]


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

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



Sec. 680.1  Allergenic Products.

    (a) Definition. Allergenic Products are products that are 
administered to man for the diagnosis, prevention or treatment of 
allergies.
    (b) Source materials--(1) Criteria for source material. Only 
specifically identified allergenic source materials that contain no more 
than a total of 1.0 percent of detectable foreign materials shall be 
used in the manufacture of Allergenic Products, except that this 
requirement shall not apply to molds and animals described under 
paragraphs (b) (2) and (3) of this section, respectively. Source 
materials such as pelts, feathers, hairs, and danders shall be collected 
in a manner that will minimize contamination of the source material.
    (2) Molds. (i) Molds (excluding rusts and smuts) used as source 
material in the manufacture of Allergenic Products shall meet the 
requirements of Sec. 610.18 of this chapter and Sec. 680.2 (a) and (b).
    (ii) Mold cultures shall be free of contaminating materials 
(including microorganisms) prior to harvest, and care shall be taken to 
minimize contamination during harvest and subsequent processing.
    (iii) Mold manufacturers shall maintain written standard operating 
procedures, developed by a qualified individual, that will ensure the 
identity of the seed culture, prescribe adequate processing of the mold, 
and specify the acceptable limits and kinds of contamination. These 
limits shall be based on results of appropriate tests performed by the 
manufacturer on at least three consecutive lots of a mold that is a 
representative species of mold subject to the standard operating 
procedures. The tests shall be performed at each manufacturing step 
during and subsequent to harvest, as specified in the standard operating 
procedures. Before use of the mold as a source material for Allergenic 
Products, in accordance with 21 CFR 601.2, the standard operating 
procedures and test data from the three representative lots described 
above shall be submitted to and approved by the Director, Center for 
Biologics Evaluation and Research (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

[[Page 126]]

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

[38 FR 32100, Nov. 20, 1973, as amended at 49 FR 25432, June 21, 1984; 
49 FR 31395, Aug. 7, 1984; 55 FR 11014, Mar. 26, 1990; 67 FR 9587, Mar. 
4, 2002]



Sec. 680.2  Manufacture of Allergenic Products.

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

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



Sec. 680.3  Tests.

    (a) Identity. When a specific identity test meeting the provisions 
of Sec. 610.14 of this chapter cannot be performed, the manufacture of 
each lot shall be separated from the manufacture of other products in a 
manner that will preclude adulteration, and records made in the course 
of manufacture shall be in sufficient detail to verify the identity of 
the product.
    (b) 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

[[Page 127]]

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 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.

[38 FR 32100, Nov. 20, 1973, as amended at 39 FR 19777, June 6, 1974; 41 
FR 4015, Jan. 28, 1976; 52 FR 37607, Oct. 8, 1987; 55 FR 11013, Mar. 26, 
1990; 67 FR 9587, Mar. 4, 2002]

[[Page 128]]



                         SUBCHAPTER G--COSMETICS





PART 700--GENERAL--Table of Contents




                      Subpart A--General Provisions

Sec.
700.3  Definitions.

         Subpart B--Requirements for Specific Cosmetic Products

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

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

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



                      Subpart A--General Provisions



Sec. 700.3  Definitions.

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

[[Page 129]]

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

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



         Subpart B--Requirements for Specific Cosmetic Products



Sec. 700.11  Cosmetics containing bithionol.

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



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

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

[[Page 130]]

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



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

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

[[Page 131]]

unconsciousness where inhaled at high concentrations. Studies also 
demonstrate carcinogenic effects in animals as a result of inhalation 
exposure to vinyl chloride. Furthermore, vinyl chloride has recently 
been linked to liver disease, including liver cancer, in workers engaged 
in the polymerization of vinyl chloride. It is the view of the 
Commissioner that vinyl chloride is a deleterious substance which may 
render any cosmetic aerosol product that contains it as an ingredient 
injurious to users. Accordingly, any cosmetic aerosol product containing 
vinyl chloride as an ingredient is deemed to be adulterated under 
section 601(a) of the Federal Food, Drug, and Cosmetic Act.
    (b) Any cosmetic aerosol product containing vinyl chloride as an 
ingredient shipped within the jurisdiction of the Act is subject to 
regulatory action.

[39 FR 30830, Aug. 26, 1974]



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

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

[40 FR 50531, Oct. 30, 1975]



Sec. 700.16  Use of aerosol cosmetic products containing zirconium.

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

[42 FR 41376, Aug. 16, 1977]



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

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

[[Page 132]]

these findings, chloroform is a deleterious substance which may render 
injurious to users any cosmetic product that contains chloroform as an 
ingredient.
    (b) Any cosmetic product containing chloroform as an ingredient is 
adulterated and is subject to regulatory action under sections 301 and 
601(a) of the Federal Food, Drug, and Cosmetic Act. Any cosmetic product 
containing chloroform in residual amounts from its use as a processing 
solvent during manufacture, or as a byproduct from the synthesis of an 
ingredient, is not, for the purpose of this section, considered to 
contain chloroform as an ingredient.

[41 FR 26845, June 29, 1976]



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

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

[54 FR 27342, June 29, 1989]



Sec. 700.23  Chlorofluorocarbon propellants.

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

[43 FR 11317, Mar. 17, 1978]



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

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

[[Page 133]]

gas to expel the contents from the container. A tamper-resistant package 
may involve an immediate-container and closure system or secondary-
container or carton system or any combination of systems intended to 
provide a visual indication of package integrity. The tamper-resistant 
feature shall be designed to and shall remain intact when handled in a 
reasonable manner during manufacture, distribution, and retail display.
    (c) Labeling. Each retail package of a cosmetic product covered by 
this section, except aerosol products as defined in paragraph (b) of 
this section, is required to bear a statement that is prominently placed 
so that consumers are alerted to the specific tamper-resistant feature 
of the package. The labeling statement is also required to be so placed 
that it will be unaffected if the tamper-resistant feature of the 
package is breached or missing. If the tamper-resistant feature chosen 
to meet the requirement in paragraph (b) of this section is one that 
uses an identifying characteristic, that characteristic is required to 
be referred to in the labeling statement. For example, the labeling 
statement on a bottle with a shrink band could say ``For your 
protection, this bottle has an imprinted seal around the neck.''
    (d) Requests for exemptions from packaging and labeling 
requirements. A manufacturer or packer may request an exemption from the 
packaging and labeling requirements of this section. A request for an 
exemption is required to be submitted in the form of a citizen petition 
under Sec. 10.30 of this chapter and should be clearly identified on the 
envelope as a ``Request for Exemption from Tamper-resistant Rule.'' The 
petition is required to contain the following:
    (1) The name of the product.
    (2) The reasons that the product's compliance with the tamper-
resistant packaging or labeling requirements of this section is 
unnecessary or cannot be achieved.
    (3) A description of alternative steps that are available, or that 
the petitioner has already taken, to reduce the likelihood that the 
product will be the subject of malicious adulteration.
    (4) Other information justifying an exemption.

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

[[Page 134]]

regulations without regard to the retail level effective date.

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

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



Sec. 700.35  Cosmetics containing sunscreen ingredients.

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

[64 FR 27693, May 21, 1999]



PART 701--COSMETIC LABELING--Table of Contents




                      Subpart A--General Provisions

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

                         Subpart B--Package Form

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

               Subpart C--Labeling of Specific Ingredients

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

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

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



                      Subpart A--General Provisions



Sec. 701.1  Misbranding.

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

[[Page 135]]



Sec. 701.2  Form of stating labeling requirements.

    (a) A word, statement, or other information required by or under 
authority of the Act to appear on the label may lack that prominence and 
conspicuousness required by section 602(c) of the Act by reason (among 
other reasons) of:
    (1) The failure of such word, statement, or information to appear on 
the part or panel of the label which is presented or displayed under 
customary conditions of purchase;
    (2) The failure of such word, statement, or information to appear on 
two or more parts or panels of the label, each of which has sufficient 
space therefor, and each of which is so designed as to render it likely 
to be, under customary conditions of purchase, the part or panel 
displayed;
    (3) The failure of the label to extend over the area of the 
container or package available for such extension, so as to provide 
sufficient label space for the prominent placing of such word, 
statement, or information;
    (4) Insufficiency of label space (for the prominent placing of such 
word, statement, or information) resulting from the use of label space 
for any word, statement, design, or device which is not required by or 
under authority of the Act to appear on the label;
    (5) Insufficiency of label space (for the prominent placing of such 
word, statement, or information) resulting from the use of label space 
to give materially greater conspicuousness to any other word, statement, 
or information, or to any design or device;
    (6) Smallness or style of type in which such word, statement, or 
information appears, insufficient background contrast, obscuring designs 
or vignettes, or crowding with other written, printed, or graphic 
matter.
    (b)(1) All words, statements, and other information required by or 
under authority of the Act to appear on the label or labeling shall 
appear thereon in the English language: Provided, however, That in the 
case of articles distributed solely in the Commonwealth of Puerto Rico 
or in a Territory where the predominant language is one other than 
English, the predominant language may be substituted for English.
    (2) If the label contains any representation in a foreign language, 
all words, statements, and other information required by or under 
authority of the Act to appear on the label shall appear thereon in the 
foreign language.
    (3) If the labeling contains any representation in a foreign 
language, all words, statements, and other information required by or 
under authority of the Act to appear on the label or labeling shall 
appear on the labeling in the foreign language.



Sec. 701.3  Designation of ingredients.

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

[[Page 136]]

by regulation an acceptable alternate, e.g., a smaller type size. A 
petition requesting such a regulation as an amendment to this paragraph 
shall be submitted pursuant to part 10 of this chapter.
    (c) A cosmetic ingredient shall be identified in the declaration of 
ingredients by:
    (1) The name specified in Sec. 701.30 as established by the 
Commissioner for that ingredient for the purpose of cosmetic ingredient 
labeling pursuant to paragraph (e) of this section;
    (2) In the absence of the name specified in Sec. 701.30, the name 
adopted for that ingredient in the following editions and supplements of 
the following compendia, listed in order as the source to be utilized:
    (i) CTFA (Cosmetic, Toiletry and Fragrance Association, Inc.) 
Cosmetic Ingredient Dictionary, Second Ed., 1977 (available from the 
Cosmetic, Toiletry and Fragrance Association, Inc. 1110 Vermont Ave. 
NW., Suite 800, Washington, DC 20005, or 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).

[[Page 137]]

    (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, 5100 Paint Branch Pkwy., College Park, MD 
20740, 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 
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 an over-the-counter drug 
product, the declaration shall declare the active drug ingredients as 
set forth in Sec. 201.66(c)(2) and (d) of this chapter, and the 
declaration shall declare the cosmetic ingredients as set forth in 
Sec. 201.66(c)(8) and (d) of this chapter.
    (e) Interested persons may submit a petition requesting the 
establishment of a specific name for a cosmetic ingredient pursuant to 
part 10 of this chapter. The Commissioner may also propose such a name 
on his own initiative.
    (f) As an alternative to listing all ingredients in descending order 
of predominance, ingredients may be grouped and the groups listed in the 
following manner and order:
    (1) Ingredients, other than color additives, present at a 
concentration greater than 1 percent, in descending order of 
predominance; followed by
    (2) Ingredients, other than color additives, present at a 
concentration of not more than 1 percent, without respect to order of 
predominance; followed by
    (3) Color additives, without respect to order of predominance. 
Ingredients specified in paragraph (f)(2) of this section may be 
included with those specified in paragraph (f)(1) of this section and 
listed in descending order of predominance.
    (g) A declaration of ingredients may include an ingredient not in 
the product if the ingredient is identified by the phrase ``may 
contain'' and:
    (1) It is a color additive added to some batches of the product for 
purposes of color matching; or
    (2)(i) The same declaration of ingredients is also used for other 
products similar in composition and intended for the same use, including 
products which may be assortments of products similar in composition and 
intended for the same use; and
    (ii) Such products are ``shaded'' products, i.e., those falling 
within the product categories identified in Sec. 720.4 (c)(3), (7) and 
(8)(v) of this chapter; and
    (iii) All products sharing the common declaration of ingredients are 
sold by the labeler under a common trade name or brand designation, and 
no trade name or brand designation not common to all such products 
appears in the labeling of any of them; and
    (iv) The ingredient is a color additive.
    (h) As an alternative to a declaration of color additive ingredients 
for each product, the color additives of an assortment of cosmetic 
products that are sold together in the same package may be declared in a 
single composite list in a manner that is not misleading and that 
indicates that the list pertains to all the products.
    (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

[[Page 138]]

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

[[Page 139]]

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

[[Page 140]]

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

[[Page 141]]

    (i) The location of the declarations of ingredients, e.g., in an 
accompanying brochure, or in a sales catalog used for ordering;
    (ii) A statement that a copy of the declaration of ingredients will 
be mailed promptly to any person requesting it; and
    (iii) The name and place of business of the mail order distributor,
    (3) The mail order distributor promptly mails a copy of the 
declaration of ingredients to any person requesting it.

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



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

[[Page 142]]

by this part with clarity and conspicuousness and without obscuring 
designs, vignettes, or crowding. Where packages bear alternate principal 
display panels, information required to be placed on the principal 
display panel shall be duplicated on each principal display panel. For 
the purpose of obtaining uniform type size in declaring the quantity of 
contents of all packages of substantially the same size, the term ``area 
of the principal display panel'' means the area of the side or surface 
that bears the principal display panel, which area shall be:
    (a) In the case of a rectangular package where one entire side 
properly can be considered to be the principal display panel side, the 
product of the height times the width of that side;
    (b) In the case of a cylindrical or nearly cylindrical container, 40 
percent of the product of the height of the container times the 
circumference; and
    (c) In the case of any other shape of container, 40 percent of the 
total surface of the container: Provided, however, That where such 
container presents an obvious ``principal display panel'' such as the 
top of a triangular or circular package, the area shall consist of the 
entire top surface.

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



Sec. 701.11  Identity labeling.

    (a) The principal display panel of a cosmetic in package form shall 
bear as one of its principal features a statement of the identity of the 
commodity.
    (b) Such statement of identity shall be in terms of:
    (1) The common or usual name of the cosmetic; or
    (2) An appropriately descriptive name or, when the nature of the 
cosmetic is obvious, a fanciful name understood by the public to 
identify such cosmetic; or
    (3) An appropriate illustration or vignette representing the 
intended cosmetic use.
    (c) The statement of identity shall be presented in bold type on the 
principal display panel, shall be in a size reasonably related to the 
most prominent printed matter on such panel, and shall be in lines 
generally parallel to the base on which the package rests as it is 
designed to be displayed.



Sec. 701.12  Name and place of business of manufacturer, packer, or distributor.

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

[[Page 143]]

place of business in lieu of the actual place where such cosmetic was 
manufactured or packed or is to be distributed, unless such statement 
would be misleading.



Sec. 701.13  Declaration of net quantity of contents.

    (a) The label of a cosmetic in package form shall bear a declaration 
of the net quantity of contents. This shall be expressed in terms of 
weight, measure, numerical count, or a combination of numerical count 
and weight or measure. The statement shall be in terms of fluid measure 
if the cosmetic is liquid or in terms of weight if the cosmetic is 
solid, semisolid, or viscous, or a mixture of solid and liquid. If there 
is a firmly established, general consumer usage and trade custom of 
declaring the net quantity of a cosmetic by numerical count, linear 
measure, or measure of area, such respective term may be used. If there 
is a firmly established, general consumer usage and trade custom of 
declaring the contents of a liquid cosmetic by weight, or a solid, 
semisolid, or viscous cosmetic by fluid measure, it may be used. 
Whenever the Commissioner determines for a specific packaged cosmetic 
that an existing practice of declaring net quantity of contents by 
weight, measure, numerical count, or a combination of these does not 
facilitate value comparisons by consumers, he shall by regulation 
designate the appropriate term or terms to be used for such cosmetic.
    (b) Statements of weight shall be in terms of avoirdupois pound and 
ounce. Statements of fluid measure shall be in terms of the U.S. gallon 
of 231 cubic inches and quart, pint, and fluid-ounce subdivisions 
thereof and shall express the volume at 68  deg.F. (20  deg.C.).
    (c) When the declaration of quantity of contents by numerical count, 
linear measure, or measure of area does not give accurate information as 
to the quantity of cosmetic in the package, it shall be augmented by 
such statement of weight, measure, or size of the individual units or 
the total weight or measure of the cosmetic as will give such 
information.
    (d) The declaration may contain common or decimal fractions. A 
common fraction shall be in terms of halves, quarters, eighths, 
sixteenths, or thirty-seconds; except that if there exists a firmly 
established, general consumer usage and trade custom of employing 
different common fractions in the net quantity declaration of a 
particular commodity they may be employed. A common fraction shall be 
reduced to its lowest terms; a decimal fraction shall not be carried out 
to more than two places. A statement that includes small fractions of an 
ounce shall be deemed to permit smaller variations than one which does 
not include such fractions.
    (e) The declaration shall be located on the principal display panel 
of the label; with respect to packages bearing alternate principal 
display panels, it shall be duplicated on each principal display panel: 
Provided, That:
    (1) The principal display panel of a cosmetic marketed in a 
``boudoir-type'' container including decorative cosmetic containers of 
the ``cartridge,'' ``pill box,'' ``compact,'' or ``pencil'' variety, and 
those with a capacity of one-fourth ounce or less, may be considered to 
be a tear-away tag or tape affixed to the decorative container and 
bearing the mandatory label information as required by this part, but 
the type size of 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

[[Page 144]]

exaggerate the amount of the cosmetic in the container. It shall be 
placed on the principal display panel within the bottom 30 percent of 
the area of the label panel in line generally parallel to the base on 
which the package rests as it is designed to be displayed: Provided, 
That:
    (1) On packages having a principal display panel of 5 square inches 
or less, the requirement for placement within the bottom 30 percent of 
the area of the label panel shall not apply when the declaration of net 
quantity of contents meets the other requirements of this part; and
    (2) In the case of a cosmetic that is marketed with both outer and 
inner retail containers bearing the mandatory label information required 
by this part, and the inner container is not intended to be sold 
separately, the net quantity of contents placement requirement of this 
section applicable to such inner containers is waived.
    (g) The declaration shall accurately reveal the quantity of cosmetic 
in the package exclusive of wrappers and other material packed 
therewith: Provided, That:
    (1) In the case of cosmetics packed in containers designed to 
deliver the cosmetic under pressure, the declaration shall state the net 
quantity of the contents that will be expelled when the instructions for 
use as shown on the container are followed. The propellant is included 
in the net quantity declaration; and
    (2) In the case of a package which contains the integral components 
making up a complete kit, and which is designed to deliver the 
components in the manner of an application (for example, a home 
permanent wave kit), the declaration may state the net quantity of the 
contents in nondeceptive terms of the number of applications available 
in the kit when the instructions for use as shown on the container are 
followed.
    (h) The declaration shall appear in conspicuous and easily legible 
boldface print or type in distinct contrast (by typography, layout, 
color, embossing, or molding) to other matter on the package; except 
that a declaration of net quantity blown, embossed, or molded on a glass 
or plastic surface is permissible when all label information is so 
formed on the surface. Requirements of conspicuousness and legibility 
shall include the specifications that:
    (1) The ratio of height to width (of the letter) shall not exceed a 
differential of 3 units to 1 unit (no more than 3 times as high as it is 
wide).
    (2) Letter heights pertain to upper case or capital letters. When 
upper and lower case or all lower case letters are used, it is the lower 
case letter ``o'' or its equivalent that shall meet the minimum 
standards.
    (3) When fractions are used, each component numeral shall meet one-
half the minimum height standards.
    (i) The declaration shall be in letters and numerals in a type size 
established in relationship to the area of the principal display panel 
of the package and shall be uniform for all packages of substantially 
the same size by complying with the following type specifications:
    (1) Not less than one-sixteenth inch in height on packages the 
principal display panel of which has an area of 5 square inches or less.
    (2) Not less than one-eighth inch in height on packages the 
principal display panel of which has an area of more 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

[[Page 145]]

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

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

    (o) On packages labeled in terms of linear measure, the declaration 
shall be expressed both in terms of inches and, if applicable (1 foot or 
more), the largest whole units (yards, yards and feet, feet). The 
declaration in terms of the largest whole units shall be in parentheses 
following the declaration in terms of inches and any remainder shall be 
in terms of inches or common or decimal fractions of the foot or yard. 
Examples are ``86 inches (2 yd. 1 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

[[Page 146]]

to exaggerate the amount of the cosmetic contained in the package; for 
example, ``giant pint'' and ``full quart.'' Dual or combination 
declarations of net quantity of contents as provided for in paragraphs 
(a), (c), and (j) of this section (for example, a combination of net 
weight plus numerical count) are not regarded as supplemental net 
quantity statements and shall be located on the principal display panel.
    (r) A separate statement of the net quantity of contents in terms of 
the metric system is not regarded as a supplemental statement and an 
accurate statement of the net quantity of contents in terms of the 
metric system of weight or measure may also appear on the principal 
display panel or on other panels.
    (s) The declaration of net quantity of contents shall express an 
accurate statement of the quantity of contents of the package. 
Reasonable variations caused by loss or gain of moisture during the 
course of good distribution practice or by unavoidable deviations in 
good manufacturing practice will be recognized. Variations from stated 
quantity of contents shall not be unreasonably large.



               Subpart C--Labeling of Specific Ingredients



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

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



Sec. 701.30  Ingredient names established for cosmetic ingredient labeling.

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

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

[[Page 147]]



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




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

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

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



Sec. 710.1  Who should register.

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



Sec. 710.2  Time for registration.

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



Sec. 710.3  How and where to register.

    Form FD-2511 (``Registration of Cosmetic Product Establishment'') is 
obtainable on request from the Food and Drug Administration, 5100 Paint 
Branch Pkwy., College Park, MD 20740, or at any Food and Drug 
Administration district office. The completed form should be mailed to 
Cosmetic Product Establishment Registration, Food and Drug 
Administration, 5100 Paint Branch Pkwy., College Park, MD 20740.

[39 FR 10059, Mar. 15, 1974, as amended at 68 FR 15355, Mar. 31, 2003]



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, 5100 Paint Branch 
Pkwy., College Park, MD 20740.

[39 FR 10059, Mar. 15, 1974, as amended at 68 FR 15355, Mar. 31, 2003]

[[Page 148]]



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

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



Sec. 710.9  Exemptions.

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



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




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

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

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



Sec. 720.1  Who should file.

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

[57 FR 3129, Jan. 28, 1992]



Sec. 720.2  Times for filing.

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

[57 FR 3129, Jan. 28, 1992]



Sec. 720.3  How and where to file.

    Forms FDA 2512 and FDA 2514 (``Discontinuance of Commercial 
Distribution of Cosmetic Product Formulation'') are obtainable on 
request from the Food and Drug Administration, 5100 Paint Branch Pkwy., 
College Park, MD 20740, or at any Food and Drug Administration district 
office. The completed form should be mailed or delivered to: Cosmetic 
Product Statement, Food and Drug Administration, 5100 Paint Branch 
Pkwy., College Park, MD 20740, according to the instructions provided 
with the forms.

[57 FR 3129, Jan. 28, 1992, as amended at 68 FR 15355, Mar. 31, 2003]



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.

[[Page 149]]

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

[[Page 150]]

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

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

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



Sec. 720.5  [Reserved]



Sec. 720.6  Amendments to statement.

    Changes in the information requested under 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.

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

[[Page 151]]



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 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

[[Page 152]]

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 the firm or the product. Any representation in 
labeling or advertising that creates an impression of official approval 
because of such filing or such number will be considered misleading.

[57 FR 3130, Jan. 28, 1992]



PART 740--COSMETIC PRODUCT WARNING STATEMENTS--Table of Contents




                           Subpart A--General

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

                      Subpart B--Warning Statements

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

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



                           Subpart A--General



Sec. 740.1  Establishment of warning statements.

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

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



Sec. 740.2  Conspicuousness of warning statements.

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

[[Page 153]]

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 misbranded unless it contains the 
following conspicuous statement on the principal display panel:

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

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

[40 FR 8917, Mar. 3, 1975]



Sec. 740.11  Cosmetics in self-pressurized containers.

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

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

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

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

    (2) The warning required by paragraph (b)(1) of this section is not 
required for the following products:
    (i) Products expelled in the form of a foam or cream, which contain 
less than 10 percent propellant in the container.
    (ii) Products in a container with a physical barrier that prevents 
escape of the propellant at the time of use.
    (iii) Products of a net quantity of contents of less than 2 ozs. 
that are designed to release a measured amount of product with each 
valve actuation.
    (iv) Products of a net quantity of contents of less than \1/2\ oz.
    (c) Labeling requirements for cosmetics packaged in a self- 
pressurized container containing or manufactured with a 
chlorofluorocarbon propellant or other ozone-depleting substance 
designated by the Environmental Protection Agency (EPA) are set forth in 
40 CFR part 82.

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

[[Page 154]]



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.



Sec. 740.19  Suntanning preparations.

    The labeling of suntanning preparations that do not contain a 
sunscreen ingredient must display the following warning: ``Warning--This 
product does not contain a sunscreen and does not protect against 
sunburn. Repeated exposure of unprotected skin while tanning may 
increase the risk of skin aging, skin cancer, and other harmful effects 
to the skin even if you do not burn.'' For purposes of this section, the 
term ``suntanning preparations'' includes gels, creams, liquids, and 
other topical products that are intended to provide cosmetic effects on 
the skin while tanning through exposure to UV radiation (e.g., 
moisturizing or conditioning products), or to give the appearance of a 
tan by imparting color to the skin through the application of approved 
color additives (e.g., dihydroxyacetone) without the need for exposure 
to UV radiation. The term ``suntanning preparations'' does not include 
products intended to provide sun

[[Page 155]]

protection or otherwise intended to affect the structure or any function 
of the body.

[64 FR 27693, May 21, 1999]

                        PARTS 741-799 [RESERVED]


[[Page 157]]



                              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 159]]

            Material Approved for Incorporation by Reference

                      (Revised as of April 1, 2003)

  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 (PARTS 600 TO 799)

FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES
                                                                  21 CFR


Cosmetic, Toiletry, and Fragrance Association, Inc.

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


National Academy Press

  2101 Constitution Ave. NW., Box 285, Washington, 
  DC 20055.
Food Chemicals Codex, 2nd Ed., 1972...............              720.4(d)
Food Chemicals Codex, 2nd Ed., 1972, First                      701.3(c)
  Supplement, 1974.
Food Chemicals Codex, 2nd Ed., 1972, Second              701.3(c)(2)(iv)
  Supplement, 1975....
  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                 630.74
  Waste Water, 13th Ed..


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)
United States Pharmacopeia (23rd revision, 1995):
  Test Procedures Using Membrane Filtration, pp. 1689 and 1690.610.12(f)



[[Page 161]]



                    Table of CFR Titles and Chapters




                      (Revised as of April 1, 2003)

                      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)

                   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)
         V  The International Organizations Employees Loyalty 
                Board (Parts 1500--1599)
        VI  Federal Retirement Thrift Investment Board (Parts 
                1600--1699)
      VIII  Office of Special Counsel (Parts 1800--1899)
        IX  Appalachian Regional Commission (Parts 1900--1999)
        XI  Armed Forces Retirement Home (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 3201)
     XXIII  Department of Energy (Part 3301)
      XXIV  Federal Energy Regulatory Commission (Part 3401)
       XXV  Department of the Interior (Part 3501)
      XXVI  Department of Defense (Part 3601)

[[Page 162]]

    XXVIII  Department of Justice (Part 3801)
      XXIX  Federal Communications Commission (Parts 3900--3999)
       XXX  Farm Credit System Insurance Corporation (Parts 4000--
                4099)
      XXXI  Farm Credit Administration (Parts 4100--4199)
    XXXIII  Overseas Private Investment Corporation (Part 4301)
      XXXV  Office of Personnel Management (Part 4501)
        XL  Interstate Commerce Commission (Part 5001)
       XLI  Commodity Futures Trading Commission (Part 5101)
      XLII  Department of Labor (Part 5201)
     XLIII  National Science Foundation (Part 5301)
       XLV  Department of Health and Human Services (Part 5501)
      XLVI  Postal Rate Commission (Part 5601)
     XLVII  Federal Trade Commission (Part 5701)
    XLVIII  Nuclear Regulatory Commission (Part 5801)
         L  Department of Transportation (Part 6001)
       LII  Export-Import Bank of the United States (Part 6201)
      LIII  Department of Education (Parts 6300--6399)
       LIV  Environmental Protection Agency (Part 6401)
      LVII  General Services Administration (Part 6701)
     LVIII  Board of Governors of the Federal Reserve System (Part 
                6801)
       LIX  National Aeronautics and Space Administration (Part 
                6901)
        LX  United States Postal Service (Part 7001)
       LXI  National Labor Relations Board (Part 7101)
      LXII  Equal Employment Opportunity Commission (Part 7201)
     LXIII  Inter-American Foundation (Part 7301)
       LXV  Department of Housing and Urban Development (Part 
                7501)
      LXVI  National Archives and Records Administration (Part 
                7601)
      LXIX  Tennessee Valley Authority (Part 7901)
      LXXI  Consumer Product Safety Commission (Part 8101)
    LXXIII  Department of Agriculture (Part 8301)
     LXXIV  Federal Mine Safety and Health Review Commission (Part 
                8401)
     LXXVI  Federal Retirement Thrift Investment Board (Part 8601)
    LXXVII  Office of Management and Budget (Part 8701)

                      Title 6--Homeland Security

         I  Department of Homeland Security, Office of the 
                Secretary (Parts 0--100)

                         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)

[[Page 163]]

        II  Food and Nutrition Service, Department of Agriculture 
                (Parts 210--299)
       III  Animal and Plant Health Inspection Service, Department 
                of Agriculture (Parts 300--399)
        IV  Federal Crop Insurance Corporation, Department of 
                Agriculture (Parts 400--499)
         V  Agricultural Research Service, Department of 
                Agriculture (Parts 500--599)
        VI  Natural Resources Conservation Service, Department of 
                Agriculture (Parts 600--699)
       VII  Farm Service Agency, Department of Agriculture (Parts 
                700--799)
      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)
       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)
        XX  Local Television Loan Guarantee Board (Parts 2200--
                2299)
      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 the Chief Financial Officer, Department of 
                Agriculture (Parts 3000--3099)
      XXXI  Office of Environmental Quality, Department of 
                Agriculture (Parts 3100--3199)
     XXXII  Office of Procurement and Property Management, 
                Department of Agriculture (Parts 3200--3299)
    XXXIII  Office of Transportation, Department of Agriculture 
                (Parts 3300--3399)

[[Page 164]]

     XXXIV  Cooperative State Research, Education, and Extension 
                Service, Department of Agriculture (Parts 3400--
                3499)
      XXXV  Rural Housing Service, Department of Agriculture 
                (Parts 3500--3599)
     XXXVI  National Agricultural Statistics Service, Department 
                of Agriculture (Parts 3600--3699)
    XXXVII  Economic Research Service, Department of Agriculture 
                (Parts 3700--3799)
   XXXVIII  World Agricultural Outlook Board, Department of 
                Agriculture (Parts 3800--3899)
       XLI  [Reserved]
      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 
                Homeland Security (Parts 1--599)
         V  Executive Office for Immigration Review, Department of 
                Justice (Parts 1000--1400)

                 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, Department of 
                Agriculture (Parts 300--599)

                           Title 10--Energy

         I  Nuclear Regulatory Commission (Parts 0--199)
        II  Department of Energy (Parts 200--699)
       III  Department of Energy (Parts 700--999)
         X  Department of Energy (General Provisions) (Parts 1000-
                -1099)
      XVII  Defense Nuclear Facilities Safety Board (Parts 1700--
                1799)
     XVIII  Northeast Interstate Low-Level Radioactive Waste 
                Commission (Part 1800)

                      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)

[[Page 165]]

        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  Department of the Treasury (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)
        IV  Emergency Steel Guarantee Loan Board (Parts 400--499)
         V  Emergency Oil and Gas Guaranteed Loan Board (Parts 
                500--599)

                    Title 14--Aeronautics and Space

         I  Federal Aviation Administration, Department of 
                Transportation (Parts 1--199)
        II  Office of the Secretary, Department of Transportation 
                (Aviation Proceedings) (Parts 200--399)
       III  Commercial Space Transportation, Federal Aviation 
                Administration, Department of Transportation 
                (Parts 400--499)
         V  National Aeronautics and Space Administration (Parts 
                1200--1299)
        VI  Air Transportation System Stabilization (Parts 1300--
                1399)

                 Title 15--Commerce and Foreign Trade

            Subtitle A--Office of the Secretary of Commerce (Parts 
                0--29)
            Subtitle B--Regulations Relating to Commerce and 
                Foreign Trade
         I  Bureau of the Census, Department of Commerce (Parts 
                30--199)
        II  National Institute of Standards and Technology, 
                Department of Commerce (Parts 200--299)

[[Page 166]]

       III  International Trade Administration, Department of 
                Commerce (Parts 300--399)
        IV  Foreign-Trade Zones Board, Department of Commerce 
                (Parts 400--499)
       VII  Bureau of Industry and Security, Department of 
                Commerce (Parts 700--799)
      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)
      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)
        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)

[[Page 167]]

       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 (Parts 200--299)
       III  Peace Corps (Parts 300--399)
        IV  International Joint Commission, United States and 
                Canada (Parts 400--499)
         V  Broadcasting Board of Governors (Parts 500--599)
       VII  Overseas Private Investment Corporation (Parts 700--
                799)
        IX  Foreign Service Grievance Board (Parts 900--999)
         X  Inter-American Foundation (Parts 1000--1099)
        XI  International Boundary and Water Commission, United 
                States and Mexico, United States Section (Parts 
                1100--1199)
       XII  United States International Development Cooperation 
                Agency (Parts 1200--1299)
       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)

[[Page 168]]

       XVI  Japan-United States Friendship Commission (Parts 1600-
                -1699)
      XVII  United States Institute of Peace (Parts 1700--1799)

                          Title 23--Highways

         I  Federal Highway Administration, Department of 
                Transportation (Parts 1--999)
        II  National Highway Traffic Safety Administration and 
                Federal Highway Administration, Department of 
                Transportation (Parts 1200--1299)
       III  National Highway Traffic Safety Administration, 
                Department of Transportation (Parts 1300--1399)

                Title 24--Housing and Urban Development

            Subtitle A--Office of the Secretary, Department of 
                Housing and Urban Development (Parts 0--99)
            Subtitle B--Regulations Relating to Housing and Urban 
                Development
         I  Office of Assistant Secretary for Equal Opportunity, 
                Department of Housing and Urban Development (Parts 
                100--199)
        II  Office of Assistant Secretary for Housing-Federal 
                Housing Commissioner, Department of Housing and 
                Urban Development (Parts 200--299)
       III  Government National Mortgage Association, Department 
                of Housing and Urban Development (Parts 300--399)
        IV  Office of Housing and Office of Multifamily Housing 
                Assistance Restructuring, Department of Housing 
                and Urban Development (Parts 400--499)
         V  Office of Assistant Secretary for Community Planning 
                and Development, Department of Housing and Urban 
                Development (Parts 500--599)
        VI  Office of Assistant Secretary for Community Planning 
                and Development, Department of Housing and Urban 
                Development (Parts 600--699) [Reserved]
       VII  Office of the Secretary, Department of Housing and 
                Urban Development (Housing Assistance Programs and 
                Public and Indian Housing Programs) (Parts 700--
                799)
      VIII  Office of the Assistant Secretary for Housing--Federal 
                Housing Commissioner, Department of Housing and 
                Urban Development (Section 8 Housing Assistance 
                Programs, Section 202 Direct Loan Program, Section 
                202 Supportive Housing for the Elderly Program and 
                Section 811 Supportive Housing for Persons With 
                Disabilities Program) (Parts 800--899)
        IX  Office of Assistant Secretary for Public and Indian 
                Housing, Department of Housing and Urban 
                Development (Parts 900--1699)
         X  Office of Assistant Secretary for Housing--Federal 
                Housing Commissioner, Department of Housing and 
                Urban Development (Interstate Land Sales 
                Registration Program) (Parts 1700--1799)

[[Page 169]]

       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--3899)
       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)
         V  Bureau of Indian Affairs, Department of the Interior, 
                and Indian Health Service, Department of Health 
                and Human Services (Part 900)
        VI  Office of the Assistant Secretary-Indian Affairs, 
                Department of the Interior (Parts 1000--1199)
       VII  Office of the Special Trustee for American Indians, 
                Department of the Interior (Part 1200)

                      Title 26--Internal Revenue

         I  Internal Revenue Service, Department of the Treasury 
                (Parts 1--899)

           Title 27--Alcohol, Tobacco Products and Firearms

         I  Alcohol and Tobacco Tax and Trade Bureau, Department 
                of the Treasury (Parts 1--299)
        II  Bureau of Alcohol, Tobacco, Firearms, and Explosives, 
                Department of Justice (Parts 400--699)

                   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)
        VI  Offices of Independent Counsel, Department of Justice 
                (Parts 600--699)
       VII  Office of Independent Counsel (Parts 700--799)
      VIII  Court Services and Offender Supervision Agency for the 
                District of Columbia (Parts 800--899)
        IX  National Crime Prevention and Privacy Compact Council 
                (Parts 900--999)

[[Page 170]]

        XI  Department of Justice and Department of State (Parts 
                1100--1199)

                            Title 29--Labor

            Subtitle A--Office of the Secretary of Labor (Parts 0-
                -99)
            Subtitle B--Regulations Relating to Labor
         I  National Labor Relations Board (Parts 100--199)
        II  Office of Labor-Management Standards, Department of 
                Labor (Parts 200--299)
       III  National Railroad Adjustment Board (Parts 300--399)
        IV  Office of Labor-Management Standards, Department of 
                Labor (Parts 400--499)
         V  Wage and Hour Division, Department of Labor (Parts 
                500--899)
        IX  Construction Industry Collective Bargaining Commission 
                (Parts 900--999)
         X  National Mediation Board (Parts 1200--1299)
       XII  Federal Mediation and Conciliation Service (Parts 
                1400--1499)
       XIV  Equal Employment Opportunity Commission (Parts 1600--
                1699)
      XVII  Occupational Safety and Health Administration, 
                Department of Labor (Parts 1900--1999)
        XX  Occupational Safety and Health Review Commission 
                (Parts 2200--2499)
       XXV  Pension and Welfare Benefits Administration, 
                Department of Labor (Parts 2500--2599)
     XXVII  Federal Mine Safety and Health Review Commission 
                (Parts 2700--2799)
        XL  Pension Benefit Guaranty Corporation (Parts 4000--
                4999)

                      Title 30--Mineral Resources

         I  Mine Safety and Health Administration, Department of 
                Labor (Parts 1--199)
        II  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)
       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 171]]

        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)
        IX  Federal Claims Collection Standards (Department of the 
                Treasury--Department of Justice) (Parts 900--999)

                      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)
     XVIII  National Counterintelligence Center (Parts 1800--1899)
       XIX  Central Intelligence Agency (Parts 1900--1999)
        XX  Information Security Oversight Office, National 
                Archives and Records Administration (Parts 2000--
                2099)
       XXI  National Security Council (Parts 2100--2199)
      XXIV  Office of Science and Technology Policy (Parts 2400--
                2499)
     XXVII  Office for Micronesian Status Negotiations (Parts 
                2700--2799)
    XXVIII  Office of the Vice President of the United States 
                (Parts 2800--2899)

               Title 33--Navigation and Navigable Waters

         I  Coast Guard, Department of 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)

[[Page 172]]

        II  Office of Elementary and Secondary Education, 
                Department of Education (Parts 200--299)
       III  Office of Special Education and Rehabilitative 
                Services, Department of Education (Parts 300--399)
        IV  Office of 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)
        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)
         X  Presidio Trust (Parts 1000--1099)
        XI  Architectural and Transportation Barriers Compliance 
                Board (Parts 1100--1199)
       XII  National Archives and Records Administration (Parts 
                1200--1299)
        XV  Oklahoma City National Memorial Trust (Part 1501)
       XVI  Morris K. Udall Scholarship and Excellence in National 
                Environmental Policy Foundation (Parts 1600--1699)

             Title 37--Patents, Trademarks, and Copyrights

         I  United States Patent and Trademark Office, Department 
                of Commerce (Parts 1--199)
        II  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)

[[Page 173]]

           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)

                  Title 40--Protection of Environment

         I  Environmental Protection Agency (Parts 1--799)
        IV  Environmental Protection Agency and Department of 
                Justice (Parts 1400--1499)
         V  Council on Environmental Quality (Parts 1500--1599)
        VI  Chemical Safety and Hazard Investigation Board (Parts 
                1600--1699)
       VII  Environmental Protection Agency and Department of 
                Defense; Uniform National Discharge Standards for 
                Vessels of the Armed Forces (Parts 1700--1799)

          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 Service, 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)
       102  Federal Management Regulation (Parts 102-1--102-299)
       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) [Reserved]
            Subtitle F--Federal Travel Regulation System
       300  General (Parts 300-1--300-99)
       301  Temporary Duty (TDY) Travel Allowances (Parts 301-1--
                301-99)

[[Page 174]]

       302  Relocation Allowances (Parts 302-1--302-99)
       303  Payment of Expenses Connected with the Death of 
                Certain Employees (Part 303-70)
       304  Payment of Travel Expenses from a Non-Federal Source 
                (Parts 304-1--304-99)

                        Title 42--Public Health

         I  Public Health Service, Department of Health and Human 
                Services (Parts 1--199)
        IV  Centers for Medicare & Medicaid Services, 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)
        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 
                (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)

[[Page 175]]

       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  Corporation for National and Community Service (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)
     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)

                          Title 46--Shipping

         I  Coast Guard, Department of Transportation (Parts 1--
                199)
        II  Maritime Administration, Department of Transportation 
                (Parts 200--399)
       III  Coast Guard (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)

[[Page 176]]

         7  United States Agency for International Development 
                (Parts 700--799)
         8  Department of Veterans Affairs (Parts 800--899)
         9  Department of Energy (Parts 900--999)
        10  Department of the Treasury (Parts 1000--1099)
        12  Department of Transportation (Parts 1200--1299)
        13  Department of Commerce (Parts 1300--1399)
        14  Department of the Interior (Parts 1400--1499)
        15  Environmental Protection Agency (Parts 1500--1599)
        16  Office of Personnel Management Federal Employees 
                Health Benefits Acquisition Regulation (Parts 
                1600--1699)
        17  Office of Personnel Management (Parts 1700--1799)
        18  National Aeronautics and Space Administration (Parts 
                1800--1899)
        19  Broadcasting Board of Governors (Parts 1900--1999)
        20  Nuclear Regulatory Commission (Parts 2000--2099)
        21  Office of Personnel Management, Federal Employees 
                Group Life Insurance Federal Acquisition 
                Regulation (Parts 2100--2199)
        23  Social Security Administration (Parts 2300--2399)
        24  Department of Housing and Urban Development (Parts 
                2400--2499)
        25  National Science Foundation (Parts 2500--2599)
        28  Department of Justice (Parts 2800--2899)
        29  Department of Labor (Parts 2900--2999)
        34  Department of Education Acquisition Regulation (Parts 
                3400--3499)
        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 (Parts 
                5400--5499)
        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)

[[Page 177]]

                       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 Motor Carrier Safety 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)
        XI  Bureau of Transportation Statistics, Department of 
                Transportation (Parts 1400--1499)
       XII  Transportation Security Administration, Department of 
                Transportation (Parts 1500--1599)

                   Title 50--Wildlife and Fisheries

         I  United States Fish and Wildlife Service, Department of 
                the Interior (Parts 1--199)
        II  National Marine Fisheries Service, National Oceanic 
                and Atmospheric Administration, Department of 
                Commerce (Parts 200--299)
       III  International Fishing and Related Activities (Parts 
                300--399)
        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 179]]





           Alphabetical List of Agencies Appearing in the CFR




                      (Revised as of April 1, 2003)

                                                  CFR Title, Subtitle or 
                     Agency                               Chapter

Administrative Committee of the Federal Register  1, I
Advanced Research Projects Agency                 32, I
Advisory Council on Historic Preservation         36, VIII
African Development Foundation                    22, XV
  Federal Acquisition Regulation                  48, 57
Agency for International Development, United      22, II
     States
  Federal Acquisition Regulation                  48, 7
Agricultural Marketing Service                    7, I, IX, X, XI
Agricultural Research Service                     7, V
Agriculture Department                            5, LXXIII
  Agricultural Marketing Service                  7, I, IX, X, XI
  Agricultural Research Service                   7, V
  Animal and Plant Health Inspection Service      7, III; 9, I
  Chief Financial Officer, Office of              7, XXX
  Commodity Credit Corporation                    7, XIV
  Cooperative State Research, Education, and      7, XXXIV
       Extension Service
  Economic Research Service                       7, XXXVII
  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
  Food and Nutrition 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
  Procurement and Property Management, Office of  7, XXXII
  Rural Business-Cooperative Service              7, XVIII, XLII
  Rural Development Administration                7, XLII
  Rural Housing Service                           7, XVIII, XXXV
  Rural 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
Air Transportation Stabilization Board            14, VI
Alcohol and Tobacco Tax and Trade Bureau          27, I
Alcohol, Tobacco, Firearms, and Explosives,       27, II
     Bureau of
AMTRAK                                            49, VII
American Battle Monuments Commission              36, IV
American Indians, Office of the Special Trustee   25, VII
Animal and Plant Health Inspection Service        7, III; 9, I
Appalachian Regional Commission                   5, IX

[[Page 180]]

Architectural and Transportation Barriers         36, XI
     Compliance Board
Arctic Research Commission                        45, XXIII
Armed Forces Retirement Home                      5, XI
Army Department                                   32, V
  Engineers, Corps of                             33, II; 36, III
  Federal Acquisition Regulation                  48, 51
Benefits Review Board                             20, VII
Bilingual Education and Minority Languages        34, V
     Affairs, Office of
Blind or Severely Disabled, Committee for         41, 51
     Purchase From People Who Are
Broadcasting Board of Governors                   22, V
  Federal Acquisition Regulation                  48, 19
Census Bureau                                     15, I
Centers for Medicare & Medicaid Services          42, IV
Central Intelligence Agency                       32, XIX
Chief Financial Officer, Office of                7, XXX
Child Support Enforcement, Office of              45, III
Children and Families, Administration for         45, II, III, IV, X
Civil Rights, Commission on                       45, VII
Civil Rights, Office for                          34, I
Coast Guard                                       33, I; 46, I; 49, IV
Coast Guard (Great Lakes Pilotage)                46, III
Commerce Department                               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
  Federal Acquisition Regulation                  48, 13
  Fishery Conservation and Management             50, VI
  Foreign-Trade Zones Board                       15, IV
  Industry and Security, Bureau of                15, VII
  International Trade Administration              15, III; 19, III
  National Institute of Standards and Technology  15, II
  National Marine Fisheries Service               50, II, IV, VI
  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, United States      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
Commercial Space Transportation                   14, III
Commodity Credit Corporation                      7, XIV
Commodity Futures Trading Commission              5, XLI; 17, I
Community Planning and Development, Office of     24, V, VI
     Assistant Secretary for
Community Services, Office of                     45, X
Comptroller of the Currency                       12, I
Construction Industry Collective Bargaining       29, IX
     Commission
Consumer Product Safety Commission                5, LXXI; 16, II
Cooperative State Research, Education, and        7, XXXIV
     Extension Service
Copyright Office                                  37, II
Corporation for National and Community Service    45, XII, XXV
Cost Accounting Standards Board                   48, 99
Council on Environmental Quality                  40, V
Court Services and Offender Supervision Agency    28, VIII
     for the District of Columbia
Customs Service, United States                    19, I
Defense Contract Audit Agency                     32, I
Defense Department                                5, XXVI; 32, Subtitle A; 
                                                  40, VII

[[Page 181]]

  Advanced Research Projects Agency               32, I
  Air Force Department                            32, VII
  Army Department                                 32, V; 33, II; 36, III, 
                                                  48, 51
  Defense Intelligence Agency                     32, I
  Defense Logistics Agency                        32, I, XII; 48, 54
  Engineers, Corps of                             33, II; 36, III
  Federal Acquisition Regulation                  48, 2
  National Imagery and Mapping Agency             32, I
  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 Nuclear Facilities Safety Board           10, XVII
Delaware River Basin Commission                   18, III
District of Columbia, Court Services and          28, VIII
     Offender Supervision Agency for the
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 Development Administration               13, III
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
Emergency Oil and Gas Guaranteed Loan Board       13, V
Emergency Steel Guarantee Loan Board              13, IV
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                             5, XXIII; 10, II, III, X
  Federal Acquisition Regulation                  48, 9
  Federal Energy Regulatory Commission            5, XXIV; 18, I
  Property Management Regulations                 41, 109
Energy, Office of                                 7, XXIX
Engineers, Corps of                               33, II; 36, III
Engraving and Printing, Bureau of                 31, VI
Environmental Protection Agency                   5, LIV; 40, I, IV, VII
  Federal Acquisition Regulation                  48, 15
  Property Management Regulations                 41, 115
Environmental Quality, Office of                  7, XXXI
Equal Employment Opportunity Commission           5, LXII; 29, XIV
Equal Opportunity, Office of Assistant Secretary  24, I
     for
Executive Office of the President                 3, I
  Administration, Office of                       5, XV
  Environmental Quality, Council on               40, V
  Management and Budget, Office of                5, III, LXXVII; 14, VI; 
                                                  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
[[Page 182]]

Export-Import Bank of the United States           5, LII; 12, IV
Family Assistance, Office of                      45, II
Farm Credit Administration                        5, XXXI; 12, VI
Farm Credit System Insurance Corporation          5, XXX; 12, XIV
Farm Service Agency                               7, VII, XVIII
Federal Acquisition Regulation                    48, 1
Federal Aviation Administration                   14, I
  Commercial Space Transportation                 14, III
Federal Claims Collection Standards               31, IX
Federal Communications Commission                 5, XXIX; 47, I
Federal Contract Compliance Programs, Office of   41, 60
Federal Crop Insurance Corporation                7, IV
Federal Deposit Insurance Corporation             5, XXII; 12, III
Federal Election Commission                       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              5, XXIV; 18, I
Federal Financial Institutions Examination        12, XI
     Council
Federal Financing Bank                            12, VIII
Federal Highway Administration                    23, I, II
Federal Home Loan Mortgage Corporation            1, IV
Federal Housing Enterprise Oversight Office       12, XVII
Federal Housing Finance Board                     12, IX
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 Management Regulation                     41, 102
Federal Maritime Commission                       46, IV
Federal Mediation and Conciliation Service        29, XII
Federal Mine Safety and Health Review Commission  5, LXXIV; 29, XXVII
Federal Motor Carrier Safety Administration       49, III
Federal Prison Industries, Inc.                   28, III
Federal Procurement Policy Office                 48, 99
Federal Property Management Regulations           41, 101
Federal Railroad Administration                   49, II
Federal Register, Administrative Committee of     1, I
Federal Register, Office of                       1, II
Federal Reserve System                            12, II
  Board of Governors                              5, LVIII
Federal Retirement Thrift Investment Board        5, VI, LXXVI
Federal Service Impasses Panel                    5, XIV
Federal Trade Commission                          5, XLVII; 16, I
Federal Transit Administration                    49, VI
Federal Travel Regulation System                  41, Subtitle F
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
Food and Drug Administration                      21, I
Food and Nutrition Service                        7, II
Food Safety and Inspection Service                9, III
Foreign Agricultural Service                      7, XV
Foreign Assets Control, Office of                 31, V
Foreign Claims Settlement Commission of the       45, V
     United States
Foreign Service Grievance Board                   22, IX
Foreign Service Impasse Disputes Panel            22, XIV
Foreign Service Labor Relations Board             22, XIV
Foreign-Trade Zones Board                         15, IV
Forest Service                                    36, II
General Accounting Office                         4, I
General Services Administration                   5, LVII; 41, 105
  Contract Appeals, Board of                      48, 61
  Federal Acquisition Regulation                  48, 5
  Federal Management Regulation                   41, 102

[[Page 183]]

  Federal Property Management Regulation          41, 101
  Federal Travel Regulation System                41, Subtitle F
  General                                         41, 300
  Payment From a Non-Federal Source for Travel    41, 304
       Expenses
  Payment of Expenses Connected With the Death    41, 303
       of Certain Employees
  Relocation Allowances                           41, 302
  Temporary Duty (TDY) Travel Allowances          41, 301
Geological Survey                                 30, IV
Government Ethics, Office of                      5, XVI
Government National Mortgage Association          24, III
Grain Inspection, Packers and Stockyards          7, VIII; 9, II
     Administration
Harry S. Truman Scholarship Foundation            45, XVIII
Health and Human Services, Department of          5, XLV; 45, Subtitle A
  Centers for Medicare & Medicaid Services        42, IV
  Child Support Enforcement, Office of            45, III
  Children and Families, Administration for       45, II, III, IV, X
  Community Services, Office of                   45, X
  Family Assistance, Office of                    45, II
  Federal Acquisition Regulation                  48, 3
  Food and Drug Administration                    21, I
  Human Development Services, Office of           45, XIII
  Indian Health Service                           25, V; 42, I
  Inspector General (Health Care), Office of      42, V
  Public Health Service                           42, I
  Refugee Resettlement, Office of                 45, IV
Homeland Security, Department of                  6, I
  Immigration and Naturalization Service          8, I
Housing and Urban Development, Department of      5, LXV; 24, Subtitle B
  Community Planning and Development, Office of   24, V, VI
       Assistant Secretary for
  Equal Opportunity, Office of Assistant          24, I
       Secretary for
  Federal Acquisition Regulation                  48, 24
  Federal Housing Enterprise Oversight, Office    12, XVII
       of
  Government National Mortgage Association        24, III
  Housing--Federal Housing Commissioner, Office   24, II, VIII, X, XX
       of Assistant Secretary for
  Housing, Office of, and Multifamily Housing     24, IV
       Assistance Restructuring, Office of
  Inspector General, Office of                    24, XII
  Public and Indian Housing, Office of Assistant  24, IX
       Secretary for
  Secretary, Office of                            24, Subtitle A, VII
Housing--Federal Housing Commissioner, Office of  24, II, VIII, X, XX
     Assistant Secretary for
Housing, Office of, and Multifamily Housing       24, IV
     Assistance Restructuring, Office of
Human Development Services, Office of             45, XIII
Immigration and Naturalization Service            8, I
Immigration Review, Executive Office for          8, V
Independent Counsel, Office of                    28, VII
Indian Affairs, Bureau of                         25, I, V
Indian Affairs, Office of the Assistant           25, VI
     Secretary
Indian Arts and Crafts Board                      25, II
Indian Health Service                             25, V; 42, I
Industry and Security, Bureau of                  15, VII
Information Resources Management, Office of       7, XXVII
Information Security Oversight Office, National   32, XX
     Archives and Records Administration
Inspector General
  Agriculture Department                          7, XXVI
  Health and Human Services Department            42, V
  Housing and Urban Development Department        24, XII
Institute of Peace, United States                 22, XVII
Inter-American Foundation                         5, LXIII; 22, X
Interior Department
  American Indians, Office of the Special         25, VII
       Trustee
  Endangered Species Committee                    50, IV

[[Page 184]]

  Federal Acquisition Regulation                  48, 14
  Federal Property Management Regulations System  41, 114
  Fish and Wildlife Service, United States        50, I, IV
  Geological Survey                               30, IV
  Indian Affairs, Bureau of                       25, I, V
  Indian Affairs, Office of the Assistant         25, VI
       Secretary
  Indian Arts and Crafts Board                    25, II
  Land Management, Bureau of                      43, II
  Minerals Management Service                     30, II
  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, United States Agency   22, II
     for
  Federal Acquisition Regulation                  48, 7
International Development Cooperation Agency,     22, XII
     United States
International Fishing and Related Activities      50, III
International Investment, Office of               31, VIII
International Joint Commission, United States     22, IV
     and Canada
International Organizations Employees Loyalty     5, V
     Board
International Trade Administration                15, III; 19, III
International Trade Commission, United States     19, II
Interstate Commerce Commission                    5, XL
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                                5, XXVIII; 28, I, XI; 40, 
                                                  IV
  Alcohol, Tobacco, Firearms, and Explosives,     27, II
       Bureau of
  Drug Enforcement Administration                 21, II
  Federal Acquisition Regulation                  48, 28
  Federal Claims Collection Standards             31, IX
  Federal Prison Industries, Inc.                 28, III
  Foreign Claims Settlement Commission of the     45, V
       United States
  Immigration Review, Executive Office for        8, V
  Offices of Independent Counsel                  28, VI
  Prisons, Bureau of                              28, V
  Property Management Regulations                 41, 128
Labor Department                                  5, XLII
  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 Standards, Office of           29, II, 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 Service,      41, 61; 20, IX
       Office of the Assistant Secretary for
  Wage and Hour Division                          29, V
  Workers' Compensation Programs, Office of       20, I
Labor-Management Standards, Office of             29, II, IV
Land Management, Bureau of                        43, II
Legal Services Corporation                        45, XVI
Library of Congress                               36, VII

[[Page 185]]

  Copyright Office                                37, II
Local Television Loan Guarantee Board             7, XX
Management and Budget, Office of                  5, III, LXXVII; 14, VI; 
                                                  48, 99
Marine Mammal Commission                          50, V
Maritime Administration                           46, II
Merit Systems Protection Board                    5, II
Micronesian Status Negotiations, Office for       32, XXVII
Mine Safety and Health Administration             30, I
Minerals Management Service                       30, II
Minority Business Development Agency              15, XIV
Miscellaneous Agencies                            1, IV
Monetary Offices                                  31, I
Morris K. Udall Scholarship and Excellence in     36, XVI
     National Environmental Policy Foundation
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 and Community Service, Corporation for   45, XII, XXV
National Archives and Records Administration      5, LXVI; 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 Council on Disability                    34, XII
National Counterintelligence Center               32, XVIII
National Credit Union Administration              12, VII
National Crime Prevention and Privacy Compact     28, IX
     Council
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 Imagery and Mapping Agency               32, I
National Indian Gaming Commission                 25, III
National Institute for Literacy                   34, XI
National Institute of Standards and Technology    15, II
National Labor Relations Board                    5, LXI; 29, I
National Marine Fisheries Service                 50, II, IV, VI
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                       5, XLIII; 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
Northeast Interstate Low-Level Radioactive Waste  10, XVIII
     Commission
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
Oklahoma City National Memorial Trust             36, XV
Operations Office                                 7, XXVIII

[[Page 186]]

Overseas Private Investment Corporation           5, XXXIII; 22, VII
Panama Canal Commission                           48, 35
Panama Canal Regulations                          35, I
Patent and Trademark Office, United States        37, I
Payment From a Non-Federal Source for Travel      41, 304
     Expenses
Payment of Expenses Connected With the Death of   41, 303
     Certain Employees
Peace Corps                                       22, III
Pennsylvania Avenue Development Corporation       36, IX
Pension and Welfare Benefits Administration       29, XXV
Pension Benefit Guaranty Corporation              29, XL
Personnel Management, Office of                   5, I, XXXV; 45, VIII
  Federal Acquisition Regulation                  48, 17
  Federal Employees Group Life Insurance Federal  48, 21
       Acquisition Regulation
  Federal Employees Health Benefits Acquisition   48, 16
       Regulation
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 Documents                            3
Presidio Trust                                    36, X
Prisons, Bureau of                                28, V
Procurement and Property Management, Office of    7, XXXII
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, XXXV
Rural Telephone Bank                              7, XVI
Rural Utilities Service                           7, XVII, XVIII, XLII
Saint Lawrence Seaway Development Corporation     33, IV
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
Smithsonian Institution                           36, V
Social Security Administration                    20, III; 48, 23
Soldiers' and Airmen's Home, United States        5, XI
Special Counsel, Office of                        5, VIII
Special Education and Rehabilitative Services,    34, III
     Office of
State Department                                  22, I; 28, XI
  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                        5, LXIX; 18, XIII
Thrift Supervision Office, Department of the      12, V
     Treasury
Trade Representative, United States, Office of    15, XX
Transportation, Department of                     5, L
  Coast Guard                                     33, I; 46, I; 49, IV

[[Page 187]]

  Coast Guard (Great Lakes Pilotage)              46, III
  Commercial Space Transportation                 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
  Federal Motor Carrier Safety Administration     49, III
  Federal Railroad Administration                 49, II
  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
  Secretary of Transportation, Office of          14, II; 49, Subtitle A
  Surface Transportation Board                    49, X
  Transportation Security Administration          49, XII
  Transportation Statistics Bureau                49, XI
Transportation, Office of                         7, XXXIII
Transportation Security Administration            49, XII
Transportation Statistics Bureau                  49, XI
Travel Allowances, Temporary Duty (TDY)           41, 301
Treasury Department                               5, XXI; 12, XV; 17, IV; 
                                                  31, IX
  Alcohol and Tobacco Tax and Trade Bureau        27, I
  Community Development Financial Institutions    12, XVIII
       Fund
  Comptroller of the Currency                     12, I
  Customs 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
Utah Reclamation Mitigation and Conservation      43, III
     Commission
Veterans Affairs Department                       38, I
  Federal Acquisition Regulation                  48, 8
Veterans' Employment and Training Service,        41, 61; 20, IX
     Office of the Assistant Secretary for
Vice President of the United States, Office of    32, XXVIII
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 189]]



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, 
2001, 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, 2001, see the ``List of CFR Sections 
Affected, 1943-1963, 1964-1972, 1973-1985, and 1986-2000'' published in 
11 separate volumes.

                                  2001

21 CFR
                                                                   66 FR
                                                                    Page
Chapter I
601.28  Regulation at 65 FR 64618 eff. date delayed to 4-30-01.....10815
601.70  Regulation at 65 FR 64618 eff. date delayed to 4-30-01.....10815
606.3   (j) revised..........................................1835, 40889
606.100  (b)(20) added.............................................31176
606.121  (e)(5)(ii) revised; (g) removed; (h)(2) and (3) amended 
                                                                   31162
606.151  (b) and (c) revised.................................1835, 40889
606.160  (b)(1)(ix), (x) and (xi) added............................31176
607  Authority citation revised....................................59158
607.3  (b) and (e) revised; (j) added..............................59158
607.7  (b) and (c) revised.........................................59158
607.20  (a) revised................................................59158
607.22  Revised....................................................59158
607.25  (a) amended; (b)(3) revised................................59158
607.26  Amended....................................................59158
607.31  Revised....................................................59158
607.35  (a) revised................................................59159
607.37  (a) introductory text and (b) revised......................59159
607.40  Revised....................................................59159
607.65  (g) removed................................................31162
    Introductory text revised......................................59159
610  Authority revised.............................................31162
610.40--610.47 (Subpart E)  Heading revised........................31162
610.40  Revised....................................................31162
610.41  Revised....................................................31164
610.42  Added......................................................31164
610.44  Added......................................................31164
610.45  Removed....................................................31165
630  Added.........................................................31176
640.2  (b) revised...........................................1836, 40889
    (d) removed....................................................31165
640.3  (c)(1) revised........................................1836, 40889
640.4  (g) introductory text, (1), (2), (4) and (5) revised........1836, 
                                                                   40889
640.5  Introductory text and (c) revised.....................1836, 40889
    (f) revised....................................................31165
640.14  Amended....................................................31165
640.15  Revised..............................................1836, 40890
640.16  (a) revised..........................................1836, 40890
640.23  (a) revised.................................................1836
    (a) amended....................................................31165
640.24  (b) revised...........................................1836,40890
640.25  (c) introductory text amended...............................1836
640.33  (a) amended................................................31165
640.34  (a) through (e)(1) revised...........................1836, 40890
640.53  (a) amended................................................31165
640.54  (a)(2) revised.......................................1837, 40890
640.56  (c) introductory text amended...............................1837
640.62  Revised.....................................................1837
640.63  (c)(11) revised......................................1837, 40890
640.67  Revised....................................................31165
640.70  (a)(2) revised.............................................31165
640.71  (a) introductory text amended...............................1837
660.20  Regulation at 65 FR 77499 confirmed........................20402
660.21  Regulation at 65 FR 77499 confirmed........................20402
660.42  Removed....................................................31165

[[Page 190]]

660.50  Regulation at 65 FR 77499 confirmed........................20402
660.51  Regulation at 65 FR 77499 confirmed........................20402
701  Nomenclature change...........................................56034

                                  2002

21 CFR
                                                                   67 FR
                                                                    Page
Chapter I
601.90--601.95 (Subpart H)  Added..................................37996
606.121    (c)(8)(i) revised........................................4907
606.170  OMB number.................................................9586
610.2  OMB number...................................................9587
610.12  OMB number..................................................9587
610.13  OMB number..................................................9587
610.18  OMB number..................................................9587
610.60  (a)(6)  amended.............................................4907
610.61  (s)  amended................................................4907
640.2  OMB number...................................................9587
640.72  OMB number..................................................9587
660.21  OMB number..................................................9587
660.22  OMB number..................................................9587
660.25  OMB number..................................................9587
660.26  OMB number..................................................9587
660.28  OMB number..................................................9587
660.34  OMB number..................................................9587
660.35  OMB number..................................................9587
660.36  OMB number..................................................9587
660.51  OMB number..................................................9587
660.52  OMB number..................................................9587
660.53  OMB number..................................................9587
660.54  OMB number..................................................9587
660.55  OMB number..................................................9587
680.1  OMB number...................................................9587
680.2  OMB number...................................................9587
680.3  OMB number...................................................9587
701  Compliance date extension.....................................16304
720.6  OMB number...................................................9587

                                  2003

   (Regulations published from January 1, 2003, through April 1, 2003)

21 CFR
                                                                   68 FR
                                                                    Page
Chapter I
610.11  (g)(2) added; eff. 5-5-03..................................10160
710  Nomenclature change...........................................15355
720  Nomenclature change...........................................15355


                      []