[Title 21 CFR ]
[Code of Federal Regulations (annual edition) - April 1, 2024 Edition]
[From the U.S. Government Publishing Office]
[[Page i]]
Title 21
Food and Drugs
________________________
Parts 600 to 799
Revised as of April 1, 2024
Containing a codification of documents of general
applicability and future effect
As of April 1, 2024
Published by the Office of the Federal Register
National Archives and Records Administration as a
Special Edition of the Federal Register
[[Page ii]]
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[[Page iii]]
Table of Contents
Page
Explanation................................................. v
Title 21:
Chapter I--Food and Drug Administration, Department
of Health and Human Services (Continued) 3
Finding Aids:
Table of CFR Titles and Chapters........................ 169
Alphabetical List of Agencies Appearing in the CFR...... 189
List of CFR Sections Affected........................... 199
[[Page iv]]
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Cite this Code: CFR
To cite the regulations in
this volume use title,
part and section number.
Thus, 21 CFR 600.2 refers
to title 21, part 600,
section 2.
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[[Page v]]
EXPLANATION
The Code of Federal Regulations is a codification of the general and
permanent rules published in the Federal Register by the Executive
departments and agencies of the Federal Government. The Code is divided
into 50 titles which represent broad areas subject to Federal
regulation. Each title is divided into chapters which usually bear the
name of the issuing agency. Each chapter is further subdivided into
parts covering specific regulatory areas.
Each volume of the Code is revised at least once each calendar year
and issued on a quarterly basis approximately as follows:
Title 1 through Title 16.................................as of January 1
Title 17 through Title 27..................................as of April 1
Title 28 through Title 41...................................as of July 1
Title 42 through Title 50................................as of October 1
The appropriate revision date is printed on the cover of each
volume.
LEGAL STATUS
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HOW TO USE THE CODE OF FEDERAL REGULATIONS
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EFFECTIVE AND EXPIRATION DATES
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OMB CONTROL NUMBERS
The Paperwork Reduction Act of 1980 (Pub. L. 96-511) requires
Federal agencies to display an OMB control number with their information
collection request.
[[Page vi]]
Many agencies have begun publishing numerous OMB control numbers as
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PAST PROVISIONS OF THE CODE
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``[RESERVED]'' TERMINOLOGY
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(a) The incorporation will substantially reduce the volume of
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(b) The matter incorporated is in fact available to the extent
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(c) The incorporating document is drafted and submitted for
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What if the material incorporated by reference cannot be found? If
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CFR INDEXES AND TABULAR GUIDES
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that volume.
[[Page vii]]
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Oliver A. Potts,
Director,
Office of the Federal Register
April 1, 2024
[[Page ix]]
THIS TITLE
Title 21--Food and Drugs is composed of nine volumes. The parts in
these volumes are arranged in the following order: Parts 1-99, 100-169,
170-199, 200-299, 300-499, 500-599, 600-799, 800-1299 and 1300-end. The
first eight volumes, containing parts 1-1299, comprise Chapter I--Food
and Drug Administration, Department of Health and Human Services. The
ninth volume, containing part 1300 to end, includes Chapter II--Drug
Enforcement Administration, Department of Justice, and Chapter III--
Office of National Drug Control Policy. The contents of these volumes
represent all current regulations codified under this title of the CFR
as of April 1, 2024.
For this volume, Christine Colaninno was Chief Editor. The Code of
Federal Regulations publication program is under the direction of John
Hyrum Martinez, assisted by Stephen J. Frattini.
[[Page 1]]
TITLE 21--FOOD AND DRUGS
(This book contains parts 600 to 799)
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Part
chapter i--Food and Drug Administration, Department of
Health and Human Services (Continued)..................... 600
[[Page 3]]
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES (CONTINUED)
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Editorial Note: Nomenclature changes to chapter I appear at 59 FR
14366, Mar. 28, 1994, and 66 FR 56035, Nov. 6, 2001.
SUBCHAPTER F--BIOLOGICS
Part Page
600 Biological products: general................ 5
601 Licensing................................... 23
606 Current good manufacturing practice for
blood and blood components.............. 46
607 Establishment registration and product
listing for manufacturers of human blood
and blood products and licensed devices. 59
610 General biological products standards....... 66
630 Requirements for blood and blood components
intended for transfusion or for further
manufacturing use....................... 83
640 Additional standards for human blood and
blood products.......................... 94
660 Additional standards for diagnostic
substances for laboratory tests......... 116
680 Additional standards for miscellaneous
products................................ 134
SUBCHAPTER G--COSMETICS
700 General..................................... 137
701 Cosmetic labeling........................... 145
710 Voluntary registration of cosmetic product
establishments.......................... 158
720 Voluntary filing of cosmetic product
ingredient composition statements....... 159
740 Cosmetic product warning statements......... 163
741-799
[Reserved]
[[Page 5]]
SUBCHAPTER F_BIOLOGICS
PART 600_BIOLOGICAL PRODUCTS: GENERAL--Table of Contents
Subpart A_General Provisions
Sec.
600.2 Mailing addresses.
600.3 Definitions.
Subpart B_Establishment Standards
600.10 Personnel.
600.11 Physical establishment, equipment, animals, and care.
600.12 Records.
600.13 Retention samples.
600.14 Reporting of biological product deviations by licenses
manufacturers.
600.15 Temperatures during shipment.
Subpart C_Establishment Inspection
600.20 Inspectors.
600.21 Time of inspection.
600.22 [Reserved]
Subpart D_Reporting of Adverse Experiences
600.80 Postmarketing reporting of adverse experiences.
600.81 Distribution reports.
600.82 Notification of a permanent discontinuance or an interruption in
manufacturing.
600.90 Waivers.
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 356c, 356e, 360, 360i,
371, 374, 379k-l; 42 U.S.C. 216, 262, 263, 263a, 264.
Cross References: For U.S. Customs Service regulations relating to
viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal
Service regulations relating to the admissibility to the United States
mails see parts 124 and 125 of the Domestic Mail Manual, that is
incorporated by reference in 39 CFR part 111.
Subpart A_General Provisions
Sec. 600.2 Mailing addresses.
(a) Licensed biological products regulated by the Center for
Biologics Evaluation and Research (CBER). Unless otherwise stated in
paragraph (c) of this section, or as otherwise prescribed by FDA
regulation, all submissions to CBER referenced in parts 600 through 680
of this chapter, as applicable, must be sent to: Food and Drug
Administration, Center for Biologics Evaluation and Research, Document
Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, Silver
Spring, MD 20993-0002. Examples of such submissions include: Biologics
license applications (BLAs) and their amendments and supplements,
biological product deviation reports, fatality reports, and other
correspondence. Biological products samples must not be sent to this
address but must be sent to the address in paragraph (c) of this
section.
(b) Licensed biological products regulated by the Center for Drug
Evaluation and Research (CDER). Unless otherwise stated in paragraphs
(b)(1), (b)(2), or (c) of this section, or as otherwise prescribed by
FDA regulation, all submissions to CDER referenced in parts 600, 601,
and 610 of this chapter, as applicable, must be sent to: CDER Central
Document Room, Center for Drug Evaluation and Research, Food and Drug
Administration, 5901B Ammendale Rd., Beltsville, MD 20705. Examples of
such submissions include: BLAs and their amendments and supplements, and
other correspondence.
(1) Biological Product Deviation Reporting (CDER). All biological
product deviation reports required under Sec. 600.14 must be sent to:
Division of Compliance Risk Management and Surveillance, Office of
Compliance, Center for Drug Evaluation and Research, Food and Drug
Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002.
(2) Advertising and Promotional Labeling (CDER). All advertising and
promotional labeling supplements required under Sec. 601.12(f) of this
chapter must be sent to: Division of Drug Marketing, Advertising and
Communication, Center for Drug Evaluation and Research, Food and Drug
Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266.
(c) Samples and Protocols for licensed biological products regulated
by CBER or CDER. (1) Biological product samples and/or protocols, other
than radioactive biological product samples and protocols, required
under Sec. Sec. 600.13, 600.22, 601.15, 610.2, 660.6, 660.36, or 660.46
[[Page 6]]
of this chapter must be sent by courier service to: Food and Drug
Administration, Center for Biologics Evaluation and Research, ATTN:
Sample Custodian, 10903 New Hampshire Ave., Bldg. 75, Rm. G707, Silver
Spring, MD 20993-0002. The protocol(s) may be placed in the box used to
ship the samples to CBER. A cover letter should not be included when
submitting the protocol with the sample unless it contains pertinent
information affecting the release of the lot.
(2) Radioactive biological products required under Sec. 610.2 of
this chapter must be sent by courier service to: Food and Drug
Administration, Center for Biologics Evaluation and Research, ATTN:
Sample Custodian, c/o White Oak Radiation Safety Program, 10903 New
Hampshire Ave., Bldg. 52-72, Rm. G406A, Silver Spring, MD 20993-0002.
(d) Address information for submissions to CBER and CDER other than
those listed in parts 600 through 680 of this chapter are included
directly in the applicable regulations.
(e) Obtain updated mailing address information for biological
products regulated by CBER at http://www.fda.gov/BiologicsBloodVaccines/
default.htm, or for biological products regulated by CDER at http://
www.fda.gov/Drugs/default.htm.
[70 FR 14981, Mar. 24, 2005, as amended at 74 FR 13114, Mar. 26, 2009;
78 FR 19585, Apr. 2, 2013; 80 FR 18091, Apr. 3, 2015; 79 FR 33090, June
10, 2014]
Sec. 600.3 Definitions.
As used in this subchapter:
(a) Act means the Public Health Service Act (58 Stat. 682), approved
July 1, 1944.
(b) Secretary means the Secretary of Health and Human Services and
any other officer or employee of the Department of Health and Human
Services to whom the authority involved has been delegated.
(c) Commissioner of Food and Drugs means the Commissioner of the
Food and Drug Administration.
(d) Center for Biologics Evaluation and Research means Center for
Biologics Evaluation and Research of the Food and Drug Administration.
(e) State means a State or the District of Columbia, Puerto Rico, or
the Virgin Islands.
(f) Possession includes among other possessions, Puerto Rico and the
Virgin Islands.
(g) Products includes biological products and trivalent organic
arsenicals.
(h) Biological product means a virus, therapeutic serum, toxin,
antitoxin, vaccine, blood, blood component or derivative, allergenic
product, protein, or analogous product, or arsphenamine or derivative of
arsphenamine (or any other trivalent organic arsenic compound),
applicable to the prevention, treatment, or cure of a disease or
condition of human beings.
(1) A virus is interpreted to be a product containing the minute
living cause of an infectious disease and includes but is not limited to
filterable viruses, bacteria, rickettsia, fungi, and protozoa.
(2) A therapeutic serum is a product obtained from blood by removing
the clot or clot components and the blood cells.
(3) A toxin is a product containing a soluble substance poisonous to
laboratory animals or to man in doses of 1 milliliter or less (or
equivalent in weight) of the product, and having the property, following
the injection of non-fatal doses into an animal, of causing to be
produced therein another soluble substance which specifically
neutralizes the poisonous substance and which is demonstrable in the
serum of the animal thus immunized.
(4) An antitoxin is a product containing the soluble substance in
serum or other body fluid of an immunized animal which specifically
neutralizes the toxin against which the animal is immune.
(5) A product is analogous:
(i) To a virus if prepared from or with a virus or agent actually or
potentially infectious, without regard to the degree of virulence or
toxicogenicity of the specific strain used.
(ii) To a therapeutic serum, if composed of whole blood or plasma or
containing some organic constituent or product other than a hormone or
an amino acid, derived from whole blood, plasma, or serum.
[[Page 7]]
(iii) To a toxin or antitoxin, if intended, irrespective of its
source of origin, to be applicable to the prevention, treatment, or cure
of disease or injuries of man through a specific immune process.
(6) A protein is any alpha amino acid polymer with a specific,
defined sequence that is greater than 40 amino acids in size. When two
or more amino acid chains in an amino acid polymer are associated with
each other in a manner that occurs in nature, the size of the amino acid
polymer for purposes of this paragraph (h)(6) will be based on the total
number of amino acids in those chains, and will not be limited to the
number of amino acids in a contiguous sequence.
(i) Trivalent organic arsenicals means arsphenamine and its
derivatives (or any other trivalent organic arsenic compound) applicable
to the prevention, treatment, or cure of diseases or injuries of man.
(j) A product is deemed applicable to the prevention, treatment, or
cure of diseases or injuries of man irrespective of the mode of
administration or application recommended, including use when intended
through administration or application to a person as an aid in
diagnosis, or in evaluating the degree of susceptibility or immunity
possessed by a person, and including also any other use for purposes of
diagnosis if the diagnostic substance so used is prepared from or with
the aid of a biological product.
(k) Proper name, as applied to a product, means the name designated
in the license for use upon each package of the product.
(l) Dating period means the period beyond which the product cannot
be expected beyond reasonable doubt to yield its specific results.
(m) Expiration date means the calendar month and year, and where
applicable, the day and hour, that the dating period ends.
(n) The word standards means specifications and procedures
applicable to an establishment or to the manufacture or release of
products, which are prescribed in this subchapter or established in the
biologics license application designed to insure the continued safety,
purity, and potency of such products.
(o) The word continued as applied to the safety, purity and potency
of products is interpreted to apply to the dating period.
(p) The word safety means the relative freedom from harmful effect
to persons affected, directly or indirectly, by a product when prudently
administered, taking into consideration the character of the product in
relation to the condition of the recipient at the time.
(q) The word sterility is interpreted to mean freedom from viable
contaminating microorganisms, as determined by the tests conducted under
Sec. 610.12 of this chapter.
(r) Purity means relative freedom from extraneous matter in the
finished product, whether or not harmful to the recipient or deleterious
to the product. Purity includes but is not limited to relative freedom
from residual moisture or other volatile substances and pyrogenic
substances.
(s) The word potency is interpreted to mean the specific ability or
capacity of the product, as indicated by appropriate laboratory tests or
by adequately controlled clinical data obtained through the
administration of the product in the manner intended, to effect a given
result.
(t) Manufacturer means any legal person or entity engaged in the
manufacture of a product subject to license under the act;
``Manufacturer'' also includes any legal person or entity who is an
applicant for a license where the applicant assumes responsibility for
compliance with the applicable product and establishment standards.
(u) Manufacture means all steps in propagation or manufacture and
preparation of products and includes but is not limited to filling,
testing, labeling, packaging, and storage by the manufacturer.
(v) Location includes all buildings, appurtenances, equipment and
animals used, and personnel engaged by a manufacturer within a
particular area designated by an address adequate for identification.
(w) Establishment has the same meaning as ``facility'' in section
351 of the
[[Page 8]]
Public Health Service Act and includes all locations.
(x) Lot means that quantity of uniform material identified by the
manufacturer as having been thoroughly mixed in a single vessel.
(y) A filling refers to a group of final containers identical in all
respects, which have been filled with the same product from the same
bulk lot without any change that will affect the integrity of the
filling assembly.
(z) Process refers to a manufacturing step that is performed on the
product itself which may affect its safety, purity or potency, in
contrast to such manufacturing steps which do not affect intrinsically
the safety, purity or potency of the product.
(aa) Selling agent or distributor means any person engaged in the
unrestricted distribution, other than by sale at retail, of products
subject to license.
(bb) Container (referred to also as ``final container'') is the
immediate unit, bottle, vial, ampule, tube, or other receptacle
containing the product as distributed for sale, barter, or exchange.
(cc) Package means the immediate carton, receptacle, or wrapper,
including all labeling matter therein and thereon, and the contents of
the one or more enclosed containers. If no package, as defined in the
preceding sentence, is used, the container shall be deemed to be the
package.
(dd) Label means any written, printed, or graphic matter on the
container or package or any such matter clearly visible through the
immediate carton, receptacle, or wrapper.
(ee) Radioactive biological product means a biological product which
is labeled with a radionuclide or intended solely to be labeled with a
radionuclide.
(ff) Amendment is the submission of information to a pending license
application or supplement, to revise or modify the application as
originally submitted.
(gg) Supplement is a request to approve a change in an approved
license application.
(hh) Distributed means the biological product has left the control
of the licensed manufacturer.
(ii) Control means having responsibility for maintaining the
continued safety, purity, and potency of the product and for compliance
with applicable product and establishment standards, and for compliance
with current good manufacturing practices.
(jj) Assess the effects of the change, as used in Sec. 601.12 of
this chapter, means to evaluate the effects of a manufacturing change on
the identity, strength, quality, purity, and potency of a product as
these factors may relate to the safety or effectiveness of the product.
(kk) Specification, as used in Sec. 601.12 of this chapter, means
the quality standard (i.e., tests, analytical procedures, and acceptance
criteria) provided in an approved application to confirm the quality of
products, intermediates, raw materials, reagents, components, in-process
materials, container closure systems, and other materials used in the
production of a product. For the purpose of this definition, acceptance
criteria means numerical limits, ranges, or other criteria for the tests
described.
(ll) Complete response letter means a written communication to an
applicant from FDA usually describing all of the deficiencies that the
agency has identified in a biologics license application or supplement
that must be satisfactorily addressed before it can be approved.
(mm) Resubmission means a submission by the biologics license
applicant or supplement applicant of all materials needed to fully
address all deficiencies identified in the complete response letter. A
biologics license application or supplement for which FDA issued a
complete response letter, but which was withdrawn before approval and
later submitted again, is not a resubmission.
[38 FR 32048, Nov. 20, 1973, as amended at 40 FR 31313, July 25, 1975;
55 FR 11014, Mar. 26, 1990; 61 FR 24232, May 14, 1996; 62 FR 39901, July
24, 1997; 64 FR 56449, Oct. 20, 1999; 65 FR 66634, Nov. 7, 2000; 69 FR
18766, Apr. 8, 2004; 70 FR 14982, Mar. 24, 2005; 73 FR 39610, July 10,
2008; 77 FR 26174, May 3, 2012; 85 FR 10063, Feb. 21, 2020]
[[Page 9]]
Subpart B_Establishment Standards
Sec. 600.10 Personnel.
(a) [Reserved]
(b) Personnel. Personnel shall have capabilities commensurate with
their assigned functions, a thorough understanding of the manufacturing
operations which they perform, the necessary training and experience
relating to individual products, and adequate information concerning the
application of the pertinent provisions of this subchapter to their
respective functions. Personnel shall include such professionally
trained persons as are necessary to insure the competent performance of
all manufacturing processes.
(c) Restrictions on personnel--(1) Specific duties. Persons whose
presence can affect adversely the safety and purity of a product shall
be excluded from the room where the manufacture of a product is in
progress.
(2) Sterile operations. Personnel performing sterile operations
shall wear clean or sterilized protective clothing and devices to the
extent necessary to protect the product from contamination.
(3) Pathogenic viruses and spore-forming organisms. Persons working
with viruses pathogenic for man or with spore-forming microorganisms,
and persons engaged in the care of animals or animal quarters, shall be
excluded from areas where other products are manufactured, or such
persons shall change outer clothing, including shoes, or wear protective
covering prior to entering such areas.
(4) Live vaccine work areas. Persons may not enter a live vaccine
processing area after having worked with other infectious agents in any
other laboratory during the same working day. Only persons actually
concerned with propagation of the culture, production of the vaccine,
and unit maintenance, shall be allowed in live vaccine processing areas
when active work is in progress. Casual visitors shall be excluded from
such units at all times and all others having business in such areas
shall be admitted only under supervision. Street clothing, including
shoes, shall be replaced or covered by suitable laboratory clothing
before entering a live vaccine processing unit. Persons caring for
animals used in the manufacture of live vaccines shall be excluded from
other animal quarters and from contact with other animals during the
same working day.
[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55
FR 11014, Mar. 26, 1990; 62 FR 53538, Oct. 15, 1997; 68 FR 75119, Dec.
30, 2003]
Sec. 600.11 Physical establishment, equipment, animals, and care.
(a) Work areas. All rooms and work areas where products are
manufactured or stored shall be kept orderly, clean, and free of dirt,
dust, vermin and objects not required for manufacturing. Precautions
shall be taken to avoid clogging and back-siphonage of drainage systems.
Precautions shall be taken to exclude extraneous infectious agents from
manufacturing areas. Work rooms shall be well lighted and ventilated.
The ventilation system shall be arranged so as to prevent the
dissemination of microorganisms from one manufacturing area to another
and to avoid other conditions unfavorable to the safety of the product.
Filling rooms, and other rooms where open, sterile operations are
conducted, shall be adequate to meet manufacturing needs and such rooms
shall be constructed and equipped to permit thorough cleaning and to
keep air-borne contaminants at a minimum. If such rooms are used for
other purposes, they shall be cleaned and prepared prior to use for
sterile operations. Refrigerators, incubators and warm rooms shall be
maintained at temperatures within applicable ranges and shall be free of
extraneous material which might affect the safety of the product.
(b) Equipment. Apparatus for sterilizing equipment and the method of
operation shall be such as to insure the destruction of contaminating
microorganisms. The effectiveness of the sterilization procedure shall
be no less than that achieved by an attained temperature of 121.5 [deg]C
maintained for 20 minutes by saturated steam or by an attained
temperature of 170 [deg]C maintained for 2 hours with dry heat.
Processing and storage containers, filters, filling apparatus, and other
pieces of
[[Page 10]]
apparatus and accessory equipment, including pipes and tubing, shall be
designed and constructed to permit thorough cleaning and, where
possible, inspection for cleanliness. All surfaces that come in contact
with products shall be clean and free of surface solids, leachable
contaminants, and other materials that will hasten the deterioration of
the product or otherwise render it less suitable for the intended use.
For products for which sterility is a factor, equipment shall be
sterile, unless sterility of the product is assured by subsequent
procedures.
(c) Laboratory and bleeding rooms. Rooms used for the processing of
products, including bleeding rooms, shall be effectively fly-proofed and
kept free of flies and vermin. Such rooms shall be so constructed as to
insure freedom from dust, smoke and other deleterious substances and to
permit thorough cleaning and disinfection. Rooms for animal injection
and bleeding, and rooms for smallpox vaccine animals, shall be
disinfected and be provided with the necessary water, electrical and
other services.
(d) Animal quarters and stables. Animal quarters, stables and food
storage areas shall be of appropriate construction, fly-proofed,
adequately lighted and ventilated, and maintained in a clean, vermin-
free and sanitary condition. No manure or refuse shall be stored as to
permit the breeding of flies on the premises, nor shall the
establishment be located in close proximity to off-property manure or
refuse storage capable of engendering fly breeding.
(e) Restrictions on building and equipment use--(1) Work of a
diagnostic nature. Laboratory procedures of a clinical diagnostic nature
involving materials that may be contaminated, shall not be performed in
space used for the manufacture of products except that manufacturing
space which is used only occasionally may be used for diagnostic work
provided spore-forming pathogenic microorganisms are not involved and
provided the space is thoroughly cleaned and disinfected before the
manufacture of products is resumed.
(2) Spore-forming organisms for supplemental sterilization procedure
control test. Spore-forming organisms used as an additional control in
sterilization procedures may be introduced into areas used for the
manufacture of products, only for the purposes of the test and only
immediately before use for such purposes: Provided, That (i) the
organism is not pathogenic for man or animals and does not produce
pyrogens or toxins, (ii) the culture is demonstrated to be pure, (iii)
transfer of test cultures to culture media shall be limited to the
sterility test area or areas designated for work with spore-forming
organisms, (iv) each culture be labeled with the name of the
microorganism and the statement ``Caution: microbial spores. See
directions for storage, use and disposition.'', and (v) the container of
each culture is designed to withstand handling without breaking.
(3) Work with spore-forming microorganisms. (i) Manufacturing
processes using spore-forming microorganisms conducted in a multiproduct
manufacturing site must be performed under appropriate controls to
prevent contamination of other products and areas within the site.
Prevention of spore contamination can be achieved by using a separate
dedicated building or by using process containment if manufacturing is
conducted in a multiproduct manufacturing building. All product and
personnel movement between the area where the spore-forming
microorganisms are manufactured and other manufacturing areas must be
conducted under conditions that will prevent the introduction of spores
into other areas of the facility.
(ii) If process containment is employed in a multiproduct
manufacturing area, procedures must be in place to demonstrate adequate
removal of the spore-forming microorganism(s) from the manufacturing
area for subsequent manufacture of other products. These procedures must
provide for adequate removal or decontamination of the spore-forming
microorganisms on and within manufacturing equipment, facilities, and
ancillary room items as well as the removal of disposable or product
dedicated items from the manufacturing area. Environmental monitoring
specific for the spore-forming microorganism(s) must be conducted in
adjacent areas during manufacturing
[[Page 11]]
operations and in the manufacturing area after completion of cleaning
and decontamination.
(4) Live vaccine processing. Live vaccine processing must be
performed under appropriate controls to prevent cross contamination of
other products and other manufacturing areas within the building.
Appropriate controls must include, at a minimum:
(i)(A) Using a dedicated manufacturing area that is either in a
separate building, in a separate wing of a building, or in quarters at
the blind end of a corridor and includes adequate space and equipment
for all processing steps up to, but not including, filling into final
containers; and
(B) Not conducting test procedures that potentially involve the
presence of microorganisms other than the vaccine strains or the use of
tissue culture cell lines other than primary cultures in space used for
processing live vaccine; or
(ii) If manufacturing is conducted in a multiproduct manufacturing
building or area, using procedural controls, and where necessary,
process containment. Process containment is deemed to be necessary
unless procedural controls are sufficient to prevent cross contamination
of other products and other manufacturing areas within the building.
Process containment is a system designed to mechanically isolate
equipment or an area that involves manufacturing using live vaccine
organisms. All product, equipment, and personnel movement between
distinct live vaccine processing areas and between live vaccine
processing areas and other manufacturing areas, up to, but not
including, filling in final containers, must be conducted under
conditions that will prevent cross contamination of other products and
manufacturing areas within the building, including the introduction of
live vaccine organisms into other areas. In addition, written procedures
and effective processes must be in place to adequately remove or
decontaminate live vaccine organisms from the manufacturing area and
equipment for subsequent manufacture of other products. Written
procedures must be in place for verification that processes to remove or
decontaminate live vaccine organisms have been followed.
(5) Equipment and supplies--contamination. Equipment and supplies
used in work on or otherwise exposed to any pathogenic or potentially
pathogenic agent shall be kept separated from equipment and supplies
used in the manufacture of products to the extent necessary to prevent
cross-contamination.
(f) Animals used in manufacture--(1) Care of animals used in
manufacturing. Caretakers and attendants for animals used for the
manufacture of products shall be sufficient in number and have adequate
experience to insure adequate care. Animal quarters and cages shall be
kept in sanitary condition. Animals on production shall be inspected
daily to observe response to production procedures. Animals that become
ill for reasons not related to production shall be isolated from other
animals and shall not be used for production until recovery is complete.
Competent veterinary care shall be provided as needed.
(2) Quarantine of animals--(i) General. No animal shall be used in
processing unless kept under competent daily inspection and preliminary
quarantine for a period of at least 7 days before use, or as otherwise
provided in this subchapter. Only healthy animals free from detectable
communicable diseases shall be used. Animals must remain in overt good
health throughout the quarantine periods and particular care shall be
taken during the quarantine periods to reject animals of the equine
genus which may be infected with glanders and animals which may be
infected with tuberculosis.
(ii) Quarantine of monkeys. In addition to observing the pertinent
general quarantine requirements, monkeys used as a source of tissue in
the manufacture of vaccine shall be maintained in quarantine for at
least 6 weeks prior to use, except when otherwise provided in this part.
Only monkeys that have reacted negatively to tuberculin at the start of
the quarantine period and again within 2 weeks prior to use shall be
used in the manufacture of vaccine. Due precaution shall be taken to
prevent cross-infection from any infected or potentially infected
monkeys on the
[[Page 12]]
premises. Monkeys to be used in the manufacture of a live vaccine shall
be maintained throughout the quarantine period in cages closed on all
sides with solid materials except the front which shall be screened,
with no more than two monkeys housed in one cage. Cage mates shall not
be interchanged.
(3) Immunization against tetanus. Horses and other animals
susceptible to tetanus, that are used in the processing steps of the
manufacture of biological products, shall be treated adequately to
maintain immunity to tetanus.
(4) Immunization and bleeding of animals used as a source of
products. Toxins or other nonviable antigens administered in the
immunization of animals used in the manufacture of products shall be
sterile. Viable antigens, when so used, shall be free of contaminants,
as determined by appropriate tests prior to use. Injections shall not be
made into horses within 6 inches of bleeding site. Horses shall not be
bled for manufacturing purposes while showing persistent general
reaction or local reaction near the site of bleeding. Blood shall not be
used if it was drawn within 5 days of injecting the animals with viable
microorganisms. Animals shall not be bled for manufacturing purposes
when they have an intercurrent disease. Blood intended for use as a
source of a biological product shall be collected in clean, sterile
vessels. When the product is intended for use by injection, such vessels
shall also be pyrogen-free.
(5) [Reserved]
(6) Reporting of certain diseases. In cases of actual or suspected
infection with foot and mouth disease, glanders, tetanus, anthrax, gas
gangrene, equine infectious anemia; equine encephalomyelitis, or any of
the pock diseases among animals intended for use or used in the
manufacture of products, the manufacturer shall immediately notify the
Director, Center for Biologics Evaluation and Research or the Director,
Center for Drug Evaluation and Research (see mailing addresses in Sec.
600.2(a) or (b)).
(7) Monkeys used previously for experimental or test purposes.
Monkeys that have been used previously for experimental or test purposes
with live microbiological agents shall not be used as a source of kidney
tissue for the manufacture of vaccine. Except as provided otherwise in
this subchapter, monkeys that have been used previously for other
experimental or test purposes may be used as a source of kidney tissue
upon their return to a normal condition, provided all quarantine
requirements have been met.
(8) Necropsy examination of monkeys. Each monkey used in the
manufacture of vaccine shall be examined at necropsy under the direction
of a qualified pathologist, physician, or veterinarian having experience
with diseases of monkeys, for evidence of ill health, particularly for
(i) evidence of tuberculosis, (ii) presence of herpes-like lesions,
including eruptions or plaques on or around the lips, in the buccal
cavity or on the gums, and (iii) signs of conjunctivitis. If there are
any such signs or other significant gross pathological lesions, the
tissue shall not be used in the manufacture of vaccine.
(g) Filling procedures. Filling procedures shall be such as will not
affect adversely the safety, purity or potency of the product.
(h) Containers and closures. All final containers and closures shall
be made of material that will not hasten the deterioration of the
product or otherwise render it less suitable for the intended use. All
final containers and closures shall be clean and free of surface solids,
leachable contaminants and other materials that will hasten the
deterioration of the product or otherwise render it less suitable for
the intended use. After filling, sealing shall be performed in a manner
that will maintain the integrity of the product during the dating
period. In addition, final containers and closures for products intended
for use by injection shall be sterile and free from pyrogens. Except as
otherwise provided in the regulations of this subchapter, final
containers for products intended for use by injection shall be colorless
and sufficiently transparent to permit visual examination of the
contents under normal light. As soon as possible after filling final
containers shall be labeled as prescribed in Sec. 610.60 et seq. of
this chapter, except that final containers may be stored
[[Page 13]]
without such prescribed labeling provided they are stored in a sealed
receptacle labeled both inside and outside with at least the name of the
product, the lot number, and the filling identification.
[38 FR 32048, Nov. 20, 1973, as amended at 41 FR 10428, Mar. 11, 1976;
49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 68 FR 75119, Dec.
30, 2003; 70 FR 14982, Mar. 24, 2005; 72 FR 59003, Oct. 18, 2007; 80 FR
18092, Apr. 3, 2015]
Sec. 600.12 Records.
(a) Maintenance of records. Records shall be made, concurrently with
the performance, of each step in the manufacture and distribution of
products, in such a manner that at any time successive steps in the
manufacture and distribution of any lot may be traced by an inspector.
Such records shall be legible and indelible, shall identify the person
immediately responsible, shall include dates of the various steps, and
be as detailed as necessary for clear understanding of each step by one
experienced in the manufacture of products.
(b) Records retention--(1) General. Records shall be retained for
such interval beyond the expiration date as is necessary for the
individual product, to permit the return of any clinical report of
unfavorable reactions. The retention period shall be no less than five
years after the records of manufacture have been completed or six months
after the latest expiration date for the individual product, whichever
represents a later date.
(2) Records of recall. Complete records shall be maintained
pertaining to the recall from distribution of any product upon
notification by the Director, Center for Biologics Evaluation and
Research or the Director, Center for Drug Evaluation and Research, to
recall for failure to conform with the standards prescribed in the
regulations of this subchapter, because of deterioration of the product
or for any other factor by reason of which the distribution of the
product would constitute a danger to health.
(3) Suspension of requirement for retention. The Director, Center
for Biologics Evaluation and Research or the Director, Center for Drug
Evaluation and Research, may authorize the suspension of the requirement
to retain records of a specific manufacturing step upon a showing that
such records no longer have significance for the purposes for which they
were made: Provided, That a summary of such records shall be retained.
(c) Records of sterilization of equipment and supplies. Records
relating to the mode of sterilization, date, duration, temperature and
other conditions relating to each sterilization of equipment and
supplies used in the processing of products shall be made by means of
automatic recording devices or by means of a system of recording which
gives equivalent assurance of the accuracy and reliability of the
record. Such records shall be maintained in a manner that permits an
identification of the product with the particular manufacturing process
to which the sterilization relates.
(d) Animal necropsy records. A necropsy record shall be kept on each
animal from which a biological product has been obtained and which dies
or is sacrificed while being so used.
(e) Records in case of divided manufacturing responsibility. If two
or more establishments participate in the manufacture of a product, the
records of each such establishment must show plainly the degree of its
responsibility. In addition, each participating manufacturer shall
furnish to the manufacturer who prepares the product in final form for
sale, barter or exchange, a copy of all records relating to the
manufacturing operations performed by such participating manufacturer
insofar as they concern the safety, purity and potency of the lots of
the product involved, and the manufacturer who prepares the product in
final form shall retain a complete record of all the manufacturing
operations relating to the product.
[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55
FR 11013, Mar. 26, 1990; 70 FR 14982, Mar. 24, 2005]
Sec. 600.13 Retention samples.
Manufacturers shall retain for a period of at least 6 months after
the expiration date, unless a different time period is specified in
additional standards, a quantity of representative material of each lot
of each product, sufficient for examination and testing for
[[Page 14]]
safety and potency, except Whole Blood, Cryoprecipitated AHF, Platelets,
Red Blood Cells, Plasma, and Source Plasma and Allergenic Products
prepared to a physician's prescription. Samples so retained shall be
selected at random from either final container material, or from bulk
and final containers, provided they include at least one final container
as a final package, or package-equivalent of such filling of each lot of
the product as intended for distribution. Such sample material shall be
stored at temperatures and under conditions which will maintain the
identity and integrity of the product. Samples retained as required in
this section shall be in addition to samples of specific products
required to be submitted to the Center for Biologics Evaluation and
Research or the Center for Drug Evaluation and Research (see mailing
addresses in Sec. 600.2). Exceptions may be authorized by the Director,
Center for Biologics Evaluation and Research or the Director, Center for
Drug Evaluation and Research, when the lot yields relatively few final
containers and when such lots are prepared by the same method in large
number and in close succession.
[41 FR 10428, Mar. 11, 1976, as amended at 49 FR 23833, June 8, 1984; 50
FR 4133, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 70 FR 14982, Mar.
24, 2005]
Sec. 600.14 Reporting of biological product deviations by licensed
manufacturers.
(a) Who must report under this section? (1) You, the manufacturer
who holds the biological product license and who had control over the
product when the deviation occurred, must report under this section. If
you arrange for another person to perform a manufacturing, holding, or
distribution step, while the product is in your control, that step is
performed under your control. You must establish, maintain, and follow a
procedure for receiving information from that person on all deviations,
complaints, and adverse events concerning the affected product.
(2) Exceptions:
(i) Persons who manufacture only in vitro diagnostic products that
are not subject to licensing under section 351 of the Public Health
Service Act do not report biological product deviations for those
products under this section but must report in accordance with part 803
of this chapter;
(ii) Persons who manufacture blood and blood components, including
licensed manufacturers, unlicensed registered blood establishments, and
transfusion services, do not report biological product deviations for
those products under this section but must report under Sec. 606.171 of
this chapter;
(iii) Persons who manufacture Source Plasma or any other blood
component and use that Source Plasma or any other blood component in the
further manufacture of another licensed biological product must report:
(A) Under Sec. 606.171 of this chapter, if a biological product
deviation occurs during the manufacture of that Source Plasma or any
other blood component; or
(B) Under this section, if a biological product deviation occurs
after the manufacture of that Source Plasma or any other blood
component, and during manufacture of the licensed biological product.
(b) What do I report under this section? You must report any event,
and information relevant to the event, associated with the
manufacturing, to include testing, processing, packing, labeling, or
storage, or with the holding or distribution, of a licensed biological
product, if that event meets all the following criteria:
(1) Either:
(i) Represents a deviation from current good manufacturing practice,
applicable regulations, applicable standards, or established
specifications that may affect the safety, purity, or potency of that
product; or
(ii) Represents an unexpected or unforeseeable event that may affect
the safety, purity, or potency of that product; and
(2) Occurs in your facility or another facility under contract with
you; and
(3) Involves a distributed biological product.
(c) When do I report under this section? You should report a
biological product deviation as soon as possible but you must report at
a date not to exceed 45-calendar days from the date you, your agent, or
another person who performs
[[Page 15]]
a manufacturing, holding, or distribution step under your control,
acquire information reasonably suggesting that a reportable event has
occurred.
(d) How do I report under this section You must report on Form FDA-
3486.
(e) Where do I report under this section? (1) For biological
products regulated by the Center for Biologics Evaluation and Research
(CBER), send the completed Form FDA 3486 to the CBER Document Control
Center (see mailing address in Sec. 600.2(a)), or submit electronically
using CBER's electronic Web-based application.
(2) For biological products regulated by the Center for Drug
Evaluation and Research (CDER), send the completed Form FDA-3486 to the
Division of Compliance Risk Management and Surveillance (HFD-330) (see
mailing addresses in Sec. 600.2). CDER does not currently accept
electronic filings.
(3) If you make a paper filing, you should identify on the envelope
that a biological product deviation report (BPDR) is enclosed.
(f) How does this regulation affect other FDA regulations? This part
supplements and does not supersede other provisions of the regulations
in this chapter. All biological product deviations, whether or not they
are required to be reported under this section, should be investigated
in accordance with the applicable provisions of parts 211 and 820 of
this chapter.
[65 FR 66634, Nov. 7, 2000, as amended at 70 FR 14982, Mar. 24, 2005; 80
FR 18092, Apr. 3, 2015]
Sec. 600.15 Temperatures during shipment.
The following products shall be maintained during shipment at the
specified temperatures:
(a) Products.
------------------------------------------------------------------------
Product Temperature
------------------------------------------------------------------------
Cryoprecipitated AHF................... -18 [deg]C or colder.
Measles and Rubella Virus Vaccine Live. 10 [deg]C or colder.
Measles Live and Smallpox Vaccine...... Do.
Measles, Mumps, and Rubella Virus Do.
Vaccine Live.
Measles and Mumps Virus Vaccine Live... Do.
Measles Virus Vaccine Live............. Do.
Mumps Virus Vaccine Live............... Do.
Fresh Frozen Plasma.................... -18 [deg]C or colder.
Liquid Plasma.......................... 1 to 10 [deg]C.
Plasma................................. -18 [deg]C or colder.
Platelet Rich Plasma................... Between 1 and 10 [deg]C if the
label indicates storage
between 1 and 6 [deg]C, or all
reasonable methods to maintain
the temperature as close as
possible to a range between 20
and 24 [deg]C, if the label
indicates storage between 20
and 24 [deg]C.
Platelets.............................. Between 1 and 10 [deg]C if the
label indicates storage
between 1 and 6 [deg]C, or all
reasonable methods to maintain
the temperature as close as
possible to a range between 20
to 24 [deg]C, if the label
indicates storage between 20
and 24 [deg]C.
Poliovirus Vaccine Live Oral Trivalent. 0 [deg]C or colder.
Poliovirus Vaccine Live Oral Type I.... Do.
Poliovirus Vaccine Live Oral Type II... Do.
Poliovirus Vaccine Live Oral Type III.. Do.
Red Blood Cells (liquid product)....... Between 1 and 10 [deg]C.
Red Blood Cells Frozen................. -65 [deg]C or colder.
Rubella and Mumps Virus Vaccine Live... 10 [deg]C or colder.
Rubella Virus Vaccine Live............. Do.
Smallpox Vaccine (Liquid Product)...... 0 [deg]C or colder.
Source Plasma.......................... -5 [deg]C or colder.
Source Plasma Liquid................... 10 [deg]C or colder.
Whole Blood............................ Blood that is transported from
the collecting facility to the
processing facility shall be
transported in an environment
capable of continuously
cooling the blood toward a
temperature range of 1 to 10
[deg]C, or at a temperature as
close as possible to 20 to 24
[deg]C for a period not to
exceed 6 hours. Blood
transported from the storage
facility shall be placed in an
appropriate environment to
maintain a temperature range
between 1 to 10 [deg]C during
shipment.
Yellow Fever Vaccine................... 0 [deg]C or colder.
------------------------------------------------------------------------
[[Page 16]]
(b) Exemptions. Exemptions or modifications shall be made only upon
written approval, in the form of a supplement to the biologics license
application, approved by the Director, Center for Biologics Evaluation
and Research.
[39 FR 39872, Nov. 12, 1974, as amended at 49 FR 23833, June 8, 1984; 50
FR 4133, Jan. 29, 1985; 50 FR 9000, Mar. 6, 1985; 55 FR 11013, Mar. 26,
1990; 59 FR 49351, Sept. 28, 1994; 64 FR 56449, Oct. 20, 1999]
Subpart C_Establishment Inspection
Sec. 600.20 Inspectors.
Inspections shall be made by an officer of the Food and Drug
Administration having special knowledge of the methods used in the
manufacture and control of products and designated for such purposes by
the Commissioner of Food and Drugs, or by any officer, agent, or
employee of the Department of Health and Human Services specifically
designated for such purpose by the Secretary.
[38 FR 32048, Nov. 20, 1973]
Sec. 600.21 Time of inspection.
The inspection of an establishment for which a biologics license
application is pending need not be made until the establishment is in
operation and is manufacturing the complete product for which a
biologics license is desired.
[38 FR 32048, Nov. 20, 1973, as amended at 48 FR 26314, June 7, 1983; 64
FR 56449, Oct. 20, 1999; 84 FR 12508, Apr. 2, 2019]
Sec. 600.22 [Reserved]
Subpart D_Reporting of Adverse Experiences
Source: 59 FR 54042, Oct. 27, 1994, unless otherwise noted.
Sec. 600.80 Postmarketing reporting of adverse experiences.
(a) Definitions. The following definitions of terms apply to this
section:
Adverse experience. Any adverse event associated with the use of a
biological product in humans, whether or not considered product related,
including the following: An adverse event occurring in the course of the
use of a biological product in professional practice; an adverse event
occurring from overdose of the product whether accidental or
intentional; an adverse event occurring from abuse of the product; an
adverse event occurring from withdrawal of the product; and any failure
of expected pharmacological action.
Blood Component. As defined in Sec. 606.3(c) of this chapter.
Disability. A substantial disruption of a person's ability to
conduct normal life functions.
Individual case safety report (ICSR). A description of an adverse
experience related to an individual patient or subject.
ICSR attachments. Documents related to the adverse experience
described in an ICSR, such as medical records, hospital discharge
summaries, or other documentation.
Life-threatening adverse experience. Any adverse experience that
places the patient, in the view of the initial reporter, at immediate
risk of death from the adverse experience as it occurred, i.e., it does
not include an adverse experience that, had it occurred in a more severe
form, might have caused death.
Serious adverse experience. Any adverse experience occurring at any
dose that results in any of the following outcomes: Death, a life-
threatening adverse experience, inpatient hospitalization or
prolongation of existing hospitalization, a persistent or significant
disability/incapacity, or a congenital anomaly/birth defect. Important
medical events that may not result in death, be life-threatening, or
require hospitalization may be considered a serious adverse experience
when, based upon appropriate medical judgment, they may jeopardize the
patient or subject and may require medical or surgical intervention to
prevent one of the outcomes listed in this definition. Examples of such
medical events include allergic bronchospasm requiring intensive
treatment in an emergency room or at home, blood dyscrasias or
convulsions that do not result in inpatient hospitalization, or the
development of drug dependency or drug abuse.
Unexpected adverse experience: Any adverse experience that is not
listed in the current labeling for the biological
[[Page 17]]
product. This includes events that may be symptomatically and
pathophysiologically related to an event listed in the labeling, but
differ from the event because of greater severity or specificity. For
example, under this definition, hepatic necrosis would be unexpected (by
virtue of greater severity) if the labeling only referred to elevated
hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and
cerebral vasculitis would be unexpected (by virtue of greater
specificity) if the labeling only listed cerebral vascular accidents.
``Unexpected,'' as used in this definition, refers to an adverse
experience that has not been previously observed (i.e., included in the
labeling) rather than from the perspective of such experience not being
anticipated from the pharmacological properties of the pharmaceutical
product.
(b) Review of adverse experiences. Any person having a biologics
license under Sec. 601.20 of this chapter must promptly review all
adverse experience information pertaining to its product obtained or
otherwise received by the applicant from any source, foreign or
domestic, including information derived from commercial marketing
experience, postmarketing clinical investigations, postmarketing
epidemiological/surveillance studies, reports in the scientific
literature, and unpublished scientific papers. Applicants are not
required to resubmit to FDA adverse product experience reports forwarded
to the applicant by FDA; applicants, however, must submit all followup
information on such reports to FDA. Any person subject to the reporting
requirements under paragraph (c) of this section must also develop
written procedures for the surveillance, receipt, evaluation, and
reporting of postmarketing adverse experiences to FDA.
(c) Reporting requirements. The applicant must submit to FDA
postmarketing 15-day Alert reports and periodic safety reports
pertaining to its biological product as described in this section. These
reports must be submitted to the Agency in electronic format as
described in paragraph (h)(1) of this section, except as provided in
paragraph (h)(2) of this section.
(1)(i) Postmarketing 15-day ``Alert reports''. The applicant must
report each adverse experience that is both serious and unexpected,
whether foreign or domestic, as soon as possible but no later than 15
calendar days from initial receipt of the information by the applicant.
(ii) Postmarketing 15-day ``Alert reports''--followup. The applicant
must promptly investigate all adverse experiences that are the subject
of these postmarketing 15-day Alert reports and must submit followup
reports within 15 calendar days of receipt of new information or as
requested by FDA. If additional information is not obtainable, records
should be maintained of the unsuccessful steps taken to seek additional
information.
(iii) Submission of reports. The requirements of paragraphs
(c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of
postmarketing 15-day Alert reports, also apply to any person whose name
appears on the label of a licensed biological product as a manufacturer,
packer, distributor, shared manufacturer, joint manufacturer, or any
other participant involved in divided manufacturing. To avoid
unnecessary duplication in the submission to FDA of reports required by
paragraphs (c)(1)(i) and (c)(1)(ii) of this section, obligations of
persons other than the applicant of the final biological product may be
met by submission of all reports of serious adverse experiences to the
applicant of the final product. If a person elects to submit adverse
experience reports to the applicant rather than to FDA, the person must
submit, by any appropriate means, each report to the applicant within 5
calendar days of initial receipt of the information by the person, and
the applicant must then comply with the requirements of this section.
Under this circumstance, a person who elects to submit reports to the
applicant of the final product shall maintain a record of this action
which must include:
(A) A copy of all adverse biological product experience reports
submitted to the applicant of the final product;
(B) The date the report was received by the person;
[[Page 18]]
(C) The date the report was submitted to the applicant of the final
product; and--
(D) The name and address of the applicant of the final product.
(2) Periodic adverse experience reports. (i) The applicant must
report each adverse experience not reported under paragraph (c)(1)(i) of
this section at quarterly intervals, for 3 years from the date of
issuance of the biologics license, and then at annual intervals. The
applicant must submit each quarterly report within 30 days of the close
of the quarter (the first quarter beginning on the date of issuance of
the biologics license) and each annual report within 60 days of the
anniversary date of the issuance of the biologics license. Upon written
notice, FDA may extend or reestablish the requirement that an applicant
submit quarterly reports, or require that the applicant submit reports
under this section at different times than those stated. Followup
information to adverse experiences submitted in a periodic report may be
submitted in the next periodic report.
(ii) Each periodic report is required to contain:
(A) Descriptive information. (1) A narrative summary and analysis of
the information in the report;
(2) An analysis of the 15-day Alert reports submitted during the
reporting interval (all 15-day Alert reports being appropriately
referenced by the applicant's patient identification code for nonvaccine
biological product reports or by the unique case identification number
for vaccine reports, adverse reaction term(s), and date of submission to
FDA);
(3) A history of actions taken since the last report because of
adverse experiences (for example, labeling changes or studies
initiated);
(4) An index consisting of a line listing of the applicant's patient
identification code for nonvaccine biological product reports or by the
unique case identification number for vaccine reports and adverse
reaction term(s) for ICSRs submitted under paragraph (c)(2)(ii)(B) of
this section; and
(B) ICSRs for serious, expected and, nonserious adverse experiences.
An ICSR for each adverse experience not reported under paragraph
(c)(1)(i) of this section (all serious, expected and nonserious adverse
experiences). All such ICSRs must be submitted to FDA (either
individually or in one or more batches) within the timeframe specified
in paragraph (c)(2)(i) of this section. ICSRs must only be submitted to
FDA once.
(iii) Periodic reporting, except for information regarding 15-day
Alert reports, does not apply to adverse experience information obtained
from postmarketing studies (whether or not conducted under an
investigational new drug application), from reports in the scientific
literature, and from foreign marketing experience.
(d) Scientific literature. A 15-day Alert report based on
information in the scientific literature must be accompanied by a copy
of the published article. The 15-day Alert reporting requirements in
paragraph (c)(1)(i) of this section (i.e., serious, unexpected adverse
experiences) apply only to reports found in scientific and medical
journals either as case reports or as the result of a formal clinical
trial.
(e) Postmarketing studies. Applicants are not required to submit a
15-day Alert report under paragraph (c) of this section for an adverse
experience obtained from a postmarketing clinical study (whether or not
conducted under a biological investigational new drug application)
unless the applicant concludes that there is a reasonable possibility
that the product caused the adverse experience.
(f) Information reported on ICSRs for nonvaccine biological
products. ICSRs for nonvaccine biological products include the following
information:
(1) Patient information.
(i) Patient identification code;
(ii) Patient age at the time of adverse experience, or date of
birth;
(iii) Patient gender; and
(iv) Patient weight.
(2) Adverse experience.
(i) Outcome attributed to adverse experience;
(ii) Date of adverse experience;
(iii) Date of report;
(iv) Description of adverse experience (including a concise medical
narrative);
(v) Adverse experience term(s);
[[Page 19]]
(vi) Description of relevant tests, including dates and laboratory
data; and
(vii) Other relevant patient history, including preexisting medical
conditions.
(3) Suspect medical product(s).
(i) Name;
(ii) Dose, frequency, and route of administration used;
(iii) Therapy dates;
(iv) Diagnosis for use (indication);
(v) Whether the product is a combination product as defined in Sec.
3.2(e) of this chapter;
(vi) Whether the product is a prescription or nonprescription
product;
(vii) Whether adverse experience abated after product use stopped or
dose reduced;
(viii) Whether adverse experience reappeared after reintroduction of
the product;
(ix) Lot number;
(x) Expiration date;
(xi) National Drug Code (NDC) number, or other unique identifier;
and
(xii) Concomitant medical products and therapy dates.
(4) Initial reporter information.
(i) Name, address, and telephone number;
(ii) Whether the initial reporter is a health care professional; and
(iii) Occupation, if a health care professional.
(5) Applicant information.
(i) Applicant name and contact office address;
(ii) Telephone number;
(iii) Report source, such as spontaneous, literature, or study;
(iv) Date the report was received by applicant;
(v) Application number and type;
(vi) Whether the ICSR is a 15-day ``Alert report'';
(vii) Whether the ICSR is an initial report or followup report; and
(viii) Unique case identification number, which must be the same in
the initial report and any subsequent followup report(s).
(g) Information reported on ICSRs for vaccine products. ICSRs for
vaccine products include the following information:
(1) Patient information.
(i) Patient name, address, telephone number;
(ii) Patient age at the time of vaccination, or date of birth;
(iii) Patient gender; and
(iv) Patient birth weight for children under age 5.
(2) Adverse experience.
(i) Outcome attributed to adverse experience;
(ii) Date and time of adverse experience;
(iii) Date of report;
(iv) Description of adverse experience (including a concise medical
narrative);
(v) Adverse experience term(s);
(vi) Illness at the time of vaccination;
(vii) Description of relevant tests, including dates and laboratory
data; and
(viii) Other relevant patient history, including preexisting medical
conditions.
(3) Suspect medical product(s), including vaccines administered on
the same date.
(i) Name;
(ii) Dose, frequency, and route or site of administration used;
(iii) Number of previous vaccine doses;
(iv) Vaccination date(s) and time(s);
(v) Diagnosis for use (indication);
(vi) Whether the product is a combination product (as defined in
Sec. 3.2(e) of this chapter);
(vii) Whether the adverse experience abated after product use
stopped or dose reduced;
(viii) Whether the adverse experience reappeared after
reintroduction of the product;
(ix) Lot number;
(x) Expiration date;
(xi) National Drug Code (NDC) number, or other unique identifier;
and
(xii) Concomitant medical products and therapy dates.
(4) Vaccine(s) administered in the 4 weeks prior to the vaccination
date.
(i) Name of vaccine;
(ii) Manufacturer;
(iii) Lot number;
(iv) Route or site of administration;
(v) Date given; and
(vi) Number of previous doses.
(5) Initial reporter information.
(i) Name, address, and telephone number;
(ii) Whether the initial reporter is a health care professional; and
[[Page 20]]
(iii) Occupation, if a health care professional.
(6) Facility and personnel where vaccine was administered.
(i) Name of person who administered vaccine;
(ii) Name of responsible physician at facility where vaccine was
administered; and
(iii) Name, address (including city, county, and state), and
telephone number of facility where vaccine was administered.
(7) Applicant information.
(i) Applicant name and contact office address;
(ii) Telephone number;
(iii) Report source, such as spontaneous, literature, or study;
(iv) Date received by applicant;
(v) Application number and type;
(vi) Whether the ICSR is a 15-day ``Alert report'';
(vii) Whether the ICSR is an initial report or followup report; and
(viii) Unique case identification number, which must be the same in
the initial report and any subsequent followup report(s).
(h) Electronic format for submissions. (1) Safety report
submissions, including ICSRs, ICSR attachments, and the descriptive
information in periodic reports, must be in an electronic format that
FDA can process, review, and archive. FDA will issue guidance on how to
provide the electronic submission (e.g., method of transmission, media,
file formats, preparation and organization of files).
(2) Persons subject to the requirements of paragraph (c) of this
section may request, in writing, a temporary waiver of the requirements
in paragraph (h)(1) of this section. These waivers will be granted on a
limited basis for good cause shown. FDA will issue guidance on
requesting a waiver of the requirements in paragraph (h)(1) of this
section. Requests for waivers must be submitted in accordance with Sec.
600.90.
(i) Multiple reports. An applicant should not include in reports
under this section any adverse experience that occurred in clinical
trials if they were previously submitted as part of the biologics
license application. If a report refers to more than one biological
product marketed by an applicant, the applicant should submit the report
to the biologics license application for the product listed first in the
report.
(j) Patient privacy. For nonvaccine biological products, an
applicant should not include in reports under this section the names and
addresses of individual patients; instead, the applicant should assign a
unique code for identification of the patient. The applicant should
include the name of the reporter from whom the information was received
as part of the initial reporter information, even when the reporter is
the patient. The names of patients, health care professionals,
hospitals, and geographical identifiers in adverse experience reports
are not releasable to the public under FDA's public information
regulations in part 20 of this chapter. For vaccine adverse experience
reports, these data will become part of the CDC Privacy Act System 09-
20-0136, ``Epidemiologic Studies and Surveillance of Disease Problems.''
Information identifying the person who received the vaccine or that
person's legal representative will not be made available to the public,
but may be available to the vaccinee or legal representative.
(k) Recordkeeping. The applicant must maintain for a period of 10
years records of all adverse experiences known to the applicant,
including raw data and any correspondence relating to the adverse
experiences.
(l) Revocation of biologics license. If an applicant fails to
establish and maintain records and make reports required under this
section with respect to a licensed biological product, FDA may revoke
the biologics license for such a product in accordance with the
procedures of Sec. 601.5 of this chapter.
(m) Exemptions. Manufacturers of the following listed products are
not required to submit adverse experience reports under this section:
(1) Whole blood or components of whole blood.
(2) In vitro diagnostic products, including assay systems for the
detection of antibodies or antigens to retroviruses. These products are
subject to the reporting requirements for devices.
(n) Disclaimer. A report or information submitted by an applicant
under
[[Page 21]]
this section (and any release by FDA of that report or information) does
not necessarily reflect a conclusion by the applicant or FDA that the
report or information constitutes an admission that the biological
product caused or contributed to an adverse effect. An applicant need
not admit, and may deny, that the report or information submitted under
this section constitutes an admission that the biological product caused
or contributed to an adverse effect. For purposes of this provision,
this paragraph also includes any person reporting under paragraph
(c)(1)(iii) of this section.
[59 FR 54042, Oct. 27, 1994, as amended at 62 FR 34168, June 25, 1997;
62 FR 52252, Oct. 7, 1997; 63 FR 14612, Mar. 26, 1998; 64 FR 56449, Oct.
20, 1999; 70 FR 14982, Mar. 24, 2005; 79 FR 33090, June 10, 2014]
Sec. 600.81 Distribution reports.
(a) Reporting requirements. The applicant must submit to the Center
for Biologics Evaluation and Research or the Center for Drug Evaluation
and Research, information about the quantity of the product distributed
under the biologics license, including the quantity distributed to
distributors. The interval between distribution reports must be 6
months. Upon written notice, FDA may require that the applicant submit
distribution reports under this section at times other than every 6
months. The distribution report must consist of the bulk lot number
(from which the final container was filled), the fill lot numbers for
the total number of dosage units of each strength or potency distributed
(e.g., fifty thousand per 10-milliliter vials), the label lot number (if
different from fill lot number), labeled date of expiration, number of
doses in fill lot/label lot, date of release of fill lot/label lot for
distribution at that time. If any significant amount of a fill lot/label
lot is returned, include this information. Disclosure of financial or
pricing data is not required. As needed, FDA may require submission of
more detailed product distribution information. Upon written notice, FDA
may require that the applicant submit reports under this section at
times other than those stated. Requests by an applicant to submit
reports at times other than those stated should be made as a request for
a waiver under Sec. 600.90.
(b)(1) Electronic format. Except as provided for in paragraph (b)(2)
of this section, the distribution reports required under paragraph (a)
of this section must be submitted to the Agency in an electronic format
that FDA can process, review, and archive. FDA will issue guidance on
how to provide the electronic submission (e.g., method of transmission,
media, file formats, preparation and organization of files).
(2) Waivers. An applicant may request, in writing, a temporary
waiver of the requirements in paragraph (b)(1) of this section. These
waivers will be granted on a limited basis for good cause shown. FDA
will issue guidance on requesting a waiver of the requirements in
paragraph (b)(1) of this section. Requests for waivers must be submitted
in accordance with Sec. 600.90.
[59 FR 54042, Oct. 27, 1994, as amended at 64 FR 56449, Oct. 20, 1999;
70 FR 14983, Mar. 24, 2005; 79 FR 33091, June 10, 2014]
Sec. 600.82 Notification of a permanent discontinuance or an
interruption in manufacturing.
(a) Notification of a permanent discontinuance or an interruption in
manufacturing. (1) An applicant of a biological product, other than
blood or blood components for transfusion, which is licensed under
section 351 of the Public Health Service Act, and which may be dispensed
only under prescription under section 503(b)(1) of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 353(b)(1)), must notify FDA in writing
of a permanent discontinuance of manufacture of the biological product
or an interruption in manufacturing of the biological product that is
likely to lead to a meaningful disruption in supply of that biological
product in the United States if:
(i) The biological product is life supporting, life sustaining, or
intended for use in the prevention or treatment of a debilitating
disease or condition, including any such biological product used in
emergency medical care or during surgery; and
(ii) The biological product is not a radiopharmaceutical biological
product.
[[Page 22]]
(2) An applicant of blood or blood components for transfusion, which
is licensed under section 351 of the Public Health Service Act, and
which may be dispensed only under prescription under section 503(b) of
the Federal Food, Drug, and Cosmetic Act, must notify FDA in writing of
a permanent discontinuance of manufacture of any product listed in its
license or an interruption in manufacturing of any such product that is
likely to lead to a significant disruption in supply of that product in
the United States if:
(i) The product is life supporting, life sustaining, or intended for
use in the prevention or treatment of a debilitating disease or
condition, including any such product used in emergency medical care or
during surgery; and
(ii) The applicant is a manufacturer of a significant percentage of
the U.S. blood supply.
(b) Submission and timing of notification. Notifications required by
paragraph (a) of this section must be submitted to FDA electronically in
a format that FDA can process, review, and archive:
(1) At least 6 months prior to the date of the permanent
discontinuance or interruption in manufacturing; or
(2) If 6 months' advance notice is not possible because the
permanent discontinuance or interruption in manufacturing was not
reasonably anticipated 6 months in advance, as soon as practicable
thereafter, but in no case later than 5 business days after such a
permanent discontinuance or interruption in manufacturing occurs.
(c) Information included in notification. Notifications required by
paragraph (a) of this section must include the following information:
(1) The name of the biological product subject to the notification,
including the National Drug Code for such biological product, or an
alternative standard for identification and labeling that has been
recognized as acceptable by the Center Director;
(2) The name of the applicant of the biological product;
(3) Whether the notification relates to a permanent discontinuance
of the biological product or an interruption in manufacturing of the
biological product;
(4) A description of the reason for the permanent discontinuance or
interruption in manufacturing; and
(5) The estimated duration of the interruption in manufacturing.
(d)(1) Public list of biological product shortages. FDA will
maintain a publicly available list of biological products that are
determined by FDA to be in shortage. This biological product shortages
list will include the following information:
(i) The names and National Drug Codes for such biological products,
or the alternative standards for identification and labeling that have
been recognized as acceptable by the Center Director;
(ii) The name of each applicant for such biological products;
(iii) The reason for the shortage, as determined by FDA, selecting
from the following categories: Requirements related to complying with
good manufacturing practices; regulatory delay; shortage of an active
ingredient; shortage of an inactive ingredient component;
discontinuation of the manufacture of the biological product; delay in
shipping of the biological product; demand increase for the biological
product; or other reason; and
(iv) The estimated duration of the shortage.
(2) Confidentiality. FDA may choose not to make information
collected to implement this paragraph available on the biological
product shortages list or available under section 506C(c) of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 356c(c)) if FDA determines that
disclosure of such information would adversely affect the public health
(such as by increasing the possibility of hoarding or other disruption
of the availability of the biological product to patients). FDA will
also not provide information on the public shortages list or under
section 506C(c) of the Federal Food, Drug, and Cosmetic Act that is
protected by 18 U.S.C. 1905 or 5 U.S.C. 552(b)(4), including trade
secrets and commercial or financial information that is considered
confidential or privileged under Sec. 20.61 of this chapter.
(e) Noncompliance letters. If an applicant fails to submit a
notification as required under paragraph (a) of this
[[Page 23]]
section and in accordance with paragraph (b) of this section, FDA will
issue a letter to the applicant informing it of such failure.
(1) Not later than 30 calendar days after the issuance of such a
letter, the applicant must submit to FDA a written response setting
forth the basis for noncompliance and providing the required
notification under paragraph (a) of this section and including the
information required under paragraph (c) of this section; and
(2) Not later than 45 calendar days after the issuance of a letter
under this paragraph, FDA will make the letter and the applicant's
response to the letter public, unless, after review of the applicant's
response, FDA determines that the applicant had a reasonable basis for
not notifying FDA as required under paragraph (a) of this section.
(f) Definitions. The following definitions of terms apply to this
section:
Biological product shortage or shortage means a period of time when
the demand or projected demand for the biological product within the
United States exceeds the supply of the biological product.
Intended for use in the prevention or treatment of a debilitating
disease or condition means a biological product intended for use in the
prevention or treatment of a disease or condition associated with
mortality or morbidity that has a substantial impact on day-to-day
functioning.
Life supporting or life sustaining means a biological product that
is essential to, or that yields information that is essential to, the
restoration or continuation of a bodily function important to the
continuation of human life.
Meaningful disruption means a change in production that is
reasonably likely to lead to a reduction in the supply of a biological
product by a manufacturer that is more than negligible and affects the
ability of the manufacturer to fill orders or meet expected demand for
its product, and does not include interruptions in manufacturing due to
matters such as routine maintenance or insignificant changes in
manufacturing so long as the manufacturer expects to resume operations
in a short period of time.
Significant disruption means a change in production that is
reasonably likely to lead to a reduction in the supply of blood or blood
components by a manufacturer that substantially affects the ability of
the manufacturer to fill orders or meet expected demand for its product,
and does not include interruptions in manufacturing due to matters such
as routine maintenance or insignificant changes in manufacturing so long
as the manufacturer expects to resume operations in a short period of
time.
[80 FR 38939, July 8, 2015]
Sec. 600.90 Waivers.
(a) An applicant may ask the Food and Drug Administration to waive
under this section any requirement that applies to the applicant under
Sec. Sec. 600.80 and 600.81. A waiver request under this section is
required to be submitted with supporting documentation. The waiver
request is required to contain one of the following:
(1) An explanation why the applicant's compliance with the
requirement is unnecessary or cannot be achieved,
(2) A description of an alternative submission that satisfies the
purpose of the requirement, or
(3) Other information justifying a waiver.
(b) FDA may grant a waiver if it finds one of the following:
(1) The applicant's compliance with the requirement is unnecessary
or cannot be achieved,
(2) The applicant's alternative submission satisfies the
requirement, or
(3) The applicant's submission otherwise justifies a waiver.
[59 FR 54042, Oct. 27, 1994, as amended at 79 FR 33092, June 10, 2014]
PART 601_LICENSING--Table of Contents
Subpart A_General Provisions
Sec.
601.2 Applications for biologics licenses; procedures for filing.
601.3 Complete response letter to the applicant.
601.4 Issuance and denial of license.
601.5 Revocation of license.
601.6 Suspension of license.
601.7 Procedure for hearings.
[[Page 24]]
601.8 Publication of revocation.
601.9 Licenses; reissuance.
Subpart B [Reserved]
Subpart C_Biologics Licensing
601.12 Changes to an approved application.
601.14 Regulatory submissions in electronic format.
601.15 Foreign establishments and products: Samples for each
importation.
601.20 Biologics licenses; issuance and conditions.
601.21 Products under development.
601.22 Products in short supply; initial manufacturing at other than
licensed location.
601.27 Pediatric studies.
601.28 Annual reports of postmarketing pediatric studies.
601.29 Guidance documents.
Subpart D_Diagnostic Radiopharmaceuticals
601.30 Scope.
601.31 Definition.
601.32 General factors relevant to safety and effectiveness.
601.33 Indications.
601.34 Evaluation of effectiveness.
601.35 Evaluation of safety.
Subpart E_Accelerated Approval of Biological Products for Serious or
Life-Threatening Illnesses
601.40 Scope.
601.41 Approval based on a surrogate endpoint or on an effect on a
clinical endpoint other than survival or irreversible
morbidity.
601.42 Approval with restrictions to assure safe use.
601.43 Withdrawal procedures.
601.44 Postmarketing safety reporting.
601.45 Promotional materials.
601.46 Termination of requirements.
Subpart F_Confidentiality of Information
601.50 Confidentiality of data and information in an investigational new
drug notice for a biological product.
601.51 Confidentiality of data and information in applications for
biologics licenses.
Subpart G_Postmarketing Studies
601.70 Annual progress reports of postmarketing studies.
Subpart H_Approval of Biological Products When Human Efficacy Studies
Are Not Ethical or Feasible
601.90 Scope.
601.91 Approval based on evidence of effectiveness from studies in
animals.
601.92 Withdrawal procedures.
601.93 Postmarketing safety reporting.
601.94 Promotional materials.
601.95 Termination of requirements.
Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 355,
356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216,
241, 262, 263, 264; sec 122, Pub. L. 105-115, 111 Stat. 2322 (21 U.S.C.
355 note), sec 7002(e), Pub. L. 111-148, 124 Stat. 817, as amended by
sec. 607, Division N, Pub. L. 116-94, 133 Stat. 3127.
Source: 38 FR 32052, Nov. 20, 1973, unless otherwise noted.
Cross References: For U.S. Customs Service regulations relating to
viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal
Service regulations relating to the admissibility to the United States
mails see parts 124 and 125 of the Domestic Mail Manual, that is
incorporated by reference in 39 CFR part 111.
Subpart A_General Provisions
Sec. 601.2 Applications for biologics licenses; procedures for filing.
(a) General. To obtain a biologics license under section 351 of the
Public Health Service Act for any biological product, the manufacturer
shall submit an application to the Director, Center for Biologics
Evaluation and Research or the Director, Center for Drug Evaluation and
Research (see mailing addresses in Sec. 600.2(a) or (b) of this
chapter), on forms prescribed for such purposes, and shall submit data
derived from nonclinical laboratory and clinical studies which
demonstrate that the manufactured product meets prescribed requirements
of safety, purity, and potency; with respect to each nonclinical
laboratory study, either a statement that the study was conducted in
compliance with the requirements set forth in part 58 of this chapter,
or, if the study was not conducted in compliance with such regulations,
a brief statement of the reason for the
[[Page 25]]
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 by the Food and Drug
Administration. The applicant shall also include either a claim for
categorical exclusion under Sec. 25.30 or Sec. 25.31 of this chapter
or an environmental assessment under Sec. 25.40 of this chapter. The
applicant, or the applicant's attorney, agent, or other authorized
official shall sign the application. An application for any of the
following specified categories of biological products subject to
licensure shall be handled as set forth in paragraph (c) of this
section:
(1) Therapeutic DNA plasmid products;
(2) Therapeutic synthetic peptide products of 40 or fewer amino
acids;
(3) Monoclonal antibody products for in vivo use; and
(4) Therapeutic recombinant DNA-derived products.
(b) [Reserved]
(c)(1) To obtain marketing approval for a biological product subject
to licensure which is a therapeutic DNA plasmid product, therapeutic
synthetic peptide product of 40 or fewer amino acids, monoclonal
antibody product for in vivo use, or therapeutic recombinant DNA-derived
product, an applicant shall submit a biologics license application in
accordance with paragraph (a) of this section except that the following
sections in parts 600 through 680 of this chapter shall not be
applicable to such products: Sec. Sec. 600.10(b) and (c), 600.11,
600.12, 600.13, 610.53, and 610.62 of this chapter.
(2) To the extent that the requirements in this paragraph (c)
conflict with other requirements in this subchapter, this paragraph (c)
shall supersede other requirements.
(d) Approval of a biologics license application or issuance of a
biologics license shall constitute a determination that the
establishment(s) and the product meet applicable requirements to ensure
the continued safety, purity, and potency of such products. Applicable
requirements for the maintenance of establishments for the manufacture
of a product subject to this section shall include but not be limited to
the good manufacturing practice requirements set forth in parts 210,
211, 600, 606, and 820 of this chapter.
(e) Any establishment and product license for a biological product
issued under section 351 of the Public Health Service Act (42 U.S.C. 201
et seq.) that has not been revoked or suspended as of December 20, 1999,
shall constitute an approved biologics license application in effect
under the same terms and conditions set forth in such product license
and such portions of the establishment license relating to such product.
(f) Withdrawal from sale of approved biological products. A holder
of a biologics license application (BLA) must report to FDA, in
accordance with the requirements of Sec. Sec. 207.61 and 207.65, the
withdrawal from sale of an approved biological product. The information
must be submitted to FDA within 30 working days of the biological
product's withdrawal from sale. The following information must be
submitted: The holder's name; product name; BLA number; the National
Drug Code; and the date on which the product is expected to be
[[Page 26]]
no longer in commercial distribution. The reason for the withdrawal of
the biological product is requested but not required to be submitted.
(g) Master files--(1) Biologics license applications under section
351 of the Public Health Service Act not permitted to incorporate by
reference drug substance, drug substance intermediate, or drug product
information contained in a master file. Except as provided in paragraphs
(g)(2) and (3) of this section, a biologics license application under
section 351 of the Public Health Service Act may not incorporate by
reference drug substance, drug substance intermediate, or drug product
information contained in a master file, including a drug master file
submitted under Sec. 314.420 of this chapter, for the product,
including for a biological product constituent part of a combination
product.
(2) Former approved applications deemed to be licenses for
biological products pursuant to section 7002(e)(4) of the Biologics
Price Competition and Innovation Act of 2009. An application for a
biological product that:
(i) Is a former approved application under section 505 of the
Federal Food, Drug, and Cosmetic Act that, pursuant to section
7002(e)(4) of the Biologics Price Competition and Innovation Act of
2009, has been deemed to be a license for the biological product under
section 351 of the Public Health Service Act; and
(ii) At the time it was so deemed, incorporated by reference drug
substance, drug substance intermediate, and/or drug product information
contained in a drug master file submitted under Sec. 314.420 of this
chapter, may continue to incorporate by reference the information
contained in that drug master file. Amendments and supplements to such
applications may also continue to incorporate by reference the
information contained in that drug master file.
(3) Non-biological product constituent parts of combination products
regulated under biologics license applications under section 351 of the
Public Health Service Act. A biologics license application under section
351 of the Public Health Service Act may incorporate by reference drug
substance, drug substance intermediate, and/or drug product information
contained in a master file, including a drug master file submitted under
Sec. 314.420 of this chapter, for any non-biological product
constituent part of a combination product.
(4) Biologics license applications under section 351 of the Public
Health Service Act permitted to incorporate by reference information
contained in a master file that is not drug substance, drug substance
intermediate, or drug product information. Nothing in paragraph (g)(1)
of this section limits or restricts a biologics license application
under section 351 of the Public Health Service Act from incorporating by
reference information contained in any master file, including a drug
master file submitted under Sec. 314.420 of this chapter, that is not
drug substance, drug substance intermediate, or drug product
information.
(5) Investigational new drug applications. Nothing in paragraph
(g)(1) of this section limits or restricts an investigational new drug
application for a product that would be subject to licensure under
section 351 of the Public Health Service Act from incorporating by
reference any information, including drug substance, drug substance
intermediate, and drug product information, contained in a master file,
including a drug master file submitted under Sec. 314.420 of this
chapter.
[64 FR 56450, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005;
80 FR 18092, Apr. 3, 2015; 80 FR 37974, July 2, 2015; 81 FR 60221, Aug.
31, 2016; 89 FR 9756, Feb. 12, 2024]
Sec. 601.3 Complete response letter to the applicant.
(a) Complete response letter. The Food and Drug Administration will
send the biologics license applicant or supplement applicant a complete
response letter if the agency determines that it will not approve the
biologics license application or supplement in its present form.
(1) Description of specific deficiencies. A complete response letter
will describe all of the deficiencies that the agency has identified in
a biologics license application or supplement, except as stated in
paragraph (a)(2) of this section.
(2) Inadequate data. If FDA determines, after a biologics license
application or supplement is filed, that the
[[Page 27]]
data submitted are inadequate to support approval, the agency might
issue a complete response letter without first conducting required
inspections, testing submitted product lots, and/or reviewing proposed
product labeling.
(3) Recommendation of actions for approval. When possible, a
complete response letter will recommend actions that the applicant might
take to place its biologics license application or supplement in
condition for approval.
(b) Applicant actions. After receiving a complete response letter,
the biologics license applicant or supplement applicant must take either
of the following actions:
(1) Resubmission. Resubmit the application or supplement, addressing
all deficiencies identified in the complete response letter.
(2) Withdrawal. Withdraw the application or supplement. A decision
to withdraw the application or supplement is without prejudice to a
subsequent submission.
(c) Failure to take action. (1) FDA may consider a biologics license
applicant or supplement applicant's failure to either resubmit or
withdraw the application or supplement within 1 year after issuance of a
complete response letter to be a request by the applicant to withdraw
the application or supplement, unless the applicant has requested an
extension of time in which to resubmit the application or supplement.
FDA will grant any reasonable request for such an extension. FDA may
consider an applicant's failure to resubmit the application or
supplement within the extended time period or request an additional
extension to be a request by the applicant to withdraw the application.
(2) If FDA considers an applicant's failure to take action in
accordance with paragraph (c)(1) of this section to be a request to
withdraw the application, the agency will notify the applicant in
writing. The applicant will have 30 days from the date of the
notification to explain why the application or supplement should not be
withdrawn and to request an extension of time in which to resubmit the
application or supplement. FDA will grant any reasonable request for an
extension. If the applicant does not respond to the notification within
30 days, the application or supplement will be deemed to be withdrawn.
[73 FR 39611, July 10, 2008]
Sec. 601.4 Issuance and denial of license.
(a) A biologics license shall be issued upon a determination by the
Director, Center for Biologics Evaluation and Research or the Director,
Center for Drug Evaluation and Research that the establishment(s) and
the product meet the applicable requirements established in this
chapter. A biologics license shall be valid until suspended or revoked.
(b) If the Commissioner determines that the establishment or product
does not meet the requirements established in this chapter, the
biologics license application shall be denied and the applicant shall be
informed of the grounds for, and of an opportunity for a hearing on, the
decision. If the applicant so requests, the Commissioner shall issue a
notice of opportunity for hearing on the matter pursuant to Sec.
12.21(b) of this chapter.
[42 FR 4718, Jan. 25, 1977, as amended at 42 FR 15676, Mar. 22, 1977; 42
FR 19142, Apr. 12, 1977; 64 FR 56450, Oct. 20, 1999; 70 FR 14983, Mar.
24, 2005]
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,
[[Page 28]]
(ii) Manufacturing of products or of a product has been discontinued
to an extent that a meaningful inspection or evaluation cannot be made,
(iii) The manufacturer has failed to report a change as required by
Sec. 601.12 of this chapter,
(iv) The establishment or any location thereof, or the product for
which the license has been issued, fails to conform to the applicable
standards established in the license and in this chapter designed to
ensure the continued safety, purity, and potency of the manufactured
product,
(v) The establishment or the manufacturing methods have been so
changed as to require a new showing that the establishment or product
meets the requirements established in this chapter in order to protect
the public health, or
(vi) The licensed product is not safe and effective for all of its
intended uses or is misbranded with respect to any such use.
(2) Except as provided in Sec. 601.6 of this chapter, or in cases
involving willfulness, the notification required in this paragraph shall
provide a reasonable period for the licensed manufacturer to demonstrate
or achieve compliance with the requirements of this chapter, before
proceedings will be instituted for the revocation of the license. If
compliance is not demonstrated or achieved and the licensed manufacturer
does not waive the opportunity for a hearing, the Commissioner shall
issue a notice of opportunity for hearing on the matter under Sec.
12.21(b) of this chapter.
[64 FR 56451, Oct. 20, 1999]
Sec. 601.6 Suspension of license.
(a) Whenever the Commissioner has reasonable grounds to believe that
any of the grounds for revocation of a license exist and that by reason
thereof there is a danger to health, the Commissioner may notify the
licensed manufacturer that the biologics license is suspended and
require that the licensed manufacturer do the following:
(1) Notify the selling agents and distributors to whom such product
or products have been delivered of such suspension, and
(2) Furnish to the Center for Biologics Evaluation and Research or
the Center for Drug Evaluation and Research, complete records of such
deliveries and notice of suspension.
(b) Upon suspension of a license, the Commissioner shall either:
(1) Proceed under the provisions of Sec. 601.5(b) of this chapter
to revoke the license, or
(2) If the licensed manufacturer agrees, hold revocation in abeyance
pending resolution of the matters involved.
[64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005]
Sec. 601.7 Procedure for hearings.
(a) A notice of opportunity for hearing, notice of appearance and
request for hearing, and grant or denial of hearing for a biological
drug pursuant to this part, for which the exemption from the Federal
Food, Drug, and Cosmetic Act in Sec. 310.4 of this chapter has been
revoked, shall be subject to the provisions of Sec. 314.200 of this
chapter except to the extent that the notice of opportunity for hearing
on the matter issued pursuant to Sec. 12.21(b) of this chapter
specifically provides otherwise.
(b) Hearings pursuant to Sec. Sec. 601.4 through 601.6 shall be
governed by part 12 of this chapter.
(c) When a license has been suspended pursuant to Sec. 601.6 and a
hearing request has been granted, the hearing shall proceed on an
expedited basis.
[42 FR 4718, Jan. 25, 1977, as amended at 42 FR 15676, Mar. 22, 1977; 42
FR 19143, Apr. 12, 1977]
Sec. 601.8 Publication of revocation.
The Commissioner, following revocation of a biologics license under
21 CFR 601.5(b), will publish a notice in the Federal Register with a
statement of the specific grounds for the revocation.
[74 FR 20585, May 5, 2009]
Sec. 601.9 Licenses; reissuance.
(a) Compliance with requirements. A biologics license, previously
suspended or revoked, may be reissued or reinstated upon a showing of
compliance with requirements and upon such inspection and examination as
may be considered necessary by the Director,
[[Page 29]]
Center for Biologics Evaluation and Research or the Director, Center for
Drug Evaluation and Research.
(b) Exclusion of noncomplying location. A biologics license,
excluding a location or locations that fail to comply with the
requirements in this chapter, may be issued without further application
and concurrently with the suspension or revocation of the license for
noncompliance at the excluded location or locations.
(c) Exclusion of noncomplying product(s). In the case of multiple
products included under a single biologics license application, a
biologics license may be issued, excluding the noncompliant product(s),
without further application and concurrently with the suspension or
revocation of the biologics license for a noncompliant product(s).
[64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005]
Subpart B [Reserved]
Subpart C_Biologics Licensing
Sec. 601.12 Changes to an approved application.
(a) General. (1) As provided by this section, an applicant must
inform the Food and Drug Administration (FDA) (see mailing addresses in
Sec. 600.2 of this chapter) about each change in the product,
production process, quality controls, equipment, facilities, responsible
personnel, or labeling established in the approved license
application(s).
(2) Before distributing a product made using a change, an applicant
must assess the effects of the change and demonstrate through
appropriate validation and/or other clinical and/or nonclinical
laboratory studies the lack of adverse effect of the change on the
identity, strength, quality, purity, or potency of the product as they
may relate to the safety or effectiveness of the product.
(3) Notwithstanding the requirements of paragraphs (b), (c), and (f)
of this section, an applicant must make a change provided for in those
paragraphs in accordance with a regulation or guidance that provides for
a less burdensome notification of the change (for example, by submission
of a supplement that does not require approval prior to distribution of
the product or in an annual report).
(4) The applicant must promptly revise all promotional labeling and
advertising to make it consistent with any labeling change implemented
in accordance with paragraphs (f)(1) and (f)(2) of this section.
(5) A supplement or annual report must include a list of all changes
contained in the supplement or annual report. For supplements, this list
must be provided in the cover letter.
(b) Changes requiring supplement submission and approval prior to
distribution of the product made using the change (major changes). (1) A
supplement shall be submitted for any change in the product, production
process, quality controls, equipment, facilities, or responsible
personnel that has a substantial potential to have an adverse effect on
the identity, strength, quality, purity, or potency of the product as
they may relate to the safety or effectiveness of the product.
(2) These changes include, but are not limited to:
(i) Except as provided in paragraphs (c) and (d) of this section,
changes in the qualitative or quantitative formulation, including
inactive ingredients, or in the specifications provided in the approved
application;
(ii) Changes requiring completion of an appropriate human study to
demonstrate the equivalence of the identity, strength, quality, purity,
or potency of the product as they may relate to the safety or
effectiveness of the product;
(iii) Changes in the virus or adventitious agent removal or
inactivation method(s);
(iv) Changes in the source material or cell line;
(v) Establishment of a new master cell bank or seed; and
(vi) Changes which may affect product sterility assurance, such as
changes in product or component sterilization method(s), or an addition,
deletion, or substitution of steps in an aseptic processing operation.
(3) The applicant must obtain approval of the supplement from FDA
prior to distribution of the product
[[Page 30]]
made using the change. Except for submissions under paragraph (e) of
this section, the following shall be contained in the supplement:
(i) A detailed description of the proposed change;
(ii) The product(s) involved;
(iii) The manufacturing site(s) or area(s) affected;
(iv) A description of the methods used and studies performed to
evaluate the effect of the change on the identity, strength, quality,
purity, or potency of the product as they may relate to the safety or
effectiveness of the product;
(v) The data derived from such studies;
(vi) Relevant validation protocols and data; and
(vii) A reference list of relevant standard operating procedures
(SOP's).
(4) An applicant may ask FDA to expedite its review of a supplement
for public health reasons or if a delay in making the change described
in it would impose an extraordinary hardship on the applicant. Such a
supplement and its mailing cover should be plainly marked: ``Prior
Approval Supplement-Expedited Review Requested.
(c) Changes requiring supplement submission at least 30 days prior
to distribution of the product made using the change. (1) A supplement
shall be submitted for any change in the product, production process,
quality controls, equipment, facilities, or responsible personnel that
has a moderate potential to have an adverse effect on the identity,
strength, quality, purity, or potency of the product as they may relate
to the safety or effectiveness of the product. The supplement shall be
labeled ``Supplement--Changes Being Effected in 30 Days'' or, if
applicable under paragraph (c)(5) of this section, ``Supplement--Changes
Being Effected.''
(2) These changes include, but are not limited to:
(i) [Reserved]
(ii) An increase or decrease in production scale during finishing
steps that involves different equipment; and
(iii) Replacement of equipment with that of similar, but not
identical, design and operating principle that does not affect the
process methodology or process operating parameters.
(iv) Relaxation of an acceptance criterion or deletion of a test to
comply with an official compendium that is consistent with FDA statutory
and regulatory requirements.
(3) Pending approval of the supplement by FDA, and except as
provided in paragraph (c)(5) of this section, distribution of the
product made using the change may begin not less than 30 days after
receipt of the supplement by FDA. The information listed in paragraph
(b)(3)(i) through (b)(3)(vii) of this section shall be contained in the
supplement.
(4) If within 30 days following FDA's receipt of the supplement, FDA
informs the applicant that either:
(i) The change requires approval prior to distribution of the
product in accordance with paragraph (b) of this section; or
(ii) Any of the information required under paragraph (c)(3) of this
section is missing; the applicant shall not distribute the product made
using the change until FDA determines that compliance with this section
is achieved.
(5) In certain circumstances, FDA may determine that, based on
experience with a particular type of change, the supplement for such
change is usually complete and provides the proper information, and on
particular assurances that the proposed change has been appropriately
submitted, the product made using the change may be distributed
immediately upon receipt of the supplement by FDA. These circumstances
may include substantial similarity with a type of change regularly
involving a ``Supplement--Changes Being Effected'' supplement or a
situation in which the applicant presents evidence that the proposed
change has been validated in accordance with an approved protocol for
such change under paragraph (e) of this section.
(6) If the agency disapproves the supplemental application, it may
order the manufacturer to cease distribution of the products made with
the manufacturing change.
(d) Changes to be described in an annual report (minor changes). (1)
Changes
[[Page 31]]
in the product, production process, quality controls, equipment,
facilities, or responsible personnel that have a minimal potential to
have an adverse effect on the identity, strength, quality, purity, or
potency of the product as they may relate to the safety or effectiveness
of the product shall be documented by the applicant in an annual report
submitted each year within 60 days of the anniversary date of approval
of the application. The Director, Center for Biologics Evaluation and
Research or the Director, Center for Drug Evaluation and Research, may
approve a written request for an alternative date to combine annual
reports for multiple approved applications into a single annual report
submission.
(2) These changes include, but are not limited to:
(i) Any change made to comply with a change to an official
compendium, except a change described in paragraph (c)(2)(iv) of this
section, that is consistent with FDA statutory and regulatory
requirements.
(ii) The deletion or reduction of an ingredient intended only to
affect the color of the product, except that a change intended only to
affect Blood Grouping Reagents requires supplement submission and
approval prior to distribution of the product made using the change in
accordance with the requirements set forth in paragraph (b) of this
section;
(iii) An extension of an expiration dating period based upon full
shelf life data on production batches obtained from a protocol approved
in the application;
(iv) A change within the container closure system for a nonsterile
product, based upon a showing of equivalency to the approved system
under a protocol approved in the application or published in an official
compendium;
(v) A change in the size and/or shape of a container containing the
same number of dosage units for a nonsterile solid dosage form product,
without a change from one container closure system to another;
(vi) The addition by embossing, debossing, or engraving of a code
imprint to a solid dosage form biological product other than a modified
release dosage form, or a minor change in an existing code imprint; and
(vii) The addition or revision of an alternative analytical
procedure that provides the same or increased assurance of the identity,
strength, quality, purity, or potency of the material being tested as
the analytical procedure described in the approved application, or
deletion of an alternative analytical procedure.
(3) The following information for each change shall be contained in
the annual report:
(i) A list of all products involved; and
(ii) A full description of the manufacturing and controls changes
including: the manufacturing site(s) or area(s) involved; the date the
change was made; a cross-reference to relevant validation protocols and/
or SOP's; and relevant data from studies and tests performed to evaluate
the effect of the change on the identity, strength, quality, purity, or
potency of the product as they may relate to the safety or effectiveness
of the product.
(iii) A statement by the holder of the approved application or
license that the effects of the change have been assessed.
(4) The applicant shall submit the report to the FDA office
responsible for reviewing the application. The report 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.
[[Page 32]]
(f) Labeling changes. (1) Labeling changes requiring supplement
submission--FDA approval must be obtained before distribution of the
product with the labeling change. Except as described in paragraphs
(f)(2) and (f)(3) of this section, an applicant shall submit a
supplement describing a proposed change in the package insert, package
label, container label, or, if applicable, a Medication Guide required
under part 208 of this chapter, and include the information necessary to
support the proposed change. An applicant cannot use paragraph (f)(2) of
this section to make any change to the information required in Sec.
201.57(a) of this chapter. An applicant may report the minor changes to
the information specified in paragraph (f)(3)(i)(D) of this section in
an annual report. The supplement shall clearly highlight the proposed
change in the labeling. The applicant shall obtain approval from FDA
prior to distribution of the product with the labeling change.
(2) Labeling changes requiring supplement submission--product with a
labeling change that may be distributed before FDA approval. (i) An
applicant shall submit, at the time such change is made, a supplement
for any change in the package insert, package label, or container label
to reflect newly acquired information, except for changes to the package
insert required in Sec. 201.57(a) of this chapter (which must be made
under paragraph (f)(1) of this section), to accomplish any of the
following:
(A) To add or strengthen a contraindication, warning, precaution, or
adverse reaction for which the evidence of a causal association
satisfies the standard for inclusion in the labeling under Sec.
201.57(c) of this chapter;
(B) To add or strengthen a statement about abuse, dependence,
psychological effect, or overdosage;
(C) To add or strengthen an instruction about dosage and
administration that is intended to increase the safety of the use of the
product; and
(D) To delete false, misleading, or unsupported indications for use
or claims for effectiveness.
(E) Any labeling change normally requiring a supplement submission
and approval prior to distribution of the product that FDA specifically
requests be submitted under this provision.
(ii) Pending approval of the supplement by FDA, the applicant may
distribute a product with a package insert, package label, or container
label bearing such change at the time the supplement is submitted. The
supplement shall clearly identify the change being made and include
necessary supporting data. The supplement and its mailing cover shall be
plainly marked: ``Special Labeling Supplement--Changes Being Effected.''
(3) Labeling changes requiring submission in an annual report. (i)
An applicant shall submit any final printed package insert, package
label, container label, or Medication Guide required under part 208 of
this chapter incorporating the following changes in an annual report
submitted to FDA each year as provided in paragraph (d)(1) of this
section:
(A) Editorial or similar minor changes;
(B) A change in the information on how the product is supplied that
does not involve a change in the dosage strength or dosage form;
(C) A change in the information specified in Sec. 208.20(b)(8)(iii)
and (b)(8)(iv) of this chapter for a Medication Guide; and
(D) A change to the information required in Sec. 201.57(a) of this
chapter as follows:
(1) Removal of a listed section(s) specified in Sec. 201.57(a)(5)
of this chapter; and
(2) Changes to the most recent revision date of the labeling as
specified in Sec. 201.57(a)(15) of this chapter.
(E) A change made pursuant to an exception or alternative granted
under Sec. 201.26 or Sec. 610.68 of this chapter.
(ii) The applicant may distribute a product with a package insert,
package label, or container label bearing such change at the time the
change is made.
(4) Advertisements and promotional labeling. Advertisements and
promotional labeling shall be submitted to the Center for Biologics
Evaluation and Research or Center for Drug Evaluation and Research in
accordance with the requirements set forth in Sec. 314.81(b)(3)(i) of
this chapter.
[[Page 33]]
(5) The submission and grant of a written request for an exception
or alternative under Sec. 201.26 or Sec. 610.68 of this chapter
satisfies the requirements in paragraphs (f)(1) through (f)(2) of this
section.
(6) For purposes of paragraph (f)(2) of this section, information
will be considered newly acquired if it consists of data, analyses, or
other information not previously submitted to the agency, which may
include (but are not limited to) data derived from new clinical studies,
reports of adverse events, or new analyses of previously submitted data
(e.g., meta-analyses) if the studies, events or analyses reveal risks of
a different type or greater severity or frequency than previously
included in submissions to FDA.
(g) Failure to comply. In addition to other remedies available in
law and regulations, in the event of repeated failure of the applicant
to comply with this section, FDA may require that the applicant submit a
supplement for any proposed change and obtain approval of the supplement
by FDA prior to distribution of the product made using the change.
(h) Administrative review. Under Sec. 10.75 of this chapter, an
applicant may request internal FDA review of FDA employee decisions
under this section.
[62 FR 39901, July 24, 1997, as amended at 63 FR 66399, Dec. 1, 1998.
Redesignated at 65 FR 59718, Oct. 6, 2000, and amended at 69 FR 18766,
Apr. 8, 2004; 70 FR 14983, Mar. 24, 2005; 71 FR 3997, Jan. 24, 2006; 72
FR 73600, Dec. 28, 2007; 73 FR 49609, Aug. 22, 2008; 73 FR 68333, Nov.
18, 2008; 80 FR 18092, Apr. 3, 2015]
Sec. 601.14 Regulatory submissions in electronic format.
(a) General. Electronic format submissions must be in a form that
FDA can process, review, and archive. FDA will periodically issue
guidance on how to provide the electronic submission (e.g., method of
transmission, media, file formats, preparation and organization of
files.)
(b) Labeling. The content of labeling required under Sec.
201.100(d)(3) of this chapter (commonly referred to as the package
insert or professional labeling), including all text, tables, and
figures, must be submitted to the agency in electronic format as
described in paragraph (a) of this section. This requirement is in
addition to the provisions of Sec. Sec. 601.2(a) and 601.12(f) that
require applicants to submit specimens of the labels, enclosures, and
containers, or to submit other final printed labeling. Submissions under
this paragraph must be made in accordance with part 11 of this chapter
except for the requirements of Sec. 11.10(a), (c) through (h), and (k),
and the corresponding requirements of Sec. 11.30.
[68 FR 69020, Dec. 11, 2003]
Sec. 601.15 Foreign establishments and products: samples for each
importation.
Random samples of each importation, obtained by the District
Director of Customs and forwarded to the Director, Center for Biologics
Evaluation and Research or the Director, Center for Drug Evaluation and
Research (see mailing addresses in Sec. 600.2(c) of this chapter) must
be at least two final containers of each lot of product. A copy of the
associated documents which describe and identify the shipment must
accompany the shipment for forwarding with the samples to the Director,
Center for Biologics Evaluation and Research or the Director, Center for
Drug Evaluation and Research (see mailing addresses in Sec. 600.2(c)).
For shipments of 20 or less final containers, samples need not be
forwarded, provided a copy of an official release from the Center for
Biologics Evaluation and Research or Center for Drug Evaluation and
Research accompanies each shipment.
[70 FR 14983, Mar. 24, 2005, as amended at 80 FR 18092, Apr. 3, 2015]
Sec. 601.20 Biologics licenses; issuance and conditions.
(a) Examination--compliance with requirements. A biologics license
application shall be approved only upon examination of the product and
upon a determination that the product complies with the standards
established in the biologics license application and the requirements
prescribed in the regulations in this chapter including but not limited
to the good manufacturing practice requirements set forth in parts 210,
211, 600, 606, and 820 of this chapter.
[[Page 34]]
(b) Availability of product. No biologics license shall be issued
unless:
(1) The product intended for introduction into interstate commerce
is available for examination, and
(2) Such product is available for inspection during all phases of
manufacture.
(c) Manufacturing process--impairment of assurances. No product
shall be licensed if any part of the process of or relating to the
manufacture of such product, in the judgment of the Director, Center for
Biologics Evaluation and Research or the Director, Center for Drug
Evaluation and Research, would impair the assurances of continued
safety, purity, and potency as provided by the regulations contained in
this chapter.
(d) Inspection--compliance with requirements. A biologics license
shall be issued or a biologics license application approved only after
inspection of the establishment(s) listed in the biologics license
application and upon a determination that the establishment(s) complies
with the standards established in the biologics license application and
the requirements prescribed in applicable regulations.
(e) One biologics license to cover all locations. One biologics
license shall be issued to cover all locations meeting the establishment
standards identified in the approved biologics license application and
each location shall be subject to inspection by FDA officials.
[64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005]
Sec. 601.21 Products under development.
A biological product undergoing development, but not yet ready for a
biologics license, may be shipped or otherwise delivered from one State
or possession into another State or possession provided such shipment or
delivery is not for introduction or delivery for introduction into
interstate commerce, except as provided in sections 505(i) and 520(g) of
the Federal Food, Drug, and Cosmetic Act, as amended, and the
regulations thereunder (21 CFR parts 312 and 812).
[64 FR 56451, Oct. 20, 1999]
Sec. 601.22 Products in short supply; initial manufacturing at other
than licensed location.
A biologics license issued to a manufacturer and covering all
locations of manufacture shall authorize persons other than such
manufacturer to conduct at places other than such locations the initial,
and partial manufacturing of a product for shipment solely to such
manufacturer only to the extent that the names of such persons and
places are registered with the Commissioner of Food and Drugs and it is
found upon application of such manufacturer, that the product is in
short supply due either to the peculiar growth requirements of the
organism involved or to the scarcity of the animal required for
manufacturing purposes, and such manufacturer has established with
respect to such persons and places such procedures, inspections, tests
or other arrangements as will ensure full compliance with the applicable
regulations of this subchapter related to continued safety, purity, and
potency. Such persons and places shall be subject to all regulations of
this subchapter except Sec. Sec. 601.2 to 601.6, 601.9, 601.10, 601.20,
601.21 to 601.33, and 610.60 to 610.65 of this chapter. For persons and
places authorized under this section to conduct the initial and partial
manufacturing of a product for shipment solely to a manufacturer of a
product subject to licensure under Sec. 601.2(c), the following
additional regulations shall not be applicable: Sec. Sec. 600.10(b) and
(c), 600.11, 600.12, 600.13, and 610.53 of this chapter. Failure of such
manufacturer to maintain such procedures, inspections, tests, or other
arrangements, or failure of any person conducting such partial
manufacturing to comply with applicable regulations shall constitute a
ground for suspension or revocation of the authority conferred pursuant
to this section on the same basis as provided in Sec. Sec. 601.6 to
601.8 with respect to the suspension and the revocation of licenses.
[42 FR 4718, Jan. 25, 1977, as amended at 61 FR 24233, May 14, 1996; 64
FR 56452, Oct. 20, 1999; 80 FR 37974, July 2, 2015]
Sec. 601.27 Pediatric studies.
(a) Required assessment. Except as provided in paragraphs (b), (c),
and (d) of
[[Page 35]]
this section, each application for a new active ingredient, new
indication, new dosage form, new dosing regimen, or new route of
administration shall contain data that are adequate to assess the safety
and effectiveness of the product for the claimed indications in all
relevant pediatric subpopulations, and to support dosing and
administration for each pediatric subpopulation for which the product is
safe and effective. Where the course of the disease and the effects of
the product are similar in adults and pediatric patients, FDA may
conclude that pediatric effectiveness can be extrapolated from adequate
and well-controlled effectiveness studies in adults, usually
supplemented with other information in pediatric patients, such as
pharmacokinetic studies. In addition, studies may not be needed in each
pediatric age group, if data from one age group can be extrapolated to
another. Assessments required under this section for a product that
represents a meaningful therapeutic benefit over existing treatments
must be carried out using appropriate formulations for the age group(s)
for which the assessment is required.
(b) Deferred submission. (1) FDA may, on its own initiative or at
the request of an applicant, defer submission of some or all assessments
of safety and effectiveness described in paragraph (a) of this section
until after licensing of the product for use in adults. Deferral may be
granted if, among other reasons, the product is ready for approval in
adults before studies in pediatric patients are complete, pediatric
studies should be delayed until additional safety or effectiveness data
have been collected. If an applicant requests deferred submission, the
request must provide an adequate justification for delaying pediatric
studies, a description of the planned or ongoing studies, and evidence
that the studies are being or will be conducted with due diligence and
at the earliest possible time.
(2) If FDA determines that there is an adequate justification for
temporarily delaying the submission of assessments of pediatric safety
and effectiveness, the product may be licensed for use in adults subject
to the requirement that the applicant submit the required assessments
within a specified time.
(c) Waivers--(1) General. FDA may grant a full or partial waiver of
the requirements of paragraph (a) of this section on its own initiative
or at the request of an applicant. A request for a waiver must provide
an adequate justification.
(2) Full waiver. An applicant may request a waiver of the
requirements of paragraph (a) of this section if the applicant certifies
that:
(i) The product does not represent a meaningful therapeutic benefit
over existing therapies for pediatric patients and is not likely to be
used in a substantial number of pediatric patients;
(ii) Necessary studies are impossible or highly impractical because,
e.g., the number of such patients is so small or geographically
dispersed; or
(iii) There is evidence strongly suggesting that the product would
be ineffective or unsafe in all pediatric age groups.
(3) Partial waiver. An applicant may request a waiver of the
requirements of 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
[[Page 36]]
cover only those pediatric age groups requiring that formulation. If a
waiver is granted because there is evidence that the product would be
ineffective or unsafe in pediatric populations, this information will be
included in the product's labeling.
(5) Definition of ``meaningful therapeutic benefit''. For purposes
of this section, a product will be considered to offer a meaningful
therapeutic benefit over existing therapies if FDA estimates that:
(i) If approved, the product would represent a significant
improvement in the treatment, diagnosis, or prevention of a disease,
compared to marketed products adequately labeled for that use in the
relevant pediatric population. Examples of how improvement might be
demonstrated include, e.g., evidence of increased effectiveness in
treatment, prevention, or diagnosis of disease; elimination or
substantial reduction of a treatment-limiting drug reaction; documented
enhancement of compliance; or evidence of safety and effectiveness in a
new subpopulation; or
(ii) The product is in a class of products or for an indication for
which there is a need for additional therapeutic options.
(d) Exemption for orphan drugs. This section does not apply to any
product for an indication or indications for which orphan designation
has been granted under part 316, subpart C, of this chapter.
[63 FR 66671, Dec. 2, 1998]
Sec. 601.28 Annual reports of postmarketing pediatric studies.
Sponsors of licensed biological products shall submit the following
information each year within 60 days of the anniversary date of approval
of each product under the license to the Director, Center for Biologics
Evaluation and Research or the Director, Center for Drug Evaluation and
Research (see mailing addresses in Sec. 600.2(a) or (b) of this
chapter):
(a) Summary. A brief summary stating whether labeling supplements
for pediatric use have been submitted and whether new studies in the
pediatric population to support appropriate labeling for the pediatric
population have been initiated. Where possible, an estimate of patient
exposure to the drug product, with special reference to the pediatric
population (neonates, infants, children, and adolescents) shall be
provided, including dosage form.
(b) Clinical data. Analysis of available safety and efficacy data in
the pediatric population and changes proposed in the labeling based on
this information. An assessment of data needed to ensure appropriate
labeling for the pediatric population shall be included.
(c) Status reports. A statement on the current status of any
postmarketing studies in the pediatric population performed by, or on
behalf of, the applicant. The statement shall include whether
postmarketing clinical studies in pediatric populations were required or
agreed to, and, if so, the status of these studies shall be reported to
FDA in annual progress reports of postmarketing studies under Sec.
601.70 rather than under this section.
[65 FR 59718, Oct. 6, 2000, as amended at 65 FR 64618, Oct. 30, 2000; 70
FR 14984, Mar. 24, 2005; 80 FR 18092, Apr. 3, 2015]
Sec. 601.29 Guidance documents.
(a) FDA has made available guidance documents under Sec. 10.115 of
this chapter to help you comply with certain requirements of this part.
(b) The Center for Biologics Evaluation and Research (CBER)
maintains a list of guidance documents that apply to the center's
regulations. The lists are maintained on the Internet and are published
annually in the Federal Register. You may request a copy of the CBER
list from the Food and Drug Administration, Center for Biologics
Evaluation and Research, Office of Communication, Outreach and
Development, 10903 New Hampshire Ave., Bldg. 71, Rm. 3103, Silver
Spring, MD 20993-0002.
[65 FR 56480, Sept. 19, 2000, as amended at 70 FR 14984, Mar. 24, 2005;
80 FR 18092, Apr. 3, 2015]
Subpart D_Diagnostic Radiopharmaceuticals
Source: 64 FR 26668, May 17, 1999, unless otherwise noted.
[[Page 37]]
Sec. 601.30 Scope.
This subpart applies to radiopharmaceuticals intended for in vivo
administration for diagnostic and monitoring use. It does not apply to
radiopharmaceuticals intended for therapeutic purposes. In situations
where a particular radiopharmaceutical is proposed for both diagnostic
and therapeutic uses, the radiopharmaceutical must be evaluated taking
into account each intended use.
Sec. 601.31 Definition.
For purposes of this part,diagnostic radiopharmaceutical means:
(a) An article that is intended for use in the diagnosis or
monitoring of a disease or a manifestation of a disease in humans and
that exhibits spontaneous disintegration of unstable nuclei with the
emission of nuclear particles or photons; or
(b) Any nonradioactive reagent kit or nuclide generator that is
intended to be used in the preparation of such article as defined in
paragraph (a) of this section.
Sec. 601.32 General factors relevant to safety and effectiveness.
FDA's determination of the safety and effectiveness of a diagnostic
radiopharmaceutical includes consideration of the following:
(a) The proposed use of the diagnostic radiopharmaceutical in the
practice of medicine;
(b) The pharmacological and toxicological activity of the diagnostic
radiopharmaceutical (including any carrier or ligand component of the
diagnostic radiopharmaceutical); and
(c) The estimated absorbed radiation dose of the diagnostic
radiopharmaceutical.
Sec. 601.33 Indications.
(a) For diagnostic radiopharmaceuticals, the categories of proposed
indications for use include, but are not limited to, the following:
(1) Structure delineation;
(2) Functional, physiological, or biochemical assessment;
(3) Disease or pathology detection or assessment; and
(4) Diagnostic or therapeutic patient management.
(b) Where a diagnostic radiopharmaceutical is not intended to
provide disease-specific information, the proposed indications for use
may refer to a biochemical, physiological, anatomical, or pathological
process or to more than one disease or condition.
Sec. 601.34 Evaluation of effectiveness.
(a) The effectiveness of a diagnostic radiopharmaceutical is
assessed by evaluating its ability to provide useful clinical
information related to its proposed indications for use. The method of
this evaluation varies depending upon the proposed indication(s) and may
use one or more of the following criteria:
(1) The claim of structure delineation is established by
demonstrating in a defined clinical setting the ability to locate
anatomical structures and to characterize their anatomy.
(2) The claim of functional, physiological, or biochemical
assessment is established by demonstrating in a defined clinical setting
reliable measurement of function(s) or physiological, biochemical, or
molecular process(es).
(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.
[[Page 38]]
Sec. 601.35 Evaluation of safety.
(a) Factors considered in the safety assessment of a diagnostic
radiopharmaceutical include, among others, the following:
(1) The radiation dose;
(2) The pharmacology and toxicology of the radiopharmaceutical,
including any radionuclide, carrier, or ligand;
(3) The risks of an incorrect diagnostic determination;
(4) The adverse reaction profile of the drug;
(5) Results of human experience with the radiopharmaceutical for
other uses; and
(6) Results of any previous human experience with the carrier or
ligand of the radiopharmaceutical when the same chemical entity as the
carrier or ligand has been used in a previously studied product.
(b) The assessment of the adverse reaction profile includes, but is
not limited to, an evaluation of the potential of the diagnostic
radiopharmaceutical, including the carrier or ligand, to elicit the
following:
(1) Allergic or hypersensitivity responses,
(2) Immunologic responses,
(3) Changes in the physiologic or biochemical function of the target
and nontarget tissues, and
(4) Clinically detectable signs or symptoms.
(c)(1) To establish the safety of a diagnostic radiopharmaceutical,
FDA may require, among other information, the following types of data:
(A) Pharmacology data,
(B) Toxicology data,
(C) Clinical adverse event data, and
(D) Radiation safety assessment.
(2) The amount of new safety data required will depend on the
characteristics of the product and available information regarding the
safety of the diagnostic radiopharmaceutical, and its carrier or ligand,
obtained from other studies and uses. Such information may include, but
is not limited to, the dose, route of administration, frequency of use,
half-life of the ligand or carrier, half-life of the radionuclide, and
results of clinical and preclinical studies. FDA will establish
categories of diagnostic radiopharmaceuticals based on defined
characteristics relevant to risk and will specify the amount and type of
safety data that are appropriate for each category (e.g., required
safety data may be limited for diagnostic radiopharmaceuticals with a
well established, low-risk profile). Upon reviewing the relevant product
characteristics and safety information, FDA will place each diagnostic
radiopharmaceutical into the appropriate safety risk category.
(d) Radiation safety assessment. The radiation safety assessment
must establish the radiation dose of a diagnostic radiopharmaceutical by
radiation dosimetry evaluations in humans and appropriate animal models.
The maximum tolerated dose need not be established.
Subpart E_Accelerated Approval of Biological Products for Serious or
Life-Threatening Illnesses
Source: 57 FR 58959, Dec. 11, 1992, unless otherwise noted.
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
[[Page 39]]
further, to verify and describe its clinical benefit, where there is
uncertainty as to the relation of the surrogate endpoint to clinical
benefit, or of the observed clinical benefit to ultimate outcome.
Postmarketing studies would usually be studies already underway. When
required to be conducted, such studies must also be adequate and well-
controlled. The applicant shall carry out any such studies with due
diligence.
Sec. 601.42 Approval with restrictions to assure safe use.
(a) If FDA concludes that a biological product shown to be effective
can be safely used only if distribution or use is restricted, FDA will
require such postmarketing restrictions as are needed to assure safe use
of the biological product, such as:
(1) Distribution restricted to certain facilities or physicians with
special training or experience; or
(2) Distribution conditioned on the performance of specified medical
procedures.
(b) The limitations imposed will be commensurate with the specific
safety concerns presented by the biological product.
Sec. 601.43 Withdrawal procedures.
(a) For biological products approved under Sec. 601.41 or Sec.
601.42, FDA may withdraw approval, following a hearing as provided in
part 15 of this chapter, as modified by this section, if:
(1) A postmarketing clinical study fails to verify clinical benefit;
(2) The applicant fails to perform the required postmarketing study
with due diligence;
(3) Use after marketing demonstrates that postmarketing restrictions
are inadequate to ensure safe use of the biological product;
(4) The applicant fails to adhere to the postmarketing restrictions
agreed upon;
(5) The promotional materials are false or misleading; or
(6) Other evidence demonstrates that the biological product is not
shown to be safe or effective under its conditions of use.
(b) Notice of opportunity for a hearing. The Director of the Center
for Biologics Evaluation and Research or the Director of the Center for
Drug Evaluation and Research will give the applicant notice of an
opportunity for a hearing on the Center's proposal to withdraw the
approval of an application approved under Sec. 601.41 or Sec. 601.42.
The notice, which will ordinarily be a letter, will state generally the
reasons for the action and the proposed grounds for the order.
(c) Submission of data and information. (1) If the applicant fails
to file a written request for a hearing within 15 days of receipt of the
notice, the applicant waives the opportunity for a hearing.
(2) If the applicant files a timely request for a hearing, the
agency will publish a notice of hearing in the Federal Register in
accordance with Sec. Sec. 12.32(e) and 15.20 of this chapter.
(3) An applicant who requests a hearing under this section must,
within 30 days of receipt of the notice of opportunity for a hearing,
submit the data and information upon which the applicant intends to rely
at the hearing.
(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
[[Page 40]]
agency action from which the applicant may petition for judicial review.
Before requesting an order from a court for a stay of action pending
review, an applicant must first submit a petition for a stay of action
under Sec. 10.35 of this chapter.
[57 FR 58959, Dec. 11, 1992, as amended at 68 FR 34797, June 11, 2003;
70 FR 14984, Mar. 24, 2005]
Sec. 601.44 Postmarketing safety reporting.
Biological products approved under this program are subject to the
postmarketing recordkeeping and safety reporting applicable to all
approved biological products.
Sec. 601.45 Promotional materials.
For biological products being considered for approval under this
subpart, unless otherwise informed by the agency, applicants must submit
to the agency for consideration during the preapproval review period
copies of all promotional materials, including promotional labeling as
well as advertisements, intended for dissemination or publication within
120 days following marketing approval. After 120 days following
marketing approval, unless otherwise informed by the agency, the
applicant must submit promotional materials at least 30 days prior to
the intended time of initial dissemination of the labeling or initial
publication of the advertisement.
Sec. 601.46 Termination of requirements.
If FDA determines after approval that the requirements established
in Sec. 601.42, Sec. 601.43, or Sec. 601.45 are no longer necessary
for the safe and effective use of a biological product, it will so
notify the applicant. Ordinarily, for biological products approved under
Sec. 601.41, these requirements will no longer apply when FDA
determines that the required postmarketing study verifies and describes
the biological product's clinical benefit and the biological product
would be appropriate for approval under traditional procedures. For
biological products approved under Sec. 601.42, the restrictions would
no longer apply when FDA determines that safe use of the biological
product can be assured through appropriate labeling. FDA also retains
the discretion to remove specific postapproval requirements upon review
of a petition submitted by the sponsor in accordance with Sec. 10.30.
Subpart F_Confidentiality of Information
Sec. 601.50 Confidentiality of data and information in an investigational
new drug notice for a biological product.
(a) The existence of an IND notice for a biological product will not
be disclosed by the Food and Drug Administration unless it has
previously been publicly disclosed or acknowledged.
(b) The availability for public disclosure of all data and
information in an IND file for a biological product shall be handled in
accordance with the provisions established in Sec. 601.51.
(c) Notwithstanding the provisions of Sec. 601.51, the Food and
Drug Administration shall disclose upon request to an individual on whom
an investigational biological product has been used a copy of any
adverse reaction report relating to such use.
[39 FR 44656, Dec. 24, 1974]
Sec. 601.51 Confidentiality of data and information in applications
for biologics licenses.
(a) For purposes of this section the biological product file
includes all data and information submitted with or incorporated by
reference in any application for a biologics license, IND's incorporated
into any such application, master files, and other related submissions.
The availability for public disclosure of any record in the biological
product file shall be handled in accordance with the provisions of this
section.
(b) The existence of a biological product file will not be disclosed
by the Food and Drug Administration before a biologics license
application has been approved unless it has previously been publicly
disclosed or acknowledged. The Food and Drug Administration will
maintain a list available for public disclosure of biological products
for which a license application has been approved.
[[Page 41]]
(c) If the existence of a biological product file has not been
publicly disclosed or acknowledged, no data or information in the
biological product file is available for public disclosure.
(d)(1) If the existence of a biological product file has been
publicly disclosed or acknowledged before a license has been issued, no
data or information contained in the file is available for public
disclosure before such license is issued, but the Commissioner may, in
his discretion, disclose a summary of such selected portions of the
safety and effectiveness data as are appropriate for public
consideration of a specific pending issue, e.g., at an open session of a
Food and Drug Administration advisory committee or pursuant to an
exchange of important regulatory information with a foreign government.
(2) Notwithstanding paragraph (d)(1) of this section, FDA will make
available to the public upon request the information in the IND that was
required to be filed in Docket Number 95S-0158 in the Dockets Management
Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm.
1061, Rockville, MD 20852, for investigations involving an exception
from informed consent under Sec. 50.24 of this chapter. Persons wishing
to request this information shall submit a request under the Freedom of
Information Act.
(e) After a license has been issued, the following data and
information in the biological product file are immediately available for
public disclosure unless extraordinary circumstances are shown:
(1) All safety and effectiveness data and information.
(2) A protocol for a test or study, unless it is shown to fall
within the exemption established for trade secrets and confidential
commercial or financial information in Sec. 20.61 of this chapter.
(3) Adverse reaction reports, product experience reports, consumer
complaints, and other similar data and information, after deletion of:
(i) Names and any information that would identify the person using
the product.
(ii) Names and any information that would identify any third party
involved with the report, such as a physician or hospital or other
institution.
(4) A list of all active ingredients and any inactive ingredients
previously disclosed to the public, as defined in Sec. 20.81 of this
chapter.
(5) An assay method or other analytical method, unless it serves no
regulatory or compliance purpose and it is shown to fall within the
exemption established in Sec. 20.61 of this chapter.
(6) All correspondence and written summaries of oral discussions
relating to the biological product file, in accordance with the
provisions of part 20 of this chapter.
(7) All records showing the manufacturer's testing of a particular
lot, after deletion of data or information that would show the volume of
the drug produced, manufacturing procedures and controls, yield from raw
materials, costs, or other material falling within Sec. 20.61 of this
chapter.
(8) All records showing the testing of and action on a particular
lot by the Food and Drug Administration.
(f) The following data and information in a biological product file
are not available for public disclosure unless 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
[[Page 42]]
studies and tests on the drug for identity, stability, purity, potency,
and bioavailability.
[39 FR 44656, Dec. 24, 1974, as amended at 42 FR 15676, Mar. 22, 1977;
49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 61 FR 51530, Oct.
2, 1996; 64 FR 56452, Oct. 20, 1999; 68 FR 24879, May 9, 2003; 69 FR
13717, Mar. 24, 2004; 70 FR 14984, Mar. 24, 2005; 88 FR 45066, July 14,
2023]
Subpart G_Postmarketing Studies
Source: 65 FR 64618, Oct. 30, 2000, unless otherwise noted.
Sec. 601.70 Annual progress reports of postmarketing studies.
(a) General requirements. This section applies to all required
postmarketing studies (e.g., accelerated approval clinical benefit
studies, pediatric studies) and postmarketing studies that an applicant
has committed, in writing, to conduct either at the time of approval of
an application or a supplement to an application, or after approval of
an application or a supplement. Postmarketing studies within the meaning
of this section are those that concern:
(1) Clinical safety;
(2) Clinical efficacy;
(3) Clinical pharmacology; and
(4) Nonclinical toxicology.
(b) What to report. Each applicant of a licensed biological product
shall submit a report to FDA on the status of postmarketing studies for
each approved product application. The status of these postmarketing
studies shall be reported annually until FDA notifies the applicant, in
writing, that the agency concurs with the applicant's determination that
the study commitment has been fulfilled, or that the study is either no
longer feasible or would no longer provide useful information. Each
annual progress report shall be accompanied by a completed transmittal
Form FDA-2252, and shall include all the information required under this
section that the applicant received or otherwise obtained during the
annual reporting interval which ends on the U.S. anniversary date. The
report must provide the following information for each postmarketing
study:
(1) Applicant's name.
(2) Product name. Include the approved product's proper name and the
proprietary name, if any.
(3) Biologics license application (BLA) and supplement number.
(4) Date of U.S. approval of BLA.
(5) Date of postmarketing study commitment.
(6) Description of postmarketing study commitment. The description
must include sufficient information to uniquely describe the study. This
information may include the purpose of the study, the type of study, the
patient population addressed by the study and the indication(s) and
dosage(s) that are to be studied.
(7) Schedule for completion and reporting of the postmarketing study
commitment. The schedule should include the actual or projected dates
for submission of the study protocol to FDA, completion of patient
accrual or initiation of an animal study, completion of the study,
submission of the final study report to FDA, and any additional
milestones or submissions for which projected dates were specified as
part of the commitment. In addition, it should include a revised
schedule, as appropriate. If the schedule has been previously revised,
provide both the original schedule and the most recent, previously
submitted revision.
(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.
[[Page 43]]
(9) Explanation of the study's status. Provide a brief description
of the status of the study, including the patient accrual rate
(expressed by providing the number of patients or subjects enrolled to
date, and the total planned enrollment), and an explanation of the
study's status identified under paragraph (b)(8) of this section. If the
study has been completed, include the date the study was completed and
the date the final study report was submitted to FDA, as applicable.
Provide a revised schedule, as well as the reason(s) for the revision,
if the schedule under paragraph (b)(7) of this section has changed since
the previous report.
(c) When to report. Annual progress reports for postmarketing study
commitments entered into by applicants shall be reported to FDA within
60 days of the anniversary date of the U.S. approval of the application
for the product.
(d) Where to report. Submit two copies of the annual progress report
of postmarketing studies to the Center for Biologics Evaluation and
Research or Center for Drug Evaluation and Research (see mailing
addresses in Sec. 600.2(a) or (b) of this chapter).
(e) Public disclosure of information. Except for the information
described in this paragraph, FDA may publicly disclose any information
concerning a postmarketing study, within the meaning of this section, if
the agency determines that the information is necessary to identify an
applicant or to establish the status of the study including the reasons,
if any, for failure to conduct, complete, and report the study. Under
this section, FDA will not publicly disclose trade secrets, as defined
in Sec. 20.61 of this chapter, or information, described in Sec. 20.63
of this chapter, the disclosure of which would constitute an unwarranted
invasion of personal privacy.
[65 FR 64618, Oct. 30, 2000, as amended at 70 FR 14984, Mar. 24, 2005;
80 FR 18092, Apr. 3, 2015]
Subpart H_Approval of Biological Products When Human Efficacy Studies
Are Not Ethical or Feasible
Source: 67 FR 37996, May 31, 2002, unless otherwise noted.
Sec. 601.90 Scope.
This subpart applies to certain biological products that have been
studied for their safety and efficacy in ameliorating or preventing
serious or life-threatening conditions caused by exposure to lethal or
permanently disabling toxic biological, chemical, radiological, or
nuclear substances. This subpart applies only to those biological
products for which: Definitive human efficacy studies cannot be
conducted because it would be unethical to deliberately expose healthy
human volunteers to a lethal or permanently disabling toxic biological,
chemical, radiological, or nuclear substance; and field trials to study
the product's efficacy after an accidental or hostile exposure have not
been feasible. This subpart does not apply to products that can be
approved based on efficacy standards described elsewhere in FDA's
regulations (e.g., accelerated approval based on surrogate markers or
clinical endpoints other than survival or irreversible morbidity), nor
does it address the safety evaluation for the products to which it does
apply.
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:
[[Page 44]]
(1) There is a reasonably well-understood pathophysiological
mechanism of the toxicity of the substance and its prevention or
substantial reduction by the product;
(2) The effect is demonstrated in more than one animal species
expected to react with a response predictive for humans, unless the
effect is demonstrated in a single animal species that represents a
sufficiently well-characterized animal model for predicting the response
in humans;
(3) The animal study endpoint is clearly related to the desired
benefit in humans, generally the enhancement of survival or prevention
of major morbidity; and
(4) The data or information on the kinetics and pharmacodynamics of
the product or other relevant data or information, in animals and
humans, allows selection of an effective dose in humans.
(b) Approval under this subpart will be subject to three
requirements:
(1) Postmarketing studies. The applicant must conduct postmarketing
studies, such as field studies, to verify and describe the biological
product's clinical benefit and to assess its safety when used as
indicated when such studies are feasible and ethical. Such postmarketing
studies would not be feasible until an exigency arises. When such
studies are feasible, the applicant must conduct such studies with due
diligence. Applicants must include as part of their application a plan
or approach to postmarketing study commitments in the event such studies
become ethical and feasible.
(2) Approval with restrictions to ensure safe use. If FDA concludes
that a biological product shown to be effective under this subpart can
be safely used only if distribution or use is restricted, FDA will
require such postmarketing restrictions as are needed to ensure safe use
of the biological product, commensurate with the specific safety
concerns presented by the biological product, such as:
(i) Distribution restricted to certain facilities or health care
practitioners with special training or experience;
(ii) Distribution conditioned on the performance of specified
medical procedures, including medical followup; and
(iii) Distribution conditioned on specified recordkeeping
requirements.
(3) Information to be provided to patient recipients. For biological
products or specific indications approved under this subpart, applicants
must prepare, as part of their proposed labeling, labeling to be
provided to patient recipients. The patient labeling must explain that,
for ethical or feasibility reasons, the biological product's approval
was based on efficacy studies conducted in animals alone and must give
the biological product's indication(s), directions for use (dosage and
administration), contraindications, a description of any reasonably
foreseeable risks, adverse reactions, anticipated benefits, drug
interactions, and any other relevant information required by FDA at the
time of approval. The patient labeling must be available with the
product to be provided to patients prior to administration or dispensing
of the biological product for the use approved under this subpart, if
possible.
Sec. 601.92 Withdrawal procedures.
(a) Reasons to withdraw approval. For biological products approved
under this subpart, FDA may withdraw approval, following a hearing as
provided in part 15 of this chapter, as modified by this section, if:
(1) A postmarketing clinical study fails to verify clinical benefit;
(2) The applicant fails to perform the postmarketing study with due
diligence;
(3) Use after marketing demonstrates that postmarketing restrictions
are inadequate to ensure safe use of the biological product;
(4) The applicant fails to adhere to the postmarketing restrictions
applied at the time of approval under this subpart;
(5) The promotional materials are false or misleading; or
(6) Other evidence demonstrates that the biological product is not
shown to be safe or effective under its conditions of use.
(b) Notice of opportunity for a hearing. The Director of the Center
for Biologics Evaluation and Research or the Director of the Center for
Drug Evaluation and Research will give the applicant notice of an
opportunity for a
[[Page 45]]
hearing on the proposal to withdraw the approval of an application
approved under this subpart. The notice, which will ordinarily be a
letter, will state generally the reasons for the action and the proposed
grounds for the order.
(c) Submission of data and information. (1) If the applicant fails
to file a written request for a hearing within 15 days of receipt of the
notice, the applicant waives the opportunity for a hearing.
(2) If the applicant files a timely request for a hearing, the
agency will publish a notice of hearing in the Federal Register in
accordance with Sec. Sec. 12.32(e) and 15.20 of this chapter.
(3) An applicant who requests a hearing under this section must,
within 30 days of receipt of the notice of opportunity for a hearing,
submit the data and information upon which the applicant intends to rely
at the hearing.
(d) Separation of functions. Separation of functions (as specified
in Sec. 10.55 of this chapter) will not apply at any point in
withdrawal proceedings under this section.
(e) Procedures for hearings. Hearings held under this section will
be conducted in accordance with the provisions of part 15 of this
chapter, with the following modifications:
(1) An advisory committee duly constituted under part 14 of this
chapter will be present at the hearing. The committee will be asked to
review the issues involved and to provide advice and recommendations to
the Commissioner of Food and Drugs.
(2) The presiding officer, the advisory committee members, up to
three representatives of the applicant, and up to three representatives
of CBER may question any person during or at the conclusion of the
person's presentation. No other person attending the hearing may
question a person making a presentation. The presiding officer may, as a
matter of discretion, permit questions to be submitted to the presiding
officer for response by a person making a presentation.
(f) Judicial review. The Commissioner of Food and Drugs' decision
constitutes final agency action from which the applicant may petition
for judicial review. Before requesting an order from a court for a stay
of action pending review, an applicant must first submit a petition for
a stay of action under Sec. 10.35 of this chapter.
[67 FR 37996, May 31, 2002, as amended at 70 FR 14984, Mar. 24, 2005]
Sec. 601.93 Postmarketing safety reporting.
Biological products approved under this subpart are subject to the
postmarketing recordkeeping and safety reporting applicable to all
approved biological products.
Sec. 601.94 Promotional materials.
For biological products being considered for approval under this
subpart, unless otherwise informed by the agency, applicants must submit
to the agency for consideration during the preapproval review period
copies of all promotional materials, including promotional labeling as
well as advertisements, intended for dissemination or publication within
120 days following marketing approval. After 120 days following
marketing approval, unless otherwise informed by the agency, the
applicant must submit promotional materials at least 30 days prior to
the intended time of initial dissemination of the labeling or initial
publication of the advertisement.
Sec. 601.95 Termination of requirements.
If FDA determines after approval under this subpart that the
requirements established in Sec. Sec. 601.91(b)(2), 601.92, and 601.93
are no longer necessary for the safe and effective use of 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.
[[Page 46]]
PART 606_CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND
BLOOD COMPONENTS--Table of Contents
Subpart A_General Provisions
Sec.
606.3 Definitions.
Subpart B_Organization and Personnel
606.20 Personnel.
Subpart C_Plant and Facilities
606.40 Facilities.
Subpart D_Equipment
606.60 Equipment.
606.65 Supplies and reagents.
Subpart E [Reserved]
Subpart F_Production and Process Controls
606.100 Standard operating procedures.
606.110 Plateletpheresis, leukapheresis, and plasmapheresis.
Subpart G_Additional Labeling Standards for Blood and Blood Components
606.120 Labeling, general requirements.
606.121 Container label.
606.122 Circular of information.
Subpart H_Laboratory Controls
606.140 Laboratory controls.
606.145 Control of bacterial contamination of platelets.
606.151 Compatibility testing.
Subpart I_Records and Reports
606.160 Records.
606.165 Distribution and receipt; procedures and records.
606.170 Adverse reaction file.
606.171 Reporting of product deviations by licensed manufacturers,
unlicensed registered blood establishments, and transfusion
services.
Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360j, 371, 374;
42 U.S.C. 216, 262, 263a, 264.
Source: 40 FR 53532, Nov. 18, 1975, unless otherwise noted.
Subpart A_General Provisions
Sec. 606.3 Definitions.
As used in this part:
(a) Blood means a product that is a fluid containing dissolved and
suspended elements which was collected from the vascular system of a
human.
(b) Unit means the volume of blood or one of its components in a
suitable volume of anticoagulant obtained from a single collection of
blood from one donor.
(c) Blood component means a product containing a part of human blood
separated by physical or mechanical means.
(d) Plasma for further manufacturing means that liquid portion of
blood separated and used as material to prepare another product.
(e) Plasmapheresis means the procedure in which blood is removed
from the donor, the plasma is separated from the formed elements and at
least the red blood cells are returned to the donor.
(f) Plateletpheresis means the procedure in which blood is removed
from a donor, a platelet concentrate is separated, and the remaining
formed elements are returned to the donor along with a portion of the
residual plasma.
(g) Leukapheresis means the procedure in which blood is removed from
the donor, a leukocyte concentrate is separated, and the remaining
formed elements and residual plasma are returned to the donor.
(h) Facilities means any area used for the collection, processing,
compatibility testing, storage or distribution of blood and blood
components.
(i) Processing means any procedure employed after collection, and
before or after compatibility testing of blood, 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
[[Page 47]]
blood component for use in the manufacture of a licensed biological
product.
(l) Control means having responsibility for maintaining the
continued safety, purity, and potency of the product and for compliance
with applicable product and establishment standards, and for compliance
with current good manufacturing practices.
[40 FR 53532, Nov. 18, 1975, as amended at 64 FR 45370, Aug. 19, 1999;
65 FR 66635, Nov. 7, 2000; 66 FR 1835, Jan. 10, 2001; 66 FR 40889, Aug.
6, 2001; 72 FR 45886, Aug. 16, 2007; 80 FR 29894, May 22, 2015]
Subpart B_Organization and Personnel
Sec. 606.20 Personnel.
(a) [Reserved]
(b) The personnel responsible for the collection, processing,
compatibility testing, storage or distribution of blood or blood
components shall be adequate in number, educational background, training
and experience, including professional training as necessary, or
combination thereof, to assure competent performance of their assigned
functions, and to ensure that the final product has the safety, purity,
potency, identity and effectiveness it purports or is represented to
possess. All personnel shall have capabilities commensurate with their
assigned functions, a thorough understanding of the procedures or
control operations they perform, the necessary training or experience,
and adequate information concerning the application of pertinent
provisions of this part to their respective functions.
(c) Persons whose presence can adversely affect the safety and
purity of the products shall be excluded from areas where the
collection, processing, compatibility testing, storage or distribution
of blood or blood components is conducted.
[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55
FR 11014, Mar. 26, 1990; 62 FR 53538, Oct. 15, 1997]
Subpart C_Plant and Facilities
Sec. 606.40 Facilities.
Facilities shall be maintained in a clean and orderly manner, and
shall be of suitable size, construction and location to facilitate
adequate cleaning, maintenance and proper operations. The facilities
shall:
(a) Provide adequate space for the following when applicable:
(1) Private and accurate examinations of individuals to determine
their eligibility as blood donors.
(2) The withdrawal of blood from donors with minimal risk of
contamination, or exposure to activities and equipment unrelated to
blood collection.
(3) The storage of blood or blood components pending completion of
tests.
(4) The quarantine storage of blood or blood components in a
designated location pending repetition of those tests that initially
gave questionable serological results.
(5) The storage of finished products prior to distribution.
(6) The quarantine storage, handling and disposition of products and
reagents not suitable for use.
(7) The orderly collection, processing, compatibility testing,
storage and distribution of blood and blood components to prevent
contamination.
(8) The adequate and proper performance of all steps in
plasmapheresis, plateletpheresis and leukapheresis procedures.
(9) The orderly conduction of all packaging, labeling and other
finishing operations.
(b) Provide adequate lighting, ventilation and screening of open
windows and doors.
(c) Provide adequate, clean, and convenient handwashing facilities
for personnel, and adequate, clean, and convenient toilet facilities for
donors and personnel. Drains shall be of adequate size and, where
connected directly to a sewer, shall be equipped with traps to prevent
back-siphonage.
(d) Provide for safe and sanitary disposal for the following:
(1) Trash and items used during the collection, processing and
compatibility testing of blood and blood components.
(2) Blood and blood components not suitable for use or distribution.
[40 FR 53532, Nov. 18, 1975, as amended at 80 FR 29895, May 22, 2015]
[[Page 48]]
Subpart D_Equipment
Sec. 606.60 Equipment.
(a) Equipment used in the collection, processing, compatibility
testing, storage and distribution of blood and blood components shall be
maintained in a clean and orderly manner and located so as to facilitate
cleaning and maintenance. The equipment shall be observed, standardized
and calibrated on a regularly scheduled basis as prescribed in the
Standard Operating Procedures Manual and shall perform in the manner for
which it was designed so as to assure compliance with the official
requirements prescribed in this chapter for blood and blood products.
(b) Equipment that shall be observed, standardized and calibrated
with at least the following frequency, include but are not limited to:
----------------------------------------------------------------------------------------------------------------
Equipment Performance check Frequency Frequency of calibration
----------------------------------------------------------------------------------------------------------------
Temperature recorder.............. Compare against Daily................ As necessary.
thermometer.
Refrigerated centrifuge........... Observe speed and Each day of use...... Do.
temperature.
Hematocrit centrifuge............. .......................... ..................... Standardize before
initial use, after
repairs or adjustments,
and annually. Timer
every 3 mo.
General lab centrifuge............ .......................... ..................... Tachometer every 6 mo.
Automated blood-typing machine.... Observe controls for Each day of use......
correct results.
Hemoglobinometer.................. Standardize against ......do.............
cyanmethemoglobin
standard.
Refractometer..................... Standardize against ......do.............
distilled water.
Blood container scale............. Standardize against ......do............. As necessary.
container of known weight.
Water bath........................ Observe temperature....... ......do............. Do.
Rh view box....................... ......do.................. ......do............. Do.
Autoclave......................... ......do.................. Each time of use..... Do.
Serologic rotators................ Observe controls for Each day of use...... Speed as necessary.
correct results.
Laboratory thermometers........... .......................... ..................... Before initial use.
Electronic thermometers........... .......................... ..................... Monthly.
Vacuum blood agitator............. Observe weight of the Each day of use...... Standardize with
first container of blood container of known mass
filled for correct or volume before initial
results. use, and after repairs
or adjustments.
----------------------------------------------------------------------------------------------------------------
(c) Equipment employed in the sterilization of materials used in
blood collection or for disposition of contaminated products shall be
designed, maintained and utilized to ensure the destruction of
contaminating microorganisms. The effectiveness of the sterilization
procedure shall be no less than that achieved by an attained temperature
of 121.5 [deg]C (251 [deg]F) maintained for 20 minutes by saturated
steam or by an attained temperature of 170 [deg]C (338 [deg]F)
maintained for 2 hours with dry heat.
[40 FR 53532, Nov. 18, 1975; 40 FR 55849, Dec. 2, 1975, as amended at 45
FR 9261, Feb. 12, 1980; 57 FR 11263, Apr. 2, 1992; 57 FR 12862, Apr. 13,
1992]
Sec. 606.65 Supplies and reagents.
All supplies and reagents used in the collection, processing,
compatibility testing, storage and distribution of blood and blood
components shall be stored in a safe, sanitary and orderly manner.
(a) All surfaces coming in contact with blood and blood components
intended for transfusion shall be sterile, pyrogen-free, and shall not
interact with the product in such a manner as to have an adverse effect
upon the safety, purity, potency or effectiveness of the product. All
final containers and closures for blood and blood components not
intended for transfusion shall be clean and free of surface solids and
other contaminants.
(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.
[[Page 49]]
(c) Representative samples of each lot of the following reagents or
solutions shall be tested on a regularly scheduled basis by methods
described in the Standard Operating Procedures Manual to determine their
capacity to perform as required:
------------------------------------------------------------------------
Reagent or solution Frequency of testing
------------------------------------------------------------------------
Anti-human globulin...................... Each day of use.
Blood grouping reagents.................. Do.
Lectins.................................. Do.
Antibody screening and reverse grouping Do.
cells.
Hepatitis test reagents.................. Each run.
Syphilis serology reagents............... Do.
Enzymes.................................. Each day of use.
------------------------------------------------------------------------
(d) Supplies and reagents that do not bear an expiration date shall
be stored in such a manner that the oldest is used first.
(e) Supplies and reagents shall be used in a manner consistent with
instructions provided by the manufacturer.
(f) Items that are required to be sterile and come into contact with
blood should be disposable whenever possible.
[40 FR 53532, Nov. 18, 1975, as amended at 59 FR 23636, May 6, 1994]
Subpart E [Reserved]
Subpart F_Production and Process Controls
Sec. 606.100 Standard operating procedures.
(a) In all instances, except clinical investigations, standard
operating procedures shall comply with published additional standards in
part 640 of this chapter for the products being processed; except that,
references in part 640 relating to licenses, licensed establishments and
submission of material or data to or approval by the Director, Center
for Biologics Evaluation and Research, are not applicable to
establishments not subject to licensure under section 351 of the Public
Health Service Act.
(b) Establishments must establish, maintain, and follow written
standard operating procedures for all steps in the collection,
processing, compatibility testing, storage, and distribution of blood
and blood components for allogeneic transfusion, autologous transfusion,
and further manufacturing purposes; for all steps in the investigation
of product deviations related to Sec. 606.171; and for all steps in
recordkeeping related to current good manufacturing practice and other
applicable requirements and standards. Such procedures must be available
to the personnel for use in the areas where the procedures are
performed. The written standard operating procedures must include, but
are not limited to, descriptions of the following, when applicable:
(1) Criteria used to determine donor eligibility, including
acceptable medical history criteria.
(2) Methods of performing donor qualifying tests and measurements,
including minimum and maximum values for a test or procedure when a
factor in determining acceptability.
(3) Solutions and methods used to prepare the site of phlebotomy to
give maximum assurance of a sterile container of blood.
(4) Method of accurately relating the product(s) to the donor.
(5) Blood collection procedure, including in-process precautions
taken to measure accurately the quantity of blood removed from the
donor.
(6) Methods of component preparation, including any time
restrictions for specific steps in processing.
(7) All tests and repeat tests performed on blood and blood
components during manufacturing.
(8) Pretransfusion testing, where applicable, including precautions
to be taken to identify accurately the recipient blood samples and
crossmatched donor units.
(9) Procedures for investigating adverse donor and recipient
reactions.
(10) Storage temperatures and methods of controlling storage
temperatures for all blood products and reagents as prescribed in
Sec. Sec. 600.15 and 610.53 of this chapter.
(11) Length of expiration dates, if any, assigned for all final
products as prescribed in Sec. 610.53 of this chapter.
(12) Criteria for determining whether returned blood is suitable for
reissue.
(13) Procedures used for relating a unit of blood or blood component
from the donor to its final disposition.
(14) Quality control procedures for supplies and reagents employed
in
[[Page 50]]
blood collection, processing and pretransfusion testing.
(15) Schedules and procedures for equipment maintenance and
calibration.
(16) Labeling procedures, including safeguards to avoid labeling
mixups.
(17) Procedures of plasmapheresis, plateletpheresis, and
leukapheresis, if performed, including precautions to be taken to ensure
reinfusion of a donor's own cells.
(18) Procedures for preparing recovered plasma, if performed,
including details of separation, pooling, labeling, storage, and
distribution.
(19) Procedures under Sec. Sec. 610.46 and 610.47 of this chapter:
(i) To identify previously donated blood and blood components from a
donor who later tests reactive for evidence of human immunodeficiency
virus (HIV) infection or hepatitis C virus (HCV) infection when tested
under Sec. 610.40 of this chapter, or when a blood establishment is
made aware of other reliable test results or information indicating
evidence of HIV or HCV infection;
(ii) To quarantine in-date blood and blood components previously
donated by such a donor that are intended for use in another person or
further manufacture into injectable products, except pooled components
intended solely for further manufacturing into products that are
manufactured using validated viral clearance procedures;
(iii) To notify consignees to quarantine in-date blood and blood
components previously donated by such a donor intended for use in
another person or for further manufacture into injectable products,
except pooled components intended solely for further manufacturing into
products that are manufactured using validated viral clearance
procedures;
(iv) To determine the suitability for release, destruction, or
relabeling of quarantined in-date blood and blood components;
(v) To notify consignees of the results of the HIV or HCV testing
performed on the donors of such blood and blood components;
(vi) To notify the transfusion recipient, the recipient's physician
of record, or the recipient's legal representative that the recipient
received blood or blood components at increased risk of transmitting HIV
or HCV, respectively.
(20) Procedures for donor deferral as prescribed in Sec. 610.41 of
this chapter.
(21) Procedures for donor notification and notification of the
referring physician of an autologous donor, including procedures for the
appropriate followup if the initial attempt at notification fails, as
prescribed in Sec. 630.40 of this chapter.
(22) Procedures to control the risks of bacterial contamination of
platelets, including all steps required under Sec. 606.145.
(c) All records pertinent to the lot or unit maintained pursuant to
these regulations shall be reviewed before the release or distribution
of a lot or unit of final product. The review or portions of the review
may be performed at appropriate periods during or after blood
collecting, processing, compatibility testing and storing. A thorough
investigation, including the conclusions and followup, of any
unexplained discrepancy or the failure of a lot or unit to meet any of
its specifications shall be made and recorded.
(d) In addition to the requirements of this subpart and in
conformity with this section, any facility may utilize current standard
operating procedures such as the manuals of the organizations, as long
as such specific procedures are consistent with, and at least as
stringent as, the requirements contained in this part.
(1) American Association of Blood Banks.
(2) American National Red Cross.
(3) Other organizations or individual blood banks, subject to
approval by the Director, Center for Biologics Evaluation and Research.
[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55
FR 11013, Mar. 26, 1990; 61 FR 47422, Sept. 9, 1996; 64 FR 45370, Aug.
19, 1999; 66 FR 31176, June 11, 2001; 72 FR 48798, Aug. 24, 2007; 80 FR
80651, Dec. 28, 2015; 80 FR 29895, May 22, 2015]
Sec. 606.110 Plateletpheresis, leukapheresis, and plasmapheresis.
(a) The use of plateletpheresis and leukapheresis procedures to
obtain a product for a specific recipient may be
[[Page 51]]
at variance with the additional standards for specific products
prescribed in this part provided that: (1) A physician has determined
that the recipient must be transfused with the leukocytes or platelets
from a specific donor, and (2) the procedure is performed under the
supervision of a responsible physician who is aware of the health status
of the donor, and the physician has determined and documented that the
donor's health permits plateletpheresis or leukapheresis.
(b) Plasmapheresis of donors who do not meet the donor requirements
of Sec. Sec. 630.10, 630.15, 640.64 and 640.65 of this chapter for the
collection of plasma containing rare antibodies shall be permitted only
with the prior approval of the Director, Center for Biologics Evaluation
and Research.
[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55
FR 11013, Mar. 26, 1990; 80 FR 29895, May 22, 2015]
Subpart G_Additional Labeling Standards for Blood and Blood Components
Sec. 606.120 Labeling, general requirements.
(a) Labeling operations shall be separated physically or spatially
from other operations in a manner adequate to prevent mixups.
(b) The labeling operation shall include the following labeling
controls:
(1) Labels shall be held upon receipt, pending review and proofing
against an approved final copy, to ensure accuracy regarding identity,
content, and conformity with the approved copy.
(2) Each type of label representing different products shall be
stored and maintained in a manner to prevent mixups, and stocks of
obsolete labels shall be destroyed.
(3) All necessary checks in labeling procedures shall be utilized to
prevent errors in translating test results to container labels.
(c) All labeling shall be clear and legible.
[50 FR 35469, Aug. 30, 1985]
Sec. 606.121 Container label.
(a) The container label requirements are designed to facilitate the
use of a uniform container label for blood and blood components intended
for use in transfusion or further manufacture by all blood
establishments.
(b) The label provided by the collecting facility and the initial
processing facility must not be removed, altered, or obscured, except
that the label may be altered to indicate the proper name of the
product, with any appropriate modifiers and attributes, and other
information required to identify accurately the contents of a container
after blood components considered finished products have been prepared.
(c) The container label must include the following information, as
well as other specialized information as required in this section for
specific products:
(1) The proper name of the product in a prominent position, with any
appropriate modifiers and attributes.
(2) The name, address, unique facility identifier, and, if a
licensed product, the license number of each manufacturer; except the
container label for blood and blood components for further manufacture
is not required to include a unique facility identifier.
(3) The donor or lot number relating the unit to the donor. If
pooled, all donor numbers, all donation numbers, or a pool number that
is traceable to each individual unit comprising the pool.
(4)(i) The expiration date, including the day, month, and year, and,
if the dating period for the product is 72 hours or less, including any
product prepared in a system that might compromise sterility, the hour
of expiration.
(ii) If Source Plasma intended for manufacturing into noninjectable
products is pooled, the expiration date for the pool is determined from
the collection date of the oldest unit in the pool, and the pooling
records must show the collection date for each unit in the pool.
(5) For Whole Blood, Plasma, Platelets, and partial units of Red
Blood Cells, the volume of the product, accurate to within 10 percent; or optionally for Platelets, the volume or
volume range within reasonable limits.
[[Page 52]]
(6) Where applicable, the name and volume of source material.
(7) The recommended storage temperature (in degrees Celsius).
(8) If the product is intended for transfusion, the statements:
(i) ``Rx only.''
(ii) ``See circular of information for indications,
contraindications, cautions, and methods of infusion.''
(iii) ``Properly identify intended recipient.''
(iv) ``This product may transmit infectious agents.''
(v) The appropriate donor classification statement, i.e., ``paid
donor'' or ``volunteer donor,'' in no less prominence than the proper
name of the product.
(A) A paid donor is a person who receives monetary payment for a
blood donation.
(B) A volunteer donor is a person who does not receive monetary
payment for a blood donation.
(C) Benefits, such as time off from work, membership in blood
assurance programs, and cancellation of nonreplacement fees that are not
readily convertible to cash, do not constitute monetary payment within
the meaning of this paragraph.
(9) If the product is intended for transfusion or as is otherwise
appropriate, the ABO group and Rh type of the donor must be designated
conspicuously. For Cryoprecipitated Antihemophiliac Factor (AHF), the Rh
type may be omitted. The Rh type must be designated as follows:
(i) If the test using Anti-D Blood Grouping Reagent is positive, the
product must be labeled: ``Rh positive.''
(ii) If the test using Anti-D Blood Grouping Reagent is negative,
but the test for weak D (formerly Du) is positive, the
product must be labeled: ``Rh positive.''
(iii) If the test using Anti-D Blood Grouping Reagent is negative
and the test for weak D (formerly Du) is negative, the
product must be labeled: ``Rh negative.''
(10) If the product is not intended for transfusion, a statement as
applicable: ``Caution: For Manufacturing Use Only,'' or ``Caution: For
Use in Manufacturing Noninjectable Products Only,'' or other cautionary
statement as approved by the Director, Center for Biologics Evaluation
and Research (CBER).
(11) If the product is intended for further manufacturing use, a
statement listing the results of all the tests for relevant transfusion-
transmitted infections required under Sec. 610.40 of this chapter for
which the donation has been tested and found negative; except that the
container label for Source Plasma is not required to list the negative
results of serological syphilis testing under Sec. 640.65(b) of this
chapter.
(12) The blood and blood components must be labeled in accordance
with Sec. 610.40 of this chapter, when the donation is tested and
demonstrates evidence of infection due to a relevant transfusion-
transmitted infection(s).
(13) The container label of blood or blood components intended for
transfusion must bear encoded information in a format that is machine-
readable and approved for use by the Director, CBER.
(i) Who is subject to this machine-readable requirement? All blood
establishments that manufacture, process, repack, or relabel blood or
blood components intended for transfusion and regulated under the
Federal Food, Drug, and Cosmetic Act or the Public Health Service Act.
(ii) What blood products are subject to this machine-readable
requirement? All blood and blood components intended for transfusion are
subject to the machine-readable information label requirement in this
section.
(iii) What information must be machine-readable? Each label must
have machine-readable information that contains, at a minimum:
(A) A unique facility identifier;
(B) Lot number relating to the donor;
(C) Product code; and
(D) ABO and Rh of the donor, except as described in paragraphs
(c)(9) and (i)(5) of this section.
(iv) How must the machine-readable information appear? The machine-
readable information must:
(A) Be unique to the blood or blood component;
(B) Be surrounded by sufficient blank space so that the machine-
readable information can be scanned correctly; and
[[Page 53]]
(C) Remain intact under normal conditions of use.
(v) Where does the machine-readable information go? The machine-
readable information must appear on the label of any blood or blood
component which is or can be transfused to a patient or from which the
blood or blood component can be taken and transfused to a patient.
(d) Unless otherwise approved by the Director, CBER, the container
label for blood and blood components intended for transfusion must be
white and print must be solid black, with the following additional
exceptions:
(1) The ABO and Rh blood groups must be printed as follows:
(i) Rh positive: Use black print on white background and use solid
black or other solid color for ABO.
(ii) Rh negative: Use white print on black background for Rh and use
black outline on a white background for ABO.
(2) The proper name of the product, with any appropriate modifiers
and attributes, the donor classification statement, and the statement
``properly identify intended recipient'' may be printed in solid red or
in solid black.
(3) The following color scheme may be used for differentiating ABO
Blood groups:
------------------------------------------------------------------------
Blood group Color of label
------------------------------------------------------------------------
O........................................... Blue
A........................................... Yellow
B........................................... Pink
AB.......................................... White
------------------------------------------------------------------------
(4) Special labels, such as those described in paragraphs (h) and
(i) of this section, may be color-coded.
(e) Container label requirements for particular products or groups
of products.
(1) Whole Blood labels must include:
(i) The name of the applicable anticoagulant approved for use by the
Director, CBER.
(ii) The volume of anticoagulant.
(iii) If tests for unexpected antibodies are positive, blood
intended for transfusion must be labeled: ``Contains (name of
antibody).''
(2) Except for frozen, deglycerolized, or washed Red Blood Cell
products, Red Blood Cell labels must include:
(i) The type of anticoagulant, and if applicable, the volume of
Whole Blood and type of additive solution, with which the product was
prepared.
(ii) If tests for unexpected antibodies are positive and the product
is intended for transfusion, the statement: ``Contains (name of
antibody).''
(3) If tests for unexpected antibodies are positive, Plasma intended
for transfusion must be labeled: ``Contains (name of antibody).''
(4) Recovered plasma labels must include:
(i) In lieu of an expiration date, the date of collection of the
oldest material in the container.
(ii) For recovered plasma not meeting the requirements for
manufacture into licensable products, the statement: ``Not for Use in
Products Subject to License Under Section 351 of the Public Health
Service Act.''
(iii) The type of anticoagulant with which the product was prepared.
(5) Source Plasma labels must include the following information:
(i) The cautionary statement, as specified in paragraph (c)(10) of
this section, must follow the proper name with any appropriate modifiers
and attributes and be of similar prominence as the proper name.
(ii) The statement ``Store at -20 [deg]C or colder,'' provided, that
where plasma is intended for manufacturing into noninjectable products,
this statement may be replaced by a statement of the temperature
appropriate for manufacture of the final product to be prepared from the
plasma.
(iii) The total volume or weight of plasma and total quantity and
type of anticoagulant used.
(iv) When plasma collected from a donor is reactive for a serologic
test for syphilis, a statement that the plasma is reactive and must be
used only for the manufacturing of positive control reagents for the
serologic test for syphilis.
(v) Source Plasma diverted for Source Plasma Salvaged must be
relabeled ``Source Plasma Salvaged'' as prescribed in Sec. 640.76 of
this chapter. Immediately following the proper
[[Page 54]]
name of the product, with any appropriate modifiers and attributes, the
labeling must prominently state as applicable, ``STORAGE TEMPERATURE
EXCEEDED -20 [deg]C'' or ``SHIPPING TEMPERATURE EXCEEDED -5 [deg]C.''
(vi) A statement as to whether the plasma was collected from normal
donors, or from donors in specific collection programs approved by the
Director, CBER. In the case of specific collection programs, the label
must state the defining characteristics of the plasma. In the case of
immunized donors, the label must state the immunizing antigen.
(f) Blood and blood components determined to be unsuitable for
transfusion must be prominently labeled ``NOT FOR TRANSFUSION,'' and the
label must state the reason the unit is considered unsuitable. The
provision does not apply to blood and blood components intended solely
for further manufacture.
(g) [Reserved]
(h) The following additional information must appear on the label
for blood and blood components shipped in an emergency prior to
completion of required tests, in accordance with Sec. 610.40(g) of this
chapter:
(1) The statement: ``FOR EMERGENCY USE ONLY BY __ .''
(2) Results of any tests prescribed under Sec. Sec. 610.40 and
640.5(b) or (c) of this chapter completed before shipment.
(3) Indication of any tests prescribed under Sec. Sec. 610.40 and
640.5(b) or (c) of this chapter not completed before shipment.
(i) The following additional information must appear on the label
for blood and blood components intended for autologous transfusion:
(1) Information adequately identifying the patient, e.g., name, date
of birth, hospital, and identification number.
(2) Date of donation.
(3) The statement: ``AUTOLOGOUS DONOR.''
(4) The ABO and Rh blood group and type, except as provided in
paragraph (c)(9) of this section.
(5) Each container of blood and blood component intended for
autologous use and obtained from a donor who fails to meet any of the
donor eligibility requirements under Sec. 630.10 of this chapter or who
is reactive to or positive for one or more tests for evidence of
infection due to relevant transfusion-transmitted infections under Sec.
610.40 of this chapter must be prominently and permanently labeled ``FOR
AUTOLOGOUS USE ONLY'' and as otherwise required under Sec. 610.40 of
this chapter. Such units also may have the ABO and Rh blood group and
type on the label.
(6) Units of blood and blood components originally intended for
autologous use, except those labeled as prescribed under paragraph
(i)(5) of this section, may be issued for allogeneic transfusion
provided the container label complies with all applicable provisions of
paragraphs (b) through (e) of this section. In such case, the special
label required under paragraphs (i)(1), (i)(2), and (i)(3) of this
section must be removed or otherwise obscured.
(j) A tie-tag attached to the container may be used for providing
the information required by paragraphs (e)(1)(iii), (e)(2)(ii), and
(e)(3), (h), or (i)(1), (i)(2), and (i)(3) of this section.
[77 FR 16, Jan. 3, 2012, as amended at 80 FR 29895, May 22, 2015]
Sec. 606.122 Circular of information.
A circular of information must be available for distribution if the
product is intended for transfusion. The circular of information must
provide adequate directions for use, including the following
information:
(a) Instructions to mix the product before use.
(b) Instructions to use a filter in the administration equipment.
(c) The statement ``Do Not Add Medications'' or an explanation
concerning allowable additives.
(d) A description of the product, its source, and preparation,
including the name and proportion of the anticoagulant used in
collecting the Whole Blood from each product is prepared.
(e) A statement that the product was prepared from blood that was
found negative when tested for relevant transfusion-transmitted
infections, as required under Sec. 610.40 of this chapter (include each
test that was performed).
(f) The statement: ``Warning: The risk of transmitting infectious
agents is present. Careful donor selection and
[[Page 55]]
available laboratory tests do not eliminate the hazard.''
(g) The names of cryoprotective agents and other additives that may
still be present in the product.
(h) The names and results of all tests performed when necessary for
safe and effective use.
(i) The use of the product, indications, contradications, side
effects and hazards, dosage and administration recommendations.
(j) [Reserved]
(k) For Red Blood Cells, the circular of information must contain:
(1) Instructions to administer a suitable plasma volume expander if
Red Blood Cells are substituted when Whole Blood is the indicated
product.
(2) A warning not to add Lactated Ringer's Injection U.S.P. solution
to Red Blood Cell products.
(l) For Platelets, the circular of information must contain:
(1) The approximate volume of plasma from which a sample unit of
Platelets is prepared.
(2) Instructions to begin administration as soon as possible, but
not more than 4 hours after entering the container.
(m) For Plasma, the circular of information must contain:
(1) A warning against further processing of the frozen product if
there is evidence of breakage or thawing.
(2) Instructions to thaw the frozen product at a temperature
appropriate for the product.
(3) When applicable, instructions to begin administration of the
product within a specified time after thawing.
(4) Instructions to administer to ABO-group-compatible recipients.
(5) A statement that this product has the same risk of transmitting
infectious agents as Whole Blood; other plasma volume expanders without
this risk are available for treating hypovolemia.
(n) For Cryoprecipitated AHF, the circular of information must
contain:
(1) A statement that the average potency is 80 or more International
Units of antihemophilic factor.
(2) The statement: ``Usually contains at least 150 milligrams of
fibrinogen''; or, alternatively, the average fibrinogen level determined
by assay of representative units.
(3) A warning against further processing of the product if there is
evidence of breakage or thawing.
(4) Instructions to thaw the product for no more than 15 minutes at
a temperature of between 30 and 37 [deg]C.
(5) Instructions to store at room temperature after thawing and to
begin administration as soon as possible but no more than 4 hours after
entering the container or after pooling and within 6 hours after
thawing.
(6) A statement that 0.9 percent Sodium Chloride Injection U.S.P. is
the preferred diluent.
(7) Adequate instructions for pooling to ensure complete removal of
all concentrated material from each container.
(8) The statement: ``Good patient management requires monitoring
treatment responses to Cryoprecipitated AHF transfusions with periodic
plasma factor VIII or fibrinogen assays in hemophilia A and
hypofibrinogenemic recipients, respectively.''
[50 FR 35470, Aug. 30, 1985, as amended at 53 FR 116, Jan. 5, 1988; 64
FR 45371, Aug. 19, 1999; 77 FR 18, Jan. 3, 2012; 80 FR 29895, May 22,
2015]
Subpart H_Laboratory Controls
Sec. 606.140 Laboratory controls.
Laboratory control procedures shall include:
(a) The establishment of scientifically sound and appropriate
specifications, standards and test procedures to assure that blood and
blood components are safe, pure, potent and effective.
(b) Adequate provisions for monitoring the reliability, accuracy,
precision and performance of laboratory test procedures and instruments.
(c) Adequate identification and handling of all test samples so that
they are accurately related to the specific unit of product being
tested, or to its donor, or to the specific recipient, where applicable.
[[Page 56]]
Sec. 606.145 Control of bacterial contamination of platelets.
(a) Blood collection establishments and transfusion services must
assure that the risk of bacterial contamination of platelets is
adequately controlled using FDA approved or cleared devices or other
adequate and appropriate methods found acceptable for this purpose by
FDA.
(b) In the event that a blood collection establishment identifies
platelets as bacterially contaminated, that establishment must not
release for transfusion the product or any other component prepared from
the same collection, and must take appropriate steps to identify the
organism.
(c) In the event that a transfusion service identifies platelets as
bacterially contaminated, the transfusion service must not release the
product and must notify the blood collection establishment that provided
the platelets. The transfusion service must take appropriate steps to
identify the organism; these steps may include contracting with the
collection establishment or a laboratory to identify the organism. The
transfusion service must further notify the blood collection
establishment either by providing information about the species of the
contaminating organism when the transfusion service has been able to
identify it, or by advising the blood collection establishment when the
transfusion service has determined that the species cannot be
identified.
(d) In the event that a contaminating organism is identified under
paragraph (b) or (c) of this section, the collection establishment's
responsible physician, as defined in Sec. 630.3(i) of this chapter,
must determine whether the contaminating organism is likely to be
associated with a bacterial infection that is endogenous to the
bloodstream of the donor, in accordance with a standard operating
procedure developed under Sec. 606.100(b)(22). This determination may
not be further delegated.
[80 FR 29895, May 22, 2015]
Sec. 606.151 Compatibility testing.
Standard operating procedures for compatibility testing shall
include the following:
(a) A method of collecting and identifying the blood samples of
recipients to ensure positive identification.
(b) The use of fresh recipient serum or plasma samples less than 3
days old for all pretransfusion testing if the recipient has been
pregnant or transfused within the previous 3 months.
(c) Procedures to demonstrate incompatibility between the donor's
cell type and the recipient's serum or plasma type.
(d) A provision that, if the unit of donor's blood has not been
screened by a method that will demonstrate agglutinating, coating and
hemolytic antibodies, the recipient's cells shall be tested with the
donor's serum (minor crossmatch) by a method that will so demonstrate.
(e) Procedures to expedite transfusion in life-threatening
emergencies. Records of all such incidents shall be maintained,
including complete documentation justifying the emergency action, which
shall be signed by a physician.
[40 FR 53532, Nov. 18, 1975, as amended at 64 FR 45371, Aug. 19, 1999;
66 FR 1835, Jan. 10, 2001; 66 FR 40889, Aug. 6, 2001]
Subpart I_Records and Reports
Sec. 606.160 Records.
(a)(1) Records shall be maintained concurrently with the performance
of each significant step in the collection, processing, compatibility
testing, storage and distribution of each unit of blood and blood
components so that all steps can be clearly traced. All records shall be
legible and indelible, and shall identify the person performing the
work, include dates of the various entries, show test results as well as
the interpretation of the results, show the expiration date assigned to
specific products, and be as detailed as necessary to provide a complete
history of the work performed.
(2) Appropriate records shall be available from which to determine
lot numbers of supplies and reagents used for specific lots or units of
the final product.
(b) Records shall be maintained that include, but are not limited
to, the following when applicable:
(1) Donor records:
[[Page 57]]
(i) Donor selection, including medical interview and examination and
where applicable, informed consent.
(ii) Permanent and temporary deferrals for health reasons including
reason(s) for deferral.
(iii) Donor adverse reaction complaints and reports, including
results of all investigations and followup.
(iv) Therapeutic bleedings, including signed requests from attending
physicians, the donor's disease and disposition of units.
(v) Immunization, including informed consent, identification of the
antigen, dosage and route of administration.
(vi) Blood collection, including identification of the phlebotomist.
(vii) Records to relate the donor with the unit number of each
previous donation from that donor.
(viii) Records concerning the following activities performed under
Sec. Sec. 610.46 and 610.47 of this chapter: Quarantine; consignee
notification; testing; notification of a transfusion recipient, the
recipient's physician of record, or the recipient's legal
representative; and disposition.
(ix) The donor's postal address provided at the time of donation
where the donor may be contacted within 8 weeks after donation.
(x) Records of notification of donors deferred or determined not to
be eligible for donation, including appropriate followup if the initial
attempt at notification fails, performed under Sec. 630.40 of this
chapter.
(xi) Records of notification of the referring physician of a
deferred autologous donor, including appropriate followup if the initial
attempt at notification fails, performed under Sec. 630.40 of this
chapter.
(2) Processing records:
(i) Blood processing, including results and interpretation of all
tests and retests.
(ii) Component preparation, including all relevant dates and times.
(iii) Separation and pooling of recovered plasma.
(iv) Centrifugation and pooling of source plasma.
(v) Labeling, including initials of the person(s) performing the
procedure.
(3) Storage and distribution records:
(i) Distribution and disposition, as appropriate, of blood and blood
products.
(ii) Visual inspection of whole blood and red blood cells during
storage and immediately before distribution.
(iii) Storage temperature, including initialed temperature recorder
charts.
(iv) Reissue, including records of proper temperature maintenance.
(v) Emergency release of blood, including signature of requesting
physician obtained before or after release.
(4) Compatibility test records:
(i) Results of all compatibility tests, including crossmatching,
testing of patient samples, antibody screening and identification.
(ii) Results of confirmatory testing.
(5) Quality control records:
(i) Calibration and standardization of equipment.
(ii) Performance checks of equipment and reagents.
(iii) Periodic check on sterile technique.
(iv) Periodic tests of capacity of shipping containers to maintain
proper temperature in transit.
(v) Proficiency test results.
(6) Transfusion reaction reports and complaints, including records
of investigations and followup.
(7) General records:
(i) Sterilization of supplies and reagents prepared within the
facility, including date, time interval, temperature and mode.
(ii) Responsible personnel.
(iii) Biological product deviations.
(iv) Maintenance records for equipment and general physical plant.
(v) Supplies and reagents, including name of manufacturer or
supplier, lot numbers, expiration date and date of receipt.
(vi) Disposition of rejected supplies and reagents used in the
collection, processing and compatibility testing of blood and blood
components.
(c) A donor number shall be assigned to each accepted donor, which
relates the unit of blood collected to that donor, to his medical
record, to any component or blood product from that donor's unit of
blood, and to all records describing the history and ultimate
disposition of these products.
[[Page 58]]
(d) Records shall be retained for such interval beyond the
expiration date for the blood or blood component as necessary to
facilitate the reporting of any unfavorable clinical reactions. You must
retain individual product records no less than 10 years after the
records of processing are completed or 6 months after the latest
expiration date for the individual product, whichever is the later date.
When there is no expiration date, records shall be retained
indefinitely.
(e) Records of deferred donors. (1) Establishments must maintain at
each location a record of all donors found to be ineligible or deferred
at that location so that blood and blood components from an ineligible
donor are not collected and/or released while the donor is ineligible or
deferred; and
(2) Establishments must maintain at all locations operating under
the same license or under common management a cumulative record of
donors deferred from donation under Sec. 610.41 of this chapter because
their donation tested reactive under Sec. 610.40(a)(1) of this chapter
for evidence of infection due to HIV, HBV, or HCV. In addition,
establishments other than Source Plasma establishments must include in
this cumulative record donors deferred from donation under Sec. 610.41
of this chapter because their donation tested reactive under Sec.
610.40(a)(2) of this chapter for evidence of infection due to HTLV or
Chagas disease.
(3) The cumulative record described in paragraph (e)(2) of this
section must be updated at least monthly to add donors newly deferred
under Sec. 610.41 of this chapter due to reactive tests for evidence of
infection due to HIV, HBV, or HCV, and, if applicable, HTLV or Chagas
disease.
(4) Establishments must revise the cumulative record described in
paragraph (e)(2) of this section to remove donors who have been
requalified under Sec. 610.41(b) of this chapter.
[40 FR 53532, Nov. 18, 1975, as amended at 61 FR 47422, Sept. 9, 1996;
64 FR 45371, Aug. 19, 1999; 65 FR 66635, Nov. 7, 2000; 66 FR 31176, June
11, 2001; 72 FR 48798, Aug. 24, 2007; 80 FR 80651, Dec. 28, 2015; 80 FR
29895, May 22, 2015]
Sec. 606.165 Distribution and receipt; procedures and records.
(a) Distribution and receipt procedures shall include a system by
which the distribution or receipt of each unit can be readily determined
to facilitate its recall, if necessary.
(b) Distribution records shall contain information to readily
facilitate the identification of the name and address of the consignee,
the date and quantity delivered, the lot number of the unit(s), the date
of expiration or the date of collection, whichever is applicable, or for
crossmatched blood and blood components, the name of the recipient.
(c) Receipt records shall contain the name and address of the
collecting facility, date received, donor or lot number assigned by the
collecting facility and the date of expiration or the date of
collection, whichever is applicable.
Sec. 606.170 Adverse reaction file.
(a) Records shall be maintained of any reports of complaints of
adverse reactions regarding each unit of blood or blood product arising
as a result of blood collection or transfusion. A thorough investigation
of each reported adverse reaction shall be made. A written report of the
investigation of adverse reactions, including conclusions and followup,
shall be prepared and maintained as part of the record for that lot or
unit of final product by the collecting or transfusing facility. When it
is determined that the product was at fault in causing a transfusion
reaction, copies of all such written reports shall be forwarded to and
maintained by the manufacturer or collecting facility.
(b) When a complication of blood collection or transfusion is
confirmed to be fatal, the Director, Office of Compliance and Biologics
Quality, CBER, must be notified by telephone, facsimile, express mail,
or electronically transmitted mail as soon as possible. A written report
of the investigation must be submitted to the Director, Office of
Compliance and Biologics Quality, CBER, by mail, facsimile, or
electronically transmitted mail (for mailing address, see Sec. 600.2(a)
of this chapter), within 7 days after the fatality by the collecting
facility in the event of a donor reaction, or by the facility that
[[Page 59]]
performed the compatibility tests in the event of a transfusion
reaction.
[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 50
FR 35471, Aug. 30, 1985; 55 FR 11014, Mar. 26, 1990; 64 FR 45371, Aug.
19, 1999; 67 FR 9586, Mar. 4, 2002; 77 FR 18, Jan. 3, 2012; 80 FR 18092,
Apr. 3, 2015]
Sec. 606.171 Reporting of product deviations by licensed manufacturers,
unlicensed registered blood establishments, and transfusion services.
(a) Who must report under this section? You, a licensed manufacturer
of blood and blood components, including Source Plasma; an unlicensed
registered blood establishment; or a transfusion service who had control
over the product when the deviation occurred, must report under this
section. If you arrange for another person to perform a manufacturing,
holding, or distribution step, while the product is in your control,
that step is performed under your control. You must establish, maintain,
and follow a procedure for receiving information from that person on all
deviations, complaints, and adverse events concerning the affected
product.
(b) What do I report under this section? You must report any event,
and information relevant to the event, associated with the
manufacturing, to include testing, processing, packing, labeling, or
storage, or with the holding or distribution, of both licensed and
unlicensed blood or blood components, including Source Plasma, if that
event meets all the following criteria:
(1) Either:
(i) Represents a deviation from current good manufacturing practice,
applicable regulations, applicable standards, or established
specifications that may affect the safety, purity, or potency of that
product; or
(ii) Represents an unexpected or unforeseeable event that may affect
the safety, purity, or potency of that product; and
(2) Occurs in your facility or another facility under contract with
you; and
(3) Involves distributed blood or blood components.
(c) When do I report under this section? You should report a
biological product deviation as soon as possible but you must report at
a date not to exceed 45-calendar days from the date you, your agent, or
another person who performs a manufacturing, holding, or distribution
step under your control, acquire information reasonably suggesting that
a reportable event has occurred.
(d) How do I report under this section? You must report on Form FDA-
3486.
(e) Where do I report under this section? You must send the
completed Form FDA 3486 to the Center for Biologics Evaluation and
Research (CBER), either in paper or electronic format.
(1) If you make a paper filing, send the completed form to the CBER
Document Control Center (see mailing address in Sec. 600.2(a) of this
chapter), and identify on the envelope that a BPDR (biological product
deviation report) is enclosed; or
(2) If you make an electronic filing, send the completed Form
FDA3486 electronically using CBER's electronic Web-based application.
(f) How does this regulation affect other FDA regulations? This part
supplements and does not supersede other provisions of the regulations
in this chapter. All biological product deviations, whether or not they
are required to be reported under this section, should be investigated
in accordance with the applicable provisions of parts 211, 606, and 820
of this chapter.
[65 FR 66635, Nov. 7, 2000, as amended at 70 FR 14984, Mar. 24, 2005; 80
FR 18092, Apr. 3, 2015]
PART 607_ESTABLISHMENT REGISTRATION AND PRODUCT LISTING FOR MANUFACTURERS
OF HUMAN BLOOD AND BLOOD PRODUCTS AND LICENSED DEVICES--Table of Contents
Subpart A_General Provisions
Sec.
607.1 Scope.
607.3 Definitions.
607.7 Establishment registration and product listing of blood banks and
other firms manufacturing human blood and blood products.
Subpart B_Procedures for Domestic Blood Product Establishments
607.20 Who must register and submit a blood product list.
[[Page 60]]
607.21 Times for establishment registration and blood product listing.
607.22 How to register establishments and list blood products.
607.25 Information required for establishment registration and blood
product listing.
607.26 Amendments to establishment registration.
607.30 Updating blood product listing information.
607.31 Additional blood product listing information.
607.35 Blood product establishment registration number.
607.37 Public disclosure of establishment registration and blood product
listing information.
607.39 Misbranding by reference to establishment registration,
validation of registration, or to registration number.
Subpart C_Procedures for Foreign Blood Product Establishments
607.40 Establishment registration and blood product listing requirements
for foreign blood product establishments.
Subpart D_Exemptions
607.65 Exemptions for blood product establishments.
Subpart E_Establishment Registration and Product Listing Of Licensed
Devices
607.80 Applicability of part 607 to licensed devices.
Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 371, 374, 381,
393; 42 U.S.C. 262, 264, 271.
Source: 40 FR 52788, Nov. 12, 1975, unless otherwise noted.
Subpart A_General Provisions
Sec. 607.1 Scope.
(a) This part establishes establishment registration and product
listing requirements for manufacturers of human blood and blood
products.
(b) This part establishes establishment registration and product
listing requirements for manufacturers of products that meet the
definition of a device under the Federal Food, Drug, and Cosmetic Act
and that are licensed under section 351 of the Public Health Service
Act, as well as licensed biological products used in the manufacture of
a licensed device.
[81 FR 60221, Aug. 31, 2016]
Sec. 607.3 Definitions.
(a) The term act means the Federal Food, Drug, and Cosmetic Act
approved June 25, 1938 (52 Stat. 1040 et seq., as amended, 21 U.S.C.
301-392).
(b) Blood and blood product means a drug which consists of human
whole blood, plasma, or serum or any product derived from human whole
blood, plasma, or serum, hereinafter referred to as ``blood product.''
For the purposes of this part only, blood and blood product also means
those products that meet the definition of a device under the Federal
Food, Drug, and Cosmetic Act and that are licensed under section 351 of
the Public Health Service Act, as well as licensed biological products
used in the manufacture of a licensed device.
(c) Establishment means a place of business under one management at
one general physical location. The term includes, among others, human
blood and plasma donor centers, blood banks, 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
[[Page 61]]
meaning except that the term shall not include distribution of any blood
or blood product that is neither imported nor offered for import into
the United States.
(f) Any material change includes but is not limited to any change in
the name of the blood product, in the quantity or identity of the active
ingredient(s) or in the quantity or identity of the inactive
ingredient(s) where quantitative listing of all ingredients is required
pursuant to Sec. 607.31(a)(2) and any significant change in the
labeling of a blood product. Changes that are not significant include
changes in arrangement or printing or changes of an editorial nature.
(g) Bulk product substance means any substance that is represented
for use in a blood product and when used in the manufacturing of a blood
product becomes an active ingredient or a finished dosage form of such
product.
(h) Advertising and labeling include the promotional material
described in Sec. 202.1(l) (1) and (2) of this chapter, respectively.
(i) The definitions and interpretations contained in sections 201
and 510 of the act shall be applicable to such terms when used in this
part 607.
(j) United States agent means a person residing or maintaining a
place of business in the United States whom a foreign establishment
designates as its agent. This definition excludes mailboxes, answering
machines or services, or other places where an individual acting as the
foreign establishment's agent is not physically present.
(k) Importer means a person in the United States that is an owner,
consignee, or recipient, at the time of entry, of a foreign
establishment's blood product that is imported into the United States.
(l) Foreign for the purpose of registration and listing under this
part when used to modify the term ``establishment'' refers to an
establishment that is located in a foreign country and is the site where
a blood product that is imported or offered for import into the United
States was manufactured.
[40 FR 52788, Nov. 12, 1975, as amended at 55 FR 11014, Mar. 26, 1990;
66 FR 59158, Nov. 27, 2001; 81 FR 60222, Aug. 31, 2016]
Sec. 607.7 Establishment registration and product listing of blood
banks and other firms manufacturing human blood and blood products.
All owners or operators of establishments that engage in the
manufacturing of blood products are required to register, pursuant to
section 510 of the Federal Food, Drug, and Cosmetic Act. Registration
and listing of blood products must comply with this part. Registration
does not permit any blood bank or similar establishment to ship blood
products in interstate commerce.
[81 FR 60222, Aug. 31, 2016]
Subpart B_Procedures for Domestic Blood Product Establishments
Sec. 607.20 Who must register and submit a blood product list.
(a) Owners or operators of all establishments, not exempt under
section 510(g) of the act or subpart D of this part, that engage in the
manufacture of blood products shall register and submit a list of every
blood product in commercial distribution (except that registration and
listing information may be submitted by the parent, subsidiary, and/or
affiliate company for all establishments when operations are conducted
at more than one establishment and there exists joint ownership and
control among all the establishments). Blood products manufactured,
prepared, propagated, compounded, or processed in any State as defined
in section 201(a)(1) of the act must be listed whether or not the output
of such blood product establishment or any particular blood product so
listed enters interstate commerce.
(b) Preparatory to engaging in the manufacture of blood products,
owners or operators of establishments who are submitting a biologics
license application to manufacture blood products are required to
register before the biologics license application is approved.
(c) Except in the case of licensed device manufacturers, no
registration fee is required. Establishment registration and blood
product listing do not constitute an admission or agreement or
determination that a blood product is a
[[Page 62]]
``drug'' within the meaning of section 201(g) of the act.
[40 FR 52788, Nov. 12, 1975, as amended at 64 FR 56452, Oct. 20, 1999;
66 FR 59158, Nov. 27, 2001; 81 FR 60222, Aug. 31, 2016]
Sec. 607.21 Times for establishment registration and blood product
listing.
The owner or operator of an establishment entering into an operation
defined in Sec. 607.3(d) shall register such establishment within 5
days after the beginning of such operation and submit a list of every
blood product in commercial distribution at the time. If the owner or
operator of the establishment has not previously entered into such
operation (defined in Sec. 607.3(d) of this chapter) for which a
license is required, registration shall follow within 5 days after the
submission of a biologics license application in order to manufacture
blood products. Owners or operators of all establishments so engaged
must register annually between October 1 and December 31 and must update
their blood product listing every June and December.
[40 FR 52788, Nov. 12, 1975, as amended at 64 FR 56453, Oct. 20, 1999;
81 FR 60222, Aug. 31, 2016]
Sec. 607.22 How to register establishments and list blood products.
(a) Initial and subsequent registrations and product listings must
be submitted electronically through the Blood Establishment Registration
and Product Listing system, or any future superseding electronic system.
This information must be submitted in accordance with part 11 of this
chapter, except for the requirements in Sec. 11.10(b), (c), and (e),
and the corresponding requirements in Sec. 11.30. All information
submitted under this part must be transmitted to FDA electronically
unless FDA has granted a request for waiver of this requirement prior to
the date on which the information is due. Submission of a request for
waiver does not excuse timely compliance with the registration and
listing requirements. FDA will grant a waiver request if FDA determines
that the use of electronic means for submission of registration and
listing information is not reasonable for the registrant making the
waiver request.
(b) Waiver requests under this section must be submitted in writing
and must include the specific reasons why electronic submission is not
reasonable for the registrant and a U.S. telephone number and mailing
address where FDA can contact the registrant. All waiver requests must
be sent to the Director of FDA's Center for Biologics Evaluation and
Research through the Document Control Center (see addresses in Sec.
600.2).
(c) If FDA grants the waiver request, FDA may limit its duration and
will specify terms of the waiver and provide information on how to
submit establishment registration, drug listings, other information, and
updates, as applicable.
[81 FR 60222, Aug. 31, 2016]
Sec. 607.25 Information required for establishment registration and
blood product listing.
(a) The Blood Establishment Registration and Product Listing system
requires furnishing or confirming registration information required by
the Federal Food, Drug, and Cosmetic Act. This information includes the
name and street address of the establishment, including post office
code; a registration number if previously assigned by FDA and a Unique
Facility Identifier in accordance with the system specified under
section 510 of the Federal Food, Drug, and Cosmetic Act; all trade names
used by the establishment; the kind of ownership or operation (that is,
individually owned partnership, or corporation); and the name of the
owner or operator of such establishment. The term ``name of the owner or
operator'' must include, in the case of a partnership, the name of each
partner and, in the case of a corporation, the name and title of each
corporate officer and director and the name of the State of
incorporation. The information required must be given separately for
each establishment, as defined in Sec. 607.3(c).
(b) The following information must also be provided:
(1) A list of blood products by established name as defined in
section 502(e) of the Federal Food, Drug, and Cosmetic Act and by
proprietary name, if any, which are being manufactured for
[[Page 63]]
commercial distribution at the identified establishment and which have
not been included in any list previously submitted to FDA through the
Blood Establishment Registration and Product Listing system or any
future superseding electronic system.
(2) For each blood product so listed that is subject to section 351
of the Public Health Service Act, the license number of the manufacturer
issued by the Center for Biologics Evaluation and Research, Food and
Drug Administration.
(3) For each blood product listed, the registration number if
previously assigned by FDA and the Unique Facility Identifier of the
parent establishment. An establishment not owned, operated, or
controlled by another firm or establishment is its own parent
establishment.
[81 FR 60222, Aug. 31, 2016]
Sec. 607.26 Amendments to establishment registration.
Changes in individual ownership, corporate or partnership structure,
location, or blood product handling activity must be submitted
electronically through the Blood Establishment Registration and Product
Listing system, or any future superseding electronic system, as an
amendment to registration within 5 calendar days of such changes.
Changes in the names of officers and directors of the corporations do
not require such amendment but must be shown at time of annual
registration.
[40 FR 52788, Nov. 12, 1975, as amended at 66 FR 59158, Nov. 27, 2001;
81 FR 60222, Aug. 31, 2016]
Sec. 607.30 Updating blood product listing information.
(a) After submission of the initial blood product listing
information, every person who is required to list blood products under
Sec. 607.20 must submit electronically through the Blood Establishment
Registration and Product Listing system, or any future superseding
electronic system, at a minimum once in June and December of every year,
the following information:
(1) A list of each blood product introduced by the registrant for
commercial distribution which has not been included in any list
previously submitted. All of the information required by Sec. 607.25(b)
shall be provided for each such blood product.
(2) A list of each blood product formerly listed pursuant to Sec.
607.25(b) for which commercial distribution has been discontinued,
including for each blood product so listed the identity by established
name and proprietary name, and date of discontinuance. It is requested
but not required that the reason for discontinuance of distribution be
included with this information.
(3) A list of each blood product for which a notice of
discontinuance was submitted pursuant to paragraph (a)(2) of this
section and for which commercial distribution has been resumed,
including for each blood product so listed the identity by established
name as defined in section 502(e) of the act and by any proprietary
name, the date of resumption, and any other information required by
Sec. 607.25(b) not previously submitted.
(4) Any material change in any information previously submitted.
(b) When no changes have occurred since the previously submitted
list, no listing information is required.
[40 FR 52788, Nov. 12, 1975, as amended at 81 FR 60222, Aug. 31, 2016]
Sec. 607.31 Additional blood product listing information.
(a) In addition to the information routinely required by Sec. Sec.
607.25 and 607.30, the Director of the Center for Biologics Evaluation
and Research may require submission of the following information by
letter or by Federal Register notice:
(1) For a particular blood product so listed, upon request made by
the Director of the Center for Biologics Evaluation and Research for
good cause, a copy of all advertisements.
(2) For a particular blood product so listed, upon a finding by the
Director of the Center for Biologics Evaluation and Research that it is
necessary to carry out the purposes of the act, a quantitative listing
of all ingredients.
(3) For each registrant, upon a finding by the Director of the
Center for Biologics Evaluation and Research that it is necessary to
carry out the purposes of the act, a list of each listed
[[Page 64]]
blood product containing a particular ingredient.
(b) [Reserved]
[66 FR 59158, Nov. 27, 2001]
Sec. 607.35 Blood product establishment registration number.
An establishment registration number will be assigned to each blood
product establishment registered in accordance with this part.
[81 FR 60223, Aug. 31, 2016]
Sec. 607.37 Public disclosure of establishment registration and blood
product listing information.
(a) Except as provided in paragraph (b) of this section, all
registration and listing information obtained under Sec. Sec. 607.25,
607.26, and 607.30 will be made available for public disclosure through
the Center for Biologics Evaluation and Research (CBER) Blood
Establishment Registration Database Web site by using the CBER
electronic Web-based application or by going in person to the Food and
Drug Administration, Division of Freedom of Information Public Reading
Room (see addresses in Sec. 20.120(a) of this chapter).
(b) FDA may find, in limited circumstances and on a case-by-case
basis, that it would be consistent with the protection of the public
health to exempt from public disclosure specific listing information
obtained under Sec. 607.25 or Sec. 607.30.
(c) Other requests for information regarding blood establishment
registrations and blood product listings should be directed to the Food
and Drug Administration, Center for Biologics Evaluation and Research
Office of Communication, Outreach, and Development, 10903 New Hampshire
Ave., Bldg. 71, Rm. 3103, Silver Spring, MD 20993-0002.
[81 FR 60223, Aug. 31, 2016]
Sec. 607.39 Misbranding by reference to establishment registration,
validation of registration, or to registration number.
Registration of an establishment, validation of registration, or
assignment of a registration number does not in any way denote approval
of the firm or its products nor does it mean that the products may be
legally marketed. Any representation that creates an impression of
official approval because of establishment registration, validation of
registration, or possession of a registration number is misleading and
constitutes misbranding.
[81 FR 60223, Aug. 31, 2016]
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).
[[Page 65]]
(d) Each foreign establishment required to register under paragraph
(a) of this section must submit the name, address, telephone number, and
email address of its United States agent as part of its initial and
updated registration information in accordance with subpart B of this
part. Each foreign establishment must designate only one United States
agent.
(1) The United States agent shall reside or maintain a place of
business in the United States.
(2) Upon request from FDA, the United States agent shall assist FDA
in communications with the foreign establishment, respond to questions
concerning the foreign establishment's products that are imported or
offered for import into the United States, and assist FDA in scheduling
inspections of the foreign establishment. If the agency is unable to
contact the foreign establishment directly or expeditiously, FDA may
provide information or documents to the United States agent, and such an
action shall be considered to be equivalent to providing the same
information or documents to the foreign establishment.
(3) The foreign establishment or the United States agent must report
changes in the United States agent's name, address, telephone number, or
email address to FDA within 30 calendar days of the change.
(e) Each foreign establishment required to register under paragraph
(a) of this section must register and list blood products using the
Blood Establishment Registration and Product Listing system, or any
superseding electronic system, unless FDA waives the electronic
submission requirement in accordance with Sec. 607.22.
[66 FR 59159, Nov. 27, 2001, as amended at 81 FR 60223, Aug. 31, 2016]
Subpart D_Exemptions
Sec. 607.65 Exemptions for blood product establishments.
The following classes of persons are exempt from registration and
blood product listing in accordance with this part 607 under the
provisions of section 510(g)(1), (g)(2), and (g)(3) of the act, or
because the Commissioner of Food and Drugs has found, under section
510(g)(5), that such registration is not necessary for the protection of
the public health. The exemptions in paragraphs (a), (b), (f), and (g)
of this section are limited to those classes of persons located in any
State as defined in section 201(a)(1) of the act.
(a) Pharmacies that are operating under applicable local laws
regulating dispensing of prescription drugs and that are not
manufacturing blood products for sale other than in the regular course
of the practice of the profession of pharmacy including the business of
dispensing and selling blood products at retail. The supplying by such
pharmacies of blood products to a practitioner licensed to administer
such blood products for his use in the course of his professional
practice or to other pharmacies to meet temporary inventory shortages
are not acts which require such pharmacies to register.
(b) Practitioners who are licensed by law to prescribe or administer
drugs and who manufacture blood products solely for use in the course of
their professional practice.
(c) Persons who manufacture blood products which are not for sale,
rather, are solely for use in research, teaching, or analysis, including
laboratory samples.
(d) Carriers, by reason of their receipt, carriage, holding, or
delivery of blood products in the usual course of business as carriers.
(e) Persons who engage solely in the manufacture of in vitro
diagnostic blood products and reagents not subject to licensing under
section 351 of the Public Health Service Act (42 U.S.C. 262). This
paragraph does not exempt such persons from registration and listing for
medical devices required under part 807 of this chapter.
(f) Transfusion services which are a part of a facility that is
certified under the Clinical Laboratory Improvement Amendments of 1988
(42 U.S.C. 263a) and 42 CFR part 493 or has met equivalent requirements
as determined by the Centers for Medicare and Medicaid Services and
which are engaged in the compatibility testing and transfusion of blood
and blood components, but which neither routinely collect nor process
blood and blood components. The collection and processing of blood
[[Page 66]]
and blood components in an emergency situation as determined by a
responsible person and documented in writing, therapeutic collection of
blood or plasma, the preparation of recovered human plasma for further
manufacturing use, or preparation of red blood cells for transfusion are
not acts requiring such transfusion services to register.
(g) Persons who engage solely in the production of any plasma
derivative, including, but not limited to, albumin, Immune Globulin,
Factor VIII and Factor IX, bulk product substances such as fractionation
intermediates or pastes, or recombinant versions of plasma derivatives
or animal derived plasma derivatives. These persons must register and
list under part 207 of this chapter.
[40 FR 52788, Nov. 12, 1975, as amended at 43 FR 37997, Aug. 25, 1978;
45 FR 85729, Dec. 30, 1980; 49 FR 34449, Aug. 31, 1984; 66 FR 31162,
June 11, 2001; 66 FR 59159, Nov. 27, 2001; 72 FR 45886, Aug. 16, 2007;
81 FR 60223, Aug. 31, 2016]
Subpart E_Establishment Registration and Product Listing Of Licensed
Devices
Sec. 607.80 Applicability of part 607 to licensed devices.
Manufacturers of products that meet the definition of a device under
the Federal Food, Drug, and Cosmetic Act and that are licensed under
section 351 of the Public Health Service Act, as well as licensed
biological products used in the manufacture of a licensed device, must
register and list following the procedures under this part, with respect
to their manufacture of those products, unless otherwise noted in this
section.
[81 FR 60223, Aug. 31, 2016]
PART 610_GENERAL BIOLOGICAL PRODUCTS STANDARDS--Table of Contents
Subpart A_Release Requirements
Sec.
610.1 Tests prior to release required for each lot.
610.2 Requests for samples and protocols; official release.
Subpart B_General Provisions
610.9 Equivalent methods and processes.
610.10 Potency.
610.11-610.11a [Reserved]
610.12 Sterility.
610.13 Purity.
610.14 Identity.
610.15 Constituent materials.
610.16 Total solids in serums.
610.17 Permissible combinations.
610.18 Cultures.
Subparts C--D [Reserved]
Subpart E_Testing Requirements for Relevant Transfusion-Transmitted
Infections
610.39 Definitions.
610.40 Test requirements.
610.41 Donor deferral.
610.42 Restrictions on use for further manufacture of medical devices.
610.44 Use of reference panels by manufacturers of test kits.
610.46 Human immunodeficiency virus (HIV) ``lookback'' requirements.
610.47 Hepatitis C virus (HCV) ``lookback'' requirements.
610.48 [Reserved]
Subpart F_Dating Period Limitations
610.50 Date of manufacture for biological products.
610.53 Dating periods for Whole Blood and blood components.
Subpart G_Labeling Standards
610.60 Container label.
610.61 Package label.
610.62 Proper name; package label; legible type.
610.63 Divided manufacturing responsibility to be shown.
610.64 Name and address of distributor.
610.65 Products for export.
610.67 Bar code label requirements.
610.68 Exceptions or alternatives to labeling requirements for
biological products held by the Strategic National Stockpile.
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 360d,
360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a, 264.
Source: 38 FR 32056, Nov. 20, 1973, unless otherwise noted.
Cross References: For U.S. Customs Service regulations relating to
viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal
Service regulations relating to the admissibility to the United States
mails see parts 124 and 125 of the Domestic Mail Manual, that is
incorporated by reference in 39 CFR part 111.
[[Page 67]]
Subpart A_Release Requirements
Sec. 610.1 Tests prior to release required for each lot.
No lot of any licensed product shall be released by the manufacturer
prior to the completion of tests for conformity with standards
applicable to such product. Each applicable test shall be made on each
lot after completion of all processes of manufacture which may affect
compliance with the standard to which the test applies. The results of
all tests performed shall be considered in determining whether or not
the test results meet the test objective, except that a test result may
be disregarded when it is established that the test is invalid due to
causes unrelated to the product.
Sec. 610.2 Requests for samples and protocols; official release.
(a) Licensed biological products regulated by CBER. Samples of any
lot of any licensed product together with the protocols showing results
of applicable tests, may at any time be required to be sent to the
Director, Center for Biologics Evaluation and Research (see mailing
addresses in Sec. 600.2(c) of this chapter). Upon notification by the
Director, Center for Biologics Evaluation and Research, a manufacturer
shall not distribute a lot of a product until the lot is released by the
Director, Center for Biologics Evaluation and Research: Provided, That
the Director, Center for Biologics Evaluation and Research, shall not
issue such notification except when deemed necessary for the safety,
purity, or potency of the product.
(b) Licensed biological products regulated by CDER. Samples of any
lot of any licensed product together with the protocols showing results
of applicable tests, may at any time be required to be sent to the
Director, Center for Drug Evaluation and Research (see mailing addresses
in Sec. 600.2(c) of this chapter) for official release. Upon
notification by the Director, Center for Drug Evaluation and Research, a
manufacturer shall not distribute a lot of a biological product until
the lot is released by the Director, Center for Drug Evaluation and
Research: Provided, That the Director, Center for Drug Evaluation and
Research shall not issue such notification except when deemed necessary
for the safety, purity, or potency of the product.
[40 FR 31313, July 25, 1975, as amended at 49 FR 23834, June 8, 1984; 50
FR 10941, Mar. 19, 1985; 55 FR 11013, 11014, Mar. 26, 1990; 67 FR 9587,
Mar. 4, 2002; 70 FR 14984, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015]
Subpart B_General Provisions
Sec. 610.9 Equivalent methods and processes.
Modification of any particular test method or manufacturing process
or the conditions under which it is conducted as required in this part
or in the additional standards for specific biological products in parts
620 through 680 of this chapter shall be permitted only under the
following conditions:
(a) The applicant presents evidence, in the form of a license
application, or a supplement to the application submitted in accordance
with Sec. 601.12(b) or (c), demonstrating that the modification will
provide assurances of the safety, purity, potency, and effectiveness of
the biological product equal to or greater than the assurances provided
by the method or process specified in the general standards or
additional standards for the biological product; and
(b) Approval of the modification is received in writing from the
Director, Center for Biologics Evaluation and Research or the Director,
Center for Drug Evaluation and Research.
[62 FR 39903, July 24, 1997, as amended at 70 FR 14984, Mar. 24, 2005]
Sec. 610.10 Potency.
Tests for potency shall consist of either in vitro or in vivo tests,
or both, which have been specifically designed for each product so as to
indicate its potency in a manner adequate to satisfy the interpretation
of potency given by the definition in Sec. 600.3(s) of this chapter.
Sec. 610.11-610.11a [Reserved]
Sec. 610.12 Sterility.
(a) The test. Except as provided in paragraph (h) of this section,
manufacturers of biological products must perform sterility testing of
each lot of
[[Page 68]]
each biological product's final container material or other material, as
appropriate and as approved in the biologics license application or
supplement for that product.
(b) Test requirements. (1) The sterility test must be appropriate to
the material being tested such that the material does not interfere with
or otherwise hinder the test.
(2) The sterility test must be validated to demonstrate that the
test is capable of reliably and consistently detecting the presence of
viable contaminating microorganisms.
(3) The sterility test and test components must be verified to
demonstrate that the test method can consistently detect the presence of
viable contaminating microorganisms.
(c) Written procedures. Manufacturers must establish, implement, and
follow written procedures for sterility testing that describe, at a
minimum, the following:
(1) The sterility test method to be used;
(i) If culture-based test methods are used, include, at a minimum:
(A) Composition of the culture media;
(B) Growth-promotion test requirements; and
(C) Incubation conditions (time and temperature).
(ii) If non-culture-based test methods are used, include, at a
minimum:
(A) Composition of test components;
(B) Test parameters, including acceptance criteria; and
(C) Controls used to verify the method's ability to detect the
presence of viable contaminating microorganisms.
(2) The method of sampling, including the number, volume, and size
of articles to be tested;
(3) Written specifications for the acceptance or rejection of each
lot; and
(4) A statement of any other function critical to the particular
sterility test method to ensure consistent and accurate results.
(d) The sample. The sample must be appropriate to the material being
tested, considering, at a minimum:
(1) The size and volume of the final product lot;
(2) The duration of manufacturing of the drug product;
(3) The final container configuration and size;
(4) The quantity or concentration of inhibitors, neutralizers, and
preservatives, if present, in the tested material;
(5) For a culture-based test method, the volume of test material
that results in a dilution of the product that is not bacteriostatic or
fungistatic; and
(6) For a non-culture-based test method, the volume of test material
that results in a dilution of the product that does not inhibit or
otherwise hinder the detection of viable contaminating microorganisms.
(e) Verification. (1) For culture-based test methods, studies must
be conducted to demonstrate that the performance of the test organisms
and culture media are suitable to consistently detect the presence of
viable contaminating microorganisms, including tests for each lot of
culture media to verify its growth-promoting properties over the shelf-
life of the media.
(2) For non-culture-based test methods, within the test itself,
appropriate controls must be used to demonstrate the ability of the test
method to continue to consistently detect the presence of viable
contaminating microorganisms.
(f) Repeat test procedures. (1) If the initial test indicates the
presence of microorganisms, the product does not comply with the
sterility test requirements unless a thorough investigation by the
quality control unit can ascribe definitively the microbial presence to
a laboratory error or faulty materials used in conducting the sterility
testing.
(2) If the investigation described in paragraph (f)(1) of this
section finds that the initial test indicated the presence of
microorganisms due to laboratory error or the use of faulty materials, a
sterility test may be repeated one time. If no evidence of
microorganisms is found in the repeat test, the product examined
complies with the sterility test requirements. If evidence of
microorganisms is found in the repeat test, the product examined does
not comply with the sterility test requirements.
(3) If a repeat test is conducted, the same test method must be used
for both the initial and repeat tests, and
[[Page 69]]
the repeat test must be conducted with comparable product that is
reflective of the initial sample in terms of sample location and the
stage in the manufacturing process from which it was obtained.
(g) Records. The records related to the test requirements of this
section must be prepared and maintained as required by Sec. Sec.
211.167 and 211.194 of this chapter.
(h) Exceptions. Sterility testing must be performed on final
container material or other appropriate material as defined in the
approved biologics license application or supplement and as described in
this section, except as follows:
(1) This section does not require sterility testing for Whole Blood,
Cryoprecipitated Antihemophilic Factor, Platelets, Red Blood Cells,
Plasma, Source Plasma, Smallpox Vaccine, Reagent Red Blood Cells, Anti-
Human Globulin, and Blood Grouping Reagents.
(2) A manufacturer is not required to comply with the sterility test
requirements if the Director of the Center for Biologics Evaluation and
Research or the Director of the Center for Drug Evaluation and Research,
as appropriate, determines that data submitted in the biologics license
application or supplement adequately establish that the route of
administration, the method of preparation, or any other aspect of the
product precludes or does not necessitate a sterility test to assure the
safety, purity, and potency of the product.
[77 FR 26174, May 3, 2012]
Sec. 610.13 Purity.
Products shall be free of extraneous material except that which is
unavoidable in the manufacturing process described in the approved
biologics license application. In addition, products shall be tested as
provided in paragraphs (a) and (b) of this section.
(a)(1) Test for residual moisture. Each lot of dried product shall
be tested for residual moisture and shall meet and not exceed
established limits as specified by an approved method on file in the
biologics license application. The test for residual moisture may be
exempted by the Director, Center for Biologics Evaluation and Research
or the Director, Center for Drug Evaluation and Research, when deemed
not necessary for the continued safety, purity, and potency of the
product.
(2) Records. Appropriate records for residual moisture under
paragraph (a)(1) of this section shall be prepared and maintained as
required by the applicable provisions of Sec. Sec. 211.188 and 211.194
of this chapter.
(b) Test for pyrogenic substances. Each lot of final containers of
any product intended for use by injection shall be tested for pyrogenic
substances by intravenous injection into rabbits as provided in
paragraphs (b) (1) and (2) of this section: Provided, That
notwithstanding any other provision of Subchapter F of this chapter, the
test for pyrogenic substances is not required for the following
products: Products containing formed blood elements; Cryoprecipitate;
Plasma; Source Plasma; Normal Horse Serum; bacterial, viral, and
rickettsial vaccines and antigens; toxoids; toxins; allergenic extracts;
venoms; diagnostic substances and trivalent organic arsenicals.
(1) Test dose. The test dose for each rabbit shall be at least 3
milliliters per kilogram of body weight of the rabbit and also shall be
at least equivalent proportionately, on a body weight basis, to the
maximum single human dose recommended, but need not exceed 10
milliliters per kilogram of body weight of the rabbit, except that: (i)
Regardless of the human dose recommended, the test dose per kilogram of
body weight of each rabbit shall be at least 1 milliliter for immune
globulins derived from human blood; (ii) for Streptokinase, the test
dose shall be at least equivalent proportionately, on a body weight
basis, to the maximum single human dose recommended.
(2) Test procedure, results, and interpretation; standards to be
met. The test for pyrogenic substances shall be performed according to
the requirements specified in United States Pharmacopeia XX.
(3) Retest. If the lot fails to meet the test requirements
prescribed in paragraph (b)(2) of this section, the test may be repeated
once using five other rabbits. The temperature rises recorded
[[Page 70]]
for all eight rabbits used in testing shall be included in determining
whether the requirements are met. The lot meets the requirements for
absence of pyrogens if not more than three of the eight rabbits show
individual rises in temperature of 0.6 [deg]C or more, and if the sum of
the eight individual maximum temperature rises does not exceed 3.7
[deg]C.
[38 FR 32056, Nov. 20, 1973, as amended at 40 FR 29710, July 15, 1975;
41 FR 10429, Mar. 11, 1976; 41 FR 41424, Sept. 22, 1976; 44 FR 40289,
July 10, 1979; 46 FR 62845, Dec. 29, 1981; 49 FR 15187, Apr. 18, 1984;
50 FR 4134, Jan. 29, 1985; 55 FR 28381, July 11, 1990; 64 FR 56453, Oct.
20, 1999; 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005]
Sec. 610.14 Identity.
The contents of a final container of each filling of each lot shall
be tested for identity after all labeling operations shall have been
completed. The identity test shall be specific for each product in a
manner that will adequately identify it as the product designated on
final container and package labels and circulars, and distinguish it
from any other product being processed in the same laboratory. Identity
may be established either through the physical or chemical
characteristics of the product, inspection by macroscopic or microscopic
methods, specific cultural tests, or in vitro or in vivo immunological
tests.
Sec. 610.15 Constituent materials.
(a) Ingredients, preservatives, diluents, adjuvants. All ingredients
used in a licensed product, and any diluent provided as an aid in the
administration of the product, shall meet generally accepted standards
of purity and quality. Any preservative used shall be sufficiently
nontoxic so that the amount present in the recommended dose of the
product will not be toxic to the recipient, and in the combination used
it shall not denature the specific substances in the product to result
in a decrease below the minimum acceptable potency within the dating
period when stored at the recommended temperature. Products in multiple-
dose containers shall contain a preservative, except that a preservative
need not be added to Yellow Fever Vaccine; Poliovirus Vaccine Live Oral;
viral vaccines labeled for use with the jet injector; dried vaccines
when the accompanying diluent contains a preservative; or to an
Allergenic Product in 50 percent or more volume in volume (v/v)
glycerin. An adjuvant shall not be introduced into a product unless
there is satisfactory evidence that it does not affect adversely the
safety or potency of the product. The amount of aluminum in the
recommended individual dose of a biological product shall not exceed:
(1) 0.85 milligrams if determined by assay;
(2) 1.14 milligrams if determined by calculation on the basis of the
amount of aluminum compound added; or
(3) 1.25 milligrams determined by assay provided that data
demonstrating that the amount of aluminum used is safe and necessary to
produce the intended effect are submitted to and approved by the
Director, Center for Biologics Evaluation and Research or the Director,
Center for Drug Evaluation and Research (see mailing addresses in Sec.
600.2(a) or (b) of this chapter).
(b) Extraneous protein; cell culture produced vaccines. Extraneous
protein known to be capable of producing allergenic effects in human
subjects shall not be added to a final virus medium of cell culture
produced vaccines intended for injection. If serum is used at any stage,
its calculated concentration in the final medium shall not exceed
1:1,000,000.
(c) Antibiotics. A minimum concentration of antibiotics, other than
penicillin, may be added to the production substrate of viral vaccines.
(d) The Director of the Center for Biologics Evaluation and Research
or the Director of the Center for Drug Evaluation and Research may
approve an exception or alternative to any requirement in this section.
Requests for such exceptions or alternatives must be in writing.
[38 FR 32056, Nov. 20, 1973, as amended at 46 FR 51903, Oct. 23, 1981;
48 FR 13025, Mar. 29, 1983; 48 FR 37023, Aug. 16, 1983; 49 FR 23834,
June 8, 1984; 50 FR 4134, Jan. 29, 1985; 51 FR 15607, Apr. 25, 1986; 55
FR 11013, Mar. 26, 1990; 70 FR 14985, Mar. 24, 2005; 76 FR 20518, Apr.
13, 2011; 80 FR 18093, Apr. 3, 2015]
[[Page 71]]
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 or the Director, Center for Drug
Evaluation and Research.
(3) Applicability. This paragraph applies to diploid and nondiploid
cell lines. Primary cell cultures that are not subcultivated and primary
cell cultures that are subsequently subcultivated for only a very
limited number of population doublings are not subject to the provisions
of this paragraph (c).
(d) Records. The records appropriate for cultures under this section
shall be prepared and maintained as required by the applicable
provisions of Sec. Sec. 211.188 and 211.194 of this chapter.
[38 FR 32056, Nov. 20, 1973, as amended at 51 FR 44453, Dec. 10, 1986;
55 FR 11013, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar.
24, 2005]
Subparts C--D [Reserved]
Subpart E_Testing Requirements for Relevant Transfusion-Transmitted
Infections
Sec. 610.39 Definitions.
The definitions set out in Sec. 630.3 of this chapter apply to this
subpart.
[80 FR 29896, May 22, 2015]
Sec. 610.40 Test requirements.
(a) Human blood and blood components. Except as specified in
paragraphs (c) and (d) of this section, you, an establishment that
collects blood and blood components for transfusion or for use in
manufacturing a product, including donations intended as a component of,
or used to manufacture, a medical device, must comply with the following
requirements:
(1) Test each donation for evidence of infection due to the relevant
transfusion-transmitted infections described in Sec. 630.3(h)(1)(i)
through (iii) of this chapter (HIV, HBV, and HCV).
(2) Test each donation for evidence of infection due to the relevant
transfusion-transmitted infections described in Sec. 630.3(h)(1)(iv)
through (vii) of this chapter (HTLV, syphilis, West Nile virus, and
Chagas disease). The following exceptions apply:
(i) To identify evidence of infection with syphilis in donors of
Source Plasma, you must test donors for evidence of such infection in
accordance with
[[Page 72]]
Sec. 640.65(b) of this chapter, and not under this section.
(ii) You are not required to test donations of Source Plasma for
evidence of infection due to the relevant transfusion-transmitted
infections described in Sec. 630.3(h)(1)(iv), (vi), and (vii) of this
chapter (HTLV, West Nile virus, and Chagas disease).
(iii) For each of the relevant transfusion-transmitted infections
described in Sec. 630.3(h)(1)(iv) through (vii) of this chapter (HTLV,
syphilis, West Nile virus, and Chagas disease):
(A) If, based on evidence related to the risk of transmission of
that relevant transfusion-transmitted infection, testing each donation
is not necessary to reduce adequately and appropriately the risk of
transmission of such infection by blood or a blood component, you may
adopt an adequate and appropriate alternative testing procedure that has
been found acceptable for this purpose by FDA.
(B) If, based on evidence related to the risk of transmission of
that relevant transfusion-transmitted infection, testing previously
required for that infection is no longer necessary to reduce adequately
and appropriately the risk of transmission of such infection by blood or
a blood component, you may stop such testing in accordance with
procedures found acceptable for this purpose by FDA.
(3) For each of the relevant transfusion-transmitted infections
described in Sec. 630.3(h)(1)(viii) through (x) of this chapter (CJD,
vCJD, malaria) and Sec. 630.3(h)(2) of this chapter (other transfusion-
transmitted infections):
(i) You must test for evidence of infection when the following
conditions are met:
(A) A test(s) for the relevant transfusion-transmitted infection is
licensed, approved or cleared by FDA for use as a donor screening test
and is available for such use; and
(B) Testing for the relevant transfusion-transmitted infection is
necessary to reduce adequately and appropriately the risk of
transmission of the relevant transfusion-transmitted infection by blood,
or blood component, or blood derivative product manufactured from the
collected blood or blood component.
(ii) You must perform this testing on each donation, unless one of
the following exceptions applies:
(A) Testing of each donation is not necessary to reduce adequately
and appropriately the risk of transmission of such infection by blood,
blood component, or blood derivative product manufactured from the
collected blood or blood component. When evidence related to the risk of
transmission of such infection supports this determination, you may
adopt an adequate and appropriate alternative testing procedure that has
been found acceptable for this purpose by FDA.
(B) Testing of each donation is not necessary to reduce adequately
and appropriately the risk of transmission of such infection by blood,
blood component, or blood derivative product manufactured from the
collected blood or blood component. When evidence related to the risk of
transmission of such infection supports this determination, you may stop
such testing in accordance with procedures found acceptable for this
purpose by FDA.
(4) Evidence related to the risk of transmission of a relevant
transfusion-transmitted infection that would support a determination
that testing is not necessary, or that testing of each donation is not
necessary, to reduce adequately and appropriately the risk of
transmission of such infection by blood or blood component, as described
in paragraphs (a)(2)(iii)(A) and (B) of this section, or by blood, blood
component, or blood derivative, as described in paragraphs (a)(3)(ii)(A)
and (B) of this section, includes epidemiological or other scientific
evidence. It may include evidence related to the seasonality or
geographic limitation of risk of transmission of such infection by blood
or blood component, or other information related to when and how a
donation is at risk of transmitting a relevant transfusion-transmitted
infection. It may also include evidence related to the effectiveness of
manufacturing steps (for example, the use of pathogen reduction
technology) that reduce the risk of transmission of the relevant
transfusion-transmitted infection by blood, blood components, or blood
derivatives, as applicable.
[[Page 73]]
(b) Testing using one or more licensed, approved, or cleared
screening tests. To perform testing for evidence of infection due to
relevant transfusion-transmitted infections as required in paragraph (a)
of this section, you must use screening tests that FDA has licensed,
approved, or cleared for such use, in accordance with the manufacturer's
instructions. You must perform one or more such tests as necessary to
reduce adequately and appropriately the risk of transmission of relevant
transfusion-transmitted infections.
(c) Exceptions to testing for dedicated donations, medical devices,
and samples.--(1) Dedicated donations. (i) You must test donations of
human blood and blood components from a donor whose donations are
dedicated to and used solely by a single identified recipient under
paragraphs (a), (b), and (e) of this section; except that, if the donor
makes multiple donations for a single identified recipient, you may
perform such testing only on the first donation in each 30-day period.
If an untested dedicated donation is made available for any use other
than transfusion to the single, identified recipient, then this
exemption from the testing required under this section no longer
applies.
(ii) Each donation must be labeled as required under Sec. 606.121
of this chapter and with a label entitled ``INTENDED RECIPIENT
INFORMATION LABEL'' containing the name and identifying information of
the recipient. Each donation must also have the following label, as
appropriate:
------------------------------------------------------------------------
Donor Testing Status Label
------------------------------------------------------------------------
Tests negative Label as required under Sec. 606.121
Tested negative within the last ``DONOR TESTED WITHIN THE LAST 30
30 days DAYS''
------------------------------------------------------------------------
(2) Medical device. (i) You are not required to test donations of
human blood or blood components intended solely as a component of, or
used to prepare, a medical device for evidence of infection due to the
relevant transfusion-transmitted infections listed in Sec. 630.3(h)(iv)
of this chapter unless the final device contains viable leukocytes.
(ii) Donations of human blood and blood components intended solely
as a component of, or used to prepare, a medical device must be labeled
``Caution: For Further Manufacturing Use as a Component of, or to
Prepare, a Medical Device.''
(3) Samples. You are not required to test samples of blood, blood
components, plasma, or sera if used or distributed for clinical
laboratory testing or research purposes and not intended for
administration to humans or in the manufacture of a product.
(d) Autologous donations. You, an establishment that collects human
blood or blood components from autologous donors, or you, an
establishment that is a consignee of a collecting establishment, are not
required to test donations of human blood or blood components from
autologous donors for evidence of infection due to relevant transfusion-
transmitted infections listed in paragraph (a) of this section, except:
(1) If you allow any autologous donation to be used for allogeneic
transfusion, you must assure that all autologous donations are tested
under this section.
(2) If you ship autologous donations to another establishment that
allows autologous donations to be used for allogeneic transfusion, you
must assure that all autologous donations shipped to that establishment
are tested under this section.
(3) If you ship autologous donations to another establishment that
does not allow autologous donations to be used for allogeneic
transfusion, you must assure that, at a minimum, the first donation in
each 30-day period is tested under this section.
(4) Each autologous donation must be labeled as required under Sec.
606.121 of this chapter and with the following label, as appropriate:
------------------------------------------------------------------------
Donor Testing Status Label
------------------------------------------------------------------------
Untested ``DONOR UNTESTED''
Tests negative Label as required under Sec. 606.121
Reactive on current collection/ ``BIOHAZARD'' legend in Sec.
reactive in the last 30 days 610.40(h)(2)(ii)(B)
Tested negative within the last ``DONOR TESTED WITHIN THE LAST 30
30 days DAYS''
------------------------------------------------------------------------
(e) Further testing. You must further test each donation, including
autologous donations, found to be reactive by a donor screening test
performed under paragraphs (a) and (b) of this section using a licensed,
approved,
[[Page 74]]
or cleared supplemental test, when available. If no such supplemental
test is available, you must perform one or more licensed, approved, or
cleared tests as adequate and appropriate to provide additional
information concerning the reactive donor's infection status. Except:
(1) For autologous donations:
(i) You must further test under this section, at a minimum, the
first reactive donation in each 30 calendar day period; or
(ii) If you have a record for that donor of a positive result on
further testing performed under this section, you do not have to further
test an autologous donation.
(2) You are not required to perform further testing of a donation
found to be reactive by a treponemal donor screening test for syphilis.
(f) Testing responsibility. Required testing under this section,
must be performed by a laboratory registered in accordance with part 607
of this chapter and either certified to perform such testing on human
specimens under the Clinical Laboratory Improvement Amendments of 1988
(42 U.S.C. 263a) under 42 CFR part 493 or has met equivalent
requirements as determined by the Centers for Medicare and Medicaid
Services in accordance with those provisions.
(g) Release or shipment prior to testing. Human blood or blood
components that are required to be tested for evidence of infection due
to relevant transfusion-transmitted infections designated in paragraph
(a) of this section may be released or shipped prior to completion of
testing in the following circumstances provided that you label the blood
or blood components under Sec. 606.121(h) of this chapter, you complete
the tests for evidence of infection due to relevant transfusion-
transmitted infections as soon as possible after release or shipment,
and that you provide the results promptly to the consignee:
(1) Only in appropriately documented medical emergency situations;
or
(2) For further manufacturing use as approved in writing by FDA.
(h) Restrictions on shipment or use--(1) Reactive screening test.
You must not ship or use human blood or blood components that have a
reactive screening test for evidence of infection due to relevant
transfusion-transmitted infection(s) designated in paragraph (a) of this
section or that are collected from a donor with a previous record of a
reactive screening test for evidence of infection due to relevant
transfusion-transmitted infection(s) designated in paragraph (a) of this
section, except as provided in paragraphs (h)(2)(i) through (h)(2)(vii)
of this section.
(2) Exceptions. (i) You may ship or use blood or blood components
intended for autologous use, including reactive donations, as described
in paragraph (d) of this section.
(ii) You must not ship or use human blood or blood components that
have a reactive screening test for evidence of infection due to a
relevant transfusion-transmitted infection(s) designated in paragraph
(a) of this section or that are collected from a donor deferred under
Sec. 610.41(a) unless you meet the following conditions:
(A) Except for autologous donations, you must obtain from FDA
written approval for the shipment or use;
(B) You must appropriately label such blood or blood components as
required under Sec. 606.121 of this chapter, and with the ``BIOHAZARD''
legend;
(C) Except for autologous donations, you must label such human blood
and blood components as reactive for the appropriate screening test for
evidence of infection due to the identified relevant transfusion-
transmitted infection(s);
(D) If the blood or blood components are intended for further
manufacturing use into injectable products, you must include a statement
on the container label indicating the exempted use specifically approved
by FDA.
(E) Each blood or blood component with a reactive screening test and
intended solely as a component of, or used to prepare a medical device,
must be labeled with the following label, as appropriate:
------------------------------------------------------------------------
Type of Medical Device Label
------------------------------------------------------------------------
A medical device other than an ``Caution: For Further Manufacturing
in vitro diagnostic reagent Use as a Component of a Medical
Device For Which There Are No
Alternative Sources''
[[Page 75]]
An in vitro diagnostic reagent ``Caution: For Further Manufacturing
Into In Vitro Diagnostic Reagents For
Which There Are No Alternative
Sources''
------------------------------------------------------------------------
(iii) The restrictions on shipment or use do not apply to samples of
blood, blood components, plasma, or sera if used or distributed for
clinical laboratory testing or research purposes, and not intended for
administration in humans or in the manufacture of a product.
(iv) You may use human blood or blood components from a donor with a
previous record of a reactive screening test(s) for evidence of
infection due to a relevant transfusion-transmitted infection(s)
designated in paragraph (a) of this section, if:
(A) At the time of donation, the donor is shown or was previously
shown to be eligible by a requalification method or process found
acceptable for such purposes by FDA under Sec. 610.41(b); and
(B) tests performed under paragraphs (a) and (b) of this section are
nonreactive.
(v) Anti-HBc reactive donations, otherwise nonreactive when tested
as required under this section, may be used for further manufacturing
into plasma derivatives without prior FDA approval or a ``BIOHAZARD''
legend as required under paragraphs (h)(2)(ii)(A) and (h)(2)(ii)(B) of
this section.
(vi) You may use human blood or blood components, excluding Source
Plasma, that test reactive by a screening test for syphilis as required
under paragraph (a) of this section if, the donation is further tested
by an adequate and appropriate test which demonstrates that the reactive
screening test is a biological false positive. You must label the blood
or blood components with both test results.
(vii) You may use Source Plasma from a donor who tests reactive by a
screening test for syphilis as required under Sec. 640.65(b)(1)(i) of
this chapter, if the donor meets the requirements of Sec.
640.65(b)(2)(ii) through (iv) of this chapter.
[66 FR 31162, June 11, 2001, as amended at 77 FR 18, Jan. 3, 2012; 80 FR
29896, May 22, 2015; 86 FR 49922, July 9, 2021]
Sec. 610.41 Donor deferral.
(a) You, an establishment that collects human blood or blood
components, must defer donors testing reactive by a screening test for
evidence of infection due to a relevant transfusion-transmitted
infection(s) under Sec. 610.40(a), from future donations of human blood
and blood components, except:
(1) You are not required to defer a donor who tests reactive for
anti-HBc or anti-HTLV, types I and II, on only one occasion. However,
you must defer the donor if further testing for HBV or HTLV has been
performed under Sec. 610.40(e) and the donor is found to be positive,
or if a second, licensed, cleared, or approved screening test for HBV or
HTLV has been performed on the same donation under Sec. 610.40(a) and
is reactive, or if the donor tests reactive for anti-HBc or anti-HTLV,
types I and II, on more than one occasion;
(2) A deferred donor who tests reactive for evidence of infection
due to a relevant transfusion-transmitted infection(s) under Sec.
610.40(a) may serve as a donor for blood or blood components shipped or
used under Sec. 610.40(h)(2)(ii);
(3) A deferred donor who showed evidence of infection due to
hepatitis B surface antigen (HBsAg) when previously tested under Sec.
610.40(a), (b), and (e) subsequently may donate Source Plasma for use in
the preparation of Hepatitis B Immune Globulin (Human) provided the
current donation tests nonreactive for HBsAg and the donor is otherwise
determined to be eligible;
(4) A deferred donor, who otherwise is determined to be eligible for
donation and tests reactive for anti-HBc or for evidence of infection
due to HTLV, types I and II, may serve as a donor of Source Plasma;
(5) A deferred donor who tests reactive for a relevant transfusion-
transmitted infections(s) under Sec. 610.40(a), may serve as an
autologous donor under Sec. 610.40(d).
(b) A deferred donor subsequently may be found to be eligible as a
donor of blood or blood components by a requalification method or
process found acceptable for such purposes by FDA. Such a donor is
considered no longer deferred.
[[Page 76]]
(c) You must comply with the requirements under Sec. Sec. 610.46
and 610.47 when a donor tests reactive by a screening test for HIV or
HCV required under Sec. 610.40(a) and (b), or when you are aware of
other reliable test results or information indicating evidence of HIV or
HCV infection.
[66 FR 31164, June 11, 2001, as amended at 72 FR 48798, Aug. 24, 2007;
80 FR 29897, May 22, 2015]
Sec. 610.42 Restrictions on use for further manufacture of medical devices.
(a) In addition to labeling requirements in subchapter H of this
chapter, when a medical device contains human blood or a blood component
as a component of the final device, and the human blood or blood
component was found to be reactive by a screening test performed under
Sec. 610.40(a) and (b), then you must include in the device labeling a
statement of warning indicating that the product was manufactured from a
donation found to be reactive by a screening test for evidence of
infection due to the identified relevant transfusion-transmitted
infection(s).
(b) FDA may approve an exception or alternative to the statement of
warning required in paragraph (a) of this section based on evidence that
the reactivity of the human blood or blood component in the medical
device presents no significant health risk through use of the medical
device.
[66 FR 31164, June 11, 2001, as amended at 80 FR 29897, May 22, 2015]
Sec. 610.44 Use of reference panels by manufacturers of test kits.
(a) When available and appropriate to verify acceptable sensitivity
and specificity, you, a manufacturer of test kits, must use a reference
panel you obtain from FDA or from an FDA designated source to test lots
of the following products. You must test each lot of the following
products, unless FDA informs you that less frequent testing is
appropriate, based on your consistent prior production of products of
acceptable sensitivity and specificity:
(1) A test kit approved for use in testing donations of human blood
and blood components for evidence of infection due to relevant
transfusion-transmitted infections under Sec. 610.40(a); and
(2) Human immunodeficiency virus (HIV) test kit approved for use in
the diagnosis, prognosis, or monitoring of this relevant transfusion-
transmitted infection.
(b) You must not distribute a lot that is found to be not acceptable
for sensitivity and specificity under Sec. 610.44(a). FDA may approve
an exception or alternative to this requirement. Applicants must submit
such requests in writing. However, in limited circumstances, such
requests may be made orally and permission may be given orally by FDA.
Oral requests and approvals must be promptly followed by written
requests and written approvals.
[66 FR 31164, June 11, 2001, as amended at 80 FR 29897, May 22, 2015]
Sec. 610.46 Human immunodeficiency virus (HIV) ``lookback''
requirements.
(a) If you are an establishment that collects Whole Blood or blood
components, including Source Plasma and Source Leukocytes, you must
establish, maintain, and follow an appropriate system for the following
actions:
(1) Within 3 calendar days after a donor tests reactive for evidence
of human immunodeficiency virus (HIV) infection when tested under Sec.
610.40(a) and (b) or when you are made aware of other reliable test
results or information indicating evidence of HIV infection, you must
review all records required under Sec. 606.160(d) of this chapter, to
identify blood and blood components previously donated by such a donor.
For those identified blood and blood components collected:
(i) Twelve months and less before the donor's most recent
nonreactive screening tests, or
(ii) Twelve months and less before the donor's reactive direct viral
detection test, e.g., nucleic acid test or HIV p24 antigen test, and
nonreactive antibody screening test, whichever is the lesser period, you
must:
(A) Quarantine all previously collected in-date blood and blood
components identified under paragraph (a)(1) of this section if intended
for use in another person or for further manufacture into injectable
products, except
[[Page 77]]
pooled blood components intended solely for further manufacturing into
products that are manufactured using validated viral clearance
procedures; and
(B) Notify consignees to quarantine all previously collected in-date
blood and blood components identified under paragraph (a)(1) of this
section if intended for use in another person or for further manufacture
into injectable products, except pooled blood components intended solely
for further manufacturing into products that are manufactured using
validated viral clearance procedures;
(2) You must perform further testing for HIV as required under Sec.
610.40(e) of this chapter on the reactive donation.
(3) You must notify consignees of the results of further testing for
HIV, or the results of the reactive screening test if further testing
under paragraph (a)(2) of this section is not available, or if under an
investigational new drug application (IND) or investigational device
exemption (IDE), is exempted for such use by FDA, within 45 calendar
days after the donor tests reactive for evidence of HIV infection under
Sec. 610.40(a) and (b) of this chapter. Notification of consignees must
include the test results for blood and blood components identified under
paragraph (a)(1) of this section that were previously collected from
donors who later test reactive for evidence of HIV infection.
(4) You must release from quarantine, destroy, or relabel
quarantined in-date blood and blood components, consistent with the
results of the further testing performed under paragraph (a)(2) of this
section or the results of the reactive screening test if further testing
is not available, or if under an IND or IDE, exempted for such use by
FDA.
(b) If you are a consignee of Whole Blood or blood components,
including Source Plasma and Source Leukocytes, you must establish,
maintain, and follow an appropriate system for the following actions:
(1) You must quarantine all previously collected in-date blood and
blood components identified under paragraph (a)(1) of this section,
except pooled blood components intended solely for further manufacturing
into products that are manufactured using validated viral clearance
procedures, when notified by the collecting establishment.
(2) You must release from quarantine, destroy, or relabel
quarantined in-date blood and blood components consistent with the
results of the further testing performed under paragraph (a)(2) of this
section, or the results of the reactive screening test if further
testing is not available, or if under an IND or IDE, is exempted for
such use by FDA.
(3) When further testing for HIV is positive or when the screening
test is reactive and further testing is not available, or if under an
IND or IDE is exempted for such use by FDA, you must notify transfusion
recipients of previous collections of blood and blood components at
increased risk of transmitting HIV infection, or the recipient's
physician of record, of the need for recipient HIV testing and
counseling. You must notify the recipient's physician of record or a
legal representative or relative if the recipient is a minor, deceased,
adjudged incompetent by a State court, or, if the recipient is competent
but State law permits a legal representative or relative to receive
information on behalf of the recipient. You must make reasonable
attempts to perform the notification within 12 weeks after receiving the
results of further testing for evidence of HIV infection from the
collecting establishment, or after receiving the donor's reactive
screening test result for HIV if further testing is not available, or if
under an IND or IDE is exempted for such use by FDA.
(c) Actions under this section do not constitute a recall as defined
in Sec. 7.3 of this chapter.
[72 FR 48799, Aug. 24, 2007, as amended at 80 FR 29897, May 22, 2015]
Sec. 610.47 Hepatitis C virus (HCV) ``lookback'' requirements.
(a) If you are an establishment that collects Whole Blood or blood
components, including Source Plasma and Source Leukocytes, you must
establish, maintain, and follow an appropriate system for the following
actions:
(1) Within 3 calendar days after a donor tests reactive for evidence
of hepatitis C virus (HCV) infection when
[[Page 78]]
tested under Sec. 610.40(a) and (b) of this chapter or when you are
made aware of other reliable test results or information indicating
evidence of HCV infection, you must review all records required under
Sec. 606.160(d) of this chapter, to identify blood and blood components
previously donated by such a donor. For those identified blood and blood
components collected:
(i) Twelve months and less before the donor's most recent
nonreactive screening tests, or
(ii) Twelve months and less before the donor's reactive direct viral
detection test, e.g., nucleic acid test and nonreactive antibody
screening test, whichever is the lesser period, you must:
(A) Quarantine all previously collected in-date blood and blood
components identified under paragraph (a)(1) of this section if intended
for use in another person or for further manufacture into injectable
products, except pooled blood components intended solely for further
manufacturing into products that are manufactured using validated viral
clearance procedures; and
(B) Notify consignees to quarantine all previously collected in-date
blood and blood components identified under paragraph (a)(1) of this
section if intended for use in another person or for further manufacture
into injectable products, except pooled blood components intended solely
for further manufacturing into products that are manufactured using
validated viral clearance procedures;
(2) You must perform further testing for HCV as required under Sec.
610.40(e) on the reactive donation.
(3) You must notify consignees of the results of further testing for
HCV, or the results of the reactive screening test if further testing is
not available, or if under an investigational new drug application (IND)
or investigational device exemption (IDE), is exempted for such use by
FDA, within 45 calendar days after the donor tests reactive for evidence
of HCV infection under Sec. 610.40(a) and (b). Notification of
consignees must include the test results for blood and blood components
identified under paragraph (a)(1) of this section that were previously
collected from donors who later test reactive for evidence of HCV
infection.
(4) You must release from quarantine, destroy, or relabel
quarantined in-date blood and blood components consistent with the
results of the further testing performed under paragraph (a)(2) of this
section, or the results of the reactive screening test if further
testing is not available, or if under an IND or IDE, exempted for such
use by FDA.
(b) If you are a consignee of Whole Blood or blood components,
including Source Plasma or Source Leukocytes, you must establish,
maintain, and follow an appropriate system for the following actions:
(1) You must quarantine all previously collected in-date blood and
blood components identified under paragraph (a)(1) of this section,
except pooled blood components intended solely for further manufacturing
into products that are manufactured using validated viral clearance
procedures, when notified by the collecting establishment.
(2) You must release from quarantine, destroy, or relabel
quarantined in-date blood and blood components, consistent with the
results of the further testing performed under paragraph (a)(2) of this
section, or the results of the reactive screening test if further
testing is not available, or if under an IND or IDE, is exempted for
such use by FDA.
(3) When the further testing for HCV is positive or when the
screening test is reactive and further testing is not available, or if
under an IND or IDE, is exempted for such use by FDA, you must notify
transfusion recipients of previous collections of blood and blood
components at increased risk of transmitting HCV infection, or the
recipient's physician of record, of the need for recipient HCV testing
and counseling. You must notify the recipient's physician of record or a
legal representative or relative if the recipient is a minor, adjudged
incompetent by a State court, or if the recipient is competent but State
law permits a legal representative or relative to receive information on
behalf of the recipient. You must make reasonable attempts to perform
the notification within 12
[[Page 79]]
weeks after receiving the results of further testing for evidence of HCV
infection from the collecting establishment, or after receiving the
donor's reactive screening test result for HCV if further testing is not
available, or if under an IND or IDE, is exempted for such use by FDA.
(c) Actions under this section do not constitute a recall as defined
in Sec. 7.3 of this chapter.
[72 FR 48799, Aug. 24, 2007, as amended at 80 FR 29897, May 22, 2015]
Sec. 610.48 [Reserved]
Subpart F_Dating Period Limitations
Sec. 610.50 Date of manufacture for biological products.
(a) When the dating period begins. The dating period for a product
must begin on the date of manufacture as described in paragraphs (b) and
(c) of this section. The dating period for a combination of two or more
products must be no longer than the dating period of the component with
the shortest dating period.
(b) Determining the date of manufacture for biological products
other than Whole Blood and blood components. The date of manufacture for
biological products, other than Whole Blood and blood components, must
be identified in the approved biologics license application as one of
the following, whichever is applicable: The date of:
(1) Potency test or other specific test as described in a biologics
license application or supplement to the application;
(2) Removal from animals or humans;
(3) Extraction;
(4) Solution;
(5) Cessation of growth;
(6) Final sterile filtration of a bulk solution;
(7) Manufacture as described in part 660 of this chapter; or
(8) Other specific manufacturing activity described in a biologics
license application or supplement to the biologics license application.
(c) Determining the date of manufacture for Whole Blood and blood
components. (1) The date of manufacture for Whole Blood and blood
components must be one of the following, whichever is applicable:
(i) Collection date and/or time;
(ii) Irradiation date;
(iii) The time the red blood cell product was removed from frozen
storage for deglycerolization;
(iv) The time the additive or rejuvenation solution was added;
(v) The time the product was entered for washing or removing plasma
(if prepared in an open system);
(vi) As specified in the instructions for use by the blood
collection, processing, and storage system approved or cleared for such
use by FDA; or
(vii) As approved by the Director, Center for Biologics Evaluation
and Research, in a biologics license application or supplement to the
application.
(2) For licensed Whole Blood and blood components, the date of
manufacture must be identified in the approved biologics license
application or supplement to the application.
[81 FR 26691, May 4, 2016]
Sec. 610.53 Dating periods for Whole Blood and blood components.
(a) General. Dating periods for Whole Blood and blood components are
specified in the table in paragraph (b) of this section.
(b) Table of dating periods. In using the table in this paragraph,
when a product in column A is stored at the storage temperature
prescribed in column B, storage of a product must not exceed the dating
period specified in column C, unless a different dating period is
specified in the instructions for use by the blood collection,
processing and storage system approved or cleared for such use by FDA.
Container labels for each product must include the recommended storage
temperatures.
[[Page 80]]
Whole Blood and Blood Components Storage Temperatures and Dating Periods
------------------------------------------------------------------------
A B C
------------------------------------------------------------------------
Product Storage temperature Dating period
------------------------------------------------------------------------
Whole Blood
------------------------------------------------------------------------
ACD, CPD, CP2D.............. Between 1 and 6 21 days from date of
[deg]C. collection.
CPDA-1...................... do \1\.............. 35 days from date of
collection.
------------------------------------------------------------------------
Red Blood Cells
------------------------------------------------------------------------
ACD, CPD, CP2D.............. Between 1 and 6 21 days from date of
[deg]C. collection.
CPDA-1...................... do.................. 35 days from date of
collection.
Additive solutions.......... do.................. 42 days from date of
collection.
Open system................. do.................. 24 hours after
(e.g., deglycerolized, entering bag.
washed).
Deglycerolized in closed do.................. 14 days after
system with additive entering bag.
solution added.
Irradiated.................. do.................. 28 days from date of
irradiation or
original dating,
whichever is
shorter.
Frozen...................... -65 [deg]C or colder 10 years from date
of collection.
------------------------------------------------------------------------
Platelets
------------------------------------------------------------------------
Platelets................... Between 20 and 24 5 days from date of
[deg]C. collection.
Platelets................... Other temperatures As specified in the
according to instructions for
storage bag use by the blood
instructions. collection,
processing and
storage system
approved or cleared
for such use by
FDA.
------------------------------------------------------------------------
Plasma
------------------------------------------------------------------------
Fresh Frozen Plasma......... -18 [deg]C or colder 1 year from date of
collection.
Plasma Frozen Within 24 do.................. 1 year from date of
Hours After Phlebotomy. collection.
Plasma Frozen Within 24 do.................. 1 year from date of
Hours After Phlebotomy Held collection.
at Room Temperature Up To
24 Hours After Phlebotomy.
Plasma Cryoprecipitate do.................. 1 year from date of
Reduced. collection.
Plasma...................... do.................. 5 years from date of
collection.
Liquid Plasma............... Between 1 and 6 5 days from end of
[deg]C. Whole Blood dating
period.
Source Plasma (frozen -20 [deg]C or colder 10 years from date
injectable). of collection.
Source Plasma Liquid 10 [deg]C or colder. According to
(injectable). approved biologics
license
application.
Source Plasma Temperature 10 years from date
(noninjectable). appropriate for of collection.
final product.
Therapeutic Exchange Plasma. -20 [deg]C or colder 10 years from date
of collection.
------------------------------------------------------------------------
Cryoprecipitated AHF
------------------------------------------------------------------------
Cryoprecipitated AHF........ -18 [deg]C or colder 1 year from date of
collection of
source blood or
from date of
collection of
oldest source blood
in pre-storage
pool.
------------------------------------------------------------------------
Source Leukocytes
------------------------------------------------------------------------
Source Leukocytes........... Temperature In lieu of
appropriate for expiration date,
final product. the collection date
must appear on the
label.
------------------------------------------------------------------------
\1\ The abbreviation ``do.'' for ditto is used in the table to indicate
that the previous line is being repeated.
[81 FR 26691, May 4, 2016]
Subpart G_Labeling Standards
Sec. 610.60 Container label.
(a) Full label. The following items shall appear on the label
affixed to each container of a product capable of bearing a full label:
(1) The proper name of the product;
(2) The name, address, and license number of manufacturer;
(3) The lot number or other lot identification;
(4) The expiration date;
[[Page 81]]
(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;
(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]
[[Page 82]]
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.
Sec. 610.67 Bar code label requirements.
Biological products must comply with the bar code requirements at
Sec. 201.25 of this chapter. However, the bar code requirements do not
apply to devices regulated by the Center for Biologics Evaluation and
Research or to blood and blood components intended for transfusion. For
blood and blood components intended for transfusion, the requirements at
Sec. 606.121(c)(13) of this chapter apply instead.
[69 FR 9171, Feb. 26, 2004]
Sec. 610.68 Exceptions or alternatives to labeling requirements for
biological products held by the Strategic National Stockpile.
(a) The appropriate FDA Center Director may grant an exception or
alternative to any provision listed in paragraph (f) of this section and
not explicitly required by statute, for specified lots, batches, or
other units of a biological product, if the Center Director determines
that compliance with such labeling requirement could adversely affect
the safety, effectiveness, or availability of such product that is or
will be included in the Strategic National Stockpile.
(b)(1)(i) A Strategic National Stockpile official or any entity that
manufactures (including labeling, packing, relabeling, or repackaging),
distributes, or stores a biological product that is or will be included
in the Strategic National Stockpile may submit, with written concurrence
from a Strategic National Stockpile official, a written request for an
exception or alternative described in paragraph (a) of this section to
the Center Director.
(ii) The Center Director may grant an exception or alternative
described in paragraph (a) of this section on his or her own initiative.
[[Page 83]]
(2) A written request for an exception or alternative described in
paragraph (a) of this section must:
(i) Identify the specified lots, batches, or other units of the
biological product that would be subject to the exception or
alternative;
(ii) Identify the labeling provision(s) listed in paragraph (f) of
this section that are the subject of the exception or alternative
request;
(iii) Explain why compliance with such labeling provision(s) could
adversely affect the safety, effectiveness, or availability of the
specified lots, batches, or other units of the biological product that
are or will be included in the Strategic National Stockpile;
(iv) Describe any proposed safeguards or conditions that will be
implemented so that the labeling of the product includes appropriate
information necessary for the safe and effective use of the product,
given the anticipated circumstances of use of the product;
(v) Provide a draft of the proposed labeling of the specified lots,
batches, or other units of the biological product subject to the
exception or alternative; and
(vi) Provide any other information requested by the Center Director
in support of the request.
(c) The Center Director must respond in writing to all requests
under this section.
(d) A grant of an exception or alternative under this section will
include any safeguards or conditions deemed appropriate by the Center
Director so that the labeling of product subject to the exception or
alternative includes the information necessary for the safe and
effective use of the product, given the anticipated circumstances of
use.
(e) If you are a sponsor receiving a grant of a request for an
exception or alternative to the labeling requirements under this
section:
(1) You need not submit a supplement under Sec. 601.12(f)(1)
through (f)(2) of this chapter; however,
(2) You must report any grant of a request for an exception or
alternative under this section as part of your annual report under Sec.
601.12(f)(3) of this chapter.
(f) The Center Director may grant an exception or alternative under
this section to the following provisions of this chapter, to the extent
that the requirements in these provisions are not explicitly required by
statute:
(1) Sec. 610.60;
(2) Sec. 610.61(c) and (e) through (r);
(3) Sec. 610.62;
(4) Sec. 610.63;
(5) Sec. 610.64;
(6) Sec. 610.65; and
(7) Sec. 312.6.
[72 FR 73600, Dec. 28, 2007]
PART 630_REQUIREMENTS FOR BLOOD AND BLOOD COMPONENTS INTENDED FOR
TRANSFUSION OR FOR FURTHER MANUFACTURING USE--Table of Contents
Subpart A_General Provisions
630.1 Purpose and scope.
630.3 Definitions.
Subpart B_Donor Eligibility Requirements
630.5 Medical supervision.
630.10 General donor eligibility requirements.
630.15 Donor eligibility requirements specific to Whole Blood, Red Blood
Cells and Plasma collected by apheresis.
630.20 Exceptions for certain ineligible donors.
630.25 Exceptions from certain donor eligibility requirements for
infrequent plasma donors.
630.30 Donation suitability requirements.
630.35 Requalification of previously deferred donors.
Subpart C_Donor Notification
630.40 Requirements for notifying deferred donors.
Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 371; 42 U.S.C.
216, 262, 264.
Source: 66 FR 31176, June 11, 2001, unless otherwise noted.
Subpart A_General Provisions
Source: 80 FR 29898, May 22, 2015, unless otherwise noted.
Sec. 630.1 Purpose and scope.
(a) What is the purpose of subparts A, B, and C of this part? The
purpose of these subparts, together with Sec. Sec. 610.40 and 610.41 of
this chapter, is to provide
[[Page 84]]
certain minimum criteria for each donation of blood and blood
components, for:
(1) Determining the eligibility of a donor of blood and blood
components;
(2) Determining the suitability of the donation of blood and blood
components; and
(3) Notifying a donor who is deferred from donation.
(b) Who must comply with subparts A, B, and C of this part? Blood
establishments that manufacture blood and blood components, as defined
in Sec. 630.3(a) and (b), must comply with subparts A, B, and C of this
part.
Sec. 630.3 Definitions.
As used in this part and in part 610, subpart E, and part 640 of
this chapter:
(a) Blood means a product that is a fluid containing dissolved and
suspended elements which was collected from the vascular system of a
human.
(b) Blood component means a product containing a part of blood
separated by physical or mechanical means.
(c) Donor means a person who: (1) Donates blood or blood components
for transfusion or for further manufacturing use; or
(2) Presents as a potential candidate for such donation.
(d) Eligibility of a donor means the determination that the donor is
qualified to donate blood and blood components.
(e) Infrequent plasma donor means a donor who has:
(1) Not donated plasma by plasmapheresis or a co-collection of
plasma with another blood component in the preceding 4 weeks; and
(2) Not donated more than 12.0 liters of plasma (14.4 liters of
plasma for donors weighing more than 175 pounds) in the past year.
(f) Intimate contact with risk for a relevant transfusion-
transmitted infection means having engaged in an activity that could
result in the transfer of potentially infectious body fluids from one
person to another.
(g) Physician substitute means a trained and qualified person(s) who
is:
(1) A graduate of an education program for health care workers that
includes clinical training;
(2) Currently licensed or certified as a health care worker in the
jurisdiction where the collection establishment is located;
(3) Currently certified in cardiopulmonary resuscitation; and
(4) Trained and authorized under State law, and/or local law when
applicable, to perform the specified functions under the direction of
the responsible physician.
(h) Relevant transfusion-transmitted infection means:
(1) Any of the following transfusion-transmitted infections:
(i) Human immunodeficiency virus, types 1 and 2 (referred to,
collectively, as HIV);
(ii) Hepatitis B virus (referred to as HBV);
(iii) Hepatitis C virus (referred to as HCV);
(iv) Human T-lymphotropic virus, types I and II (referred to,
collectively, as HTLV);
(v) Treponema pallidum (referred to as syphilis);
(vi) West Nile virus;
(vii) Trypanosoma cruzi (referred to as Chagas disease);
(viii) Creutzfeldt-Jakob disease (referred to as CJD);
(ix) Variant Creutzfeldt-Jakob disease (referred to as vCJD); and
(x) Plasmodium species (referred to as malaria).
(2) A transfusion-transmitted infection not listed in paragraph
(h)(1) of this section when the following conditions are met:
(i) Appropriate screening measures for the transfusion-transmitted
infection have been developed and/or an appropriate screening test has
been licensed, approved, or cleared for such use by FDA and is
available; and
(ii) The disease or disease agent:
(A) May have sufficient incidence and/or prevalence to affect the
potential donor population; or
(B) May have been released accidentally or intentionally in a manner
that could place potential donors at risk of infection.
(i) Responsible physician means an individual who is:
(1) Licensed to practice medicine in the jurisdiction where the
collection establishment is located;
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(2) Adequately trained and qualified to direct and control personnel
and relevant procedures concerning the determination of donor
eligibility; collection of blood and blood components; the immunization
of a donor; and the return of red blood cells or other blood components
to the donor during collection of blood component(s) by apheresis; and
(3) Designated by the collection establishment to perform the
activities described in paragraph (i)(2) of this section.
(j) Suitability of the donation means a determination of whether the
donation is acceptable for transfusion or for further manufacturing use.
(k) Trained person means an individual, including a physician
substitute, who is authorized under State law, and/or local law when
applicable, and adequately instructed and qualified to perform the
specified functions under the direction of the responsible physician.
(l) Transfusion-transmitted infection means a disease or disease
agent:
(1) That could be fatal or life-threatening, could result in
permanent impairment of a body function or permanent damage to a body
structure, or could necessitate medical or surgical intervention to
preclude permanent impairment of body function or permanent damage to a
body structure; and
(2) For which there may be a risk of transmission by blood or blood
components, or by a blood derivative product manufactured from blood or
blood components, because the disease or disease agent is potentially
transmissible by that blood, blood component, or blood derivative
product.
Subpart B_Donor Eligibility Requirements
Source: 80 FR 29898, May 22, 2015, unless otherwise noted.
Sec. 630.5 Medical supervision.
(a) Who must determine the eligibility of a donor? The responsible
physician must determine the eligibility of a donor of blood or blood
components in accordance with this subchapter.
(b) Which activities related to the collection of blood and blood
components, other than Source Plasma and plasma collected by
plasmapheresis, may the responsible physician delegate?
(1) The responsible physician may delegate the following activities
to a physician substitute or other trained person:
(i) Determining the eligibility of a donor and documenting
assessments related to that determination, except the responsible
physician must not delegate:
(A) The examination and determination of the donor's health required
in Sec. 630.10(f)(2) for donors with blood pressure measurements
outside specified limits, or for certain more frequent donations under
Sec. 630.15(a)(1)(ii);
(B) The determination of the health of the donor required in
Sec. Sec. 630.10(f)(4), 630.20(a), and 640.21(e)(4) of this chapter.
The responsible physician may make this determination by telephonic or
other offsite consultation; or
(C) The determination of the health of the donor and the
determination that the blood or blood component collected would present
no undue medical risk to the transfusion recipient, as required in Sec.
630.20(c). The responsible physician may make these determinations by
telephonic or other offsite consultation.
(ii) Collecting blood or blood components;
(iii) Returning red blood cells to the donor during apheresis;
(iv) Obtaining the informed consent of a plateletpheresis donor as
described in Sec. 640.21(g) of this chapter; or
(v) Other activities provided that the Director, Center for
Biologics Evaluation and Research, determines that delegating the
activities would present no undue medical risk to the donor or to the
transfusion recipient, and authorizes the delegation of such activities.
(2) The responsible physician need not be present at the collection
site when activities delegated under paragraph (b)(1) of this section
are performed, provided that the responsible physician has delegated
oversight of these activities to a trained person who is adequately
trained and experienced in the performance of these activities and is
also adequately trained and experienced in the recognition of and
response to the known adverse responses
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associated with blood collection procedures.
(c) Which activities related to the collection of Source Plasma and
plasma collected by plasmapheresis may the responsible physician
delegate?
(1) Donor eligibility and blood component collection activities. (i)
The responsible physician may delegate to a physician substitute or
other trained person any of the activities described in paragraph
(c)(1)(i)(A) of this section, provided that the responsible physician or
a physician substitute is on the premises at the collection site:
(A) The activities listed in paragraphs (b)(1)(i) through (iii) and
(b)(1)(v) of this section, with respect to Source Plasma and plasma
collected by plasmapheresis. However, the responsible physician must not
delegate:
(1) The examination and determination of the donor's health required
in Sec. 630.10(f)(2) for donors with blood pressure measurements
outside specified limits, or in Sec. 630.15(b)(7) for certain donors
who have experienced red blood cell loss;
(2) The determination of the health of the donor required in
Sec. Sec. 630.10(f)(4) and 630.20(a) and (b). The responsible physician
may make this determination by telephonic or other offsite consultation;
(3) The determination of the health of the donor and the
determination that the blood component would present no undue medical
risk to the transfusion recipient, as required in Sec. 630.20(c). The
responsible physician may make this determination by telephonic or other
offsite consultation.
(4) The determination related to a donor's false-positive reaction
to a serologic test for syphilis in accordance with Sec.
640.65(b)(2)(iii) of this chapter; and
(5) The determination to permit plasmapheresis of a donor with a
reactive serological test for syphilis in accordance with Sec.
640.65(b)(2)(iv) of this chapter.
(B) The collection of Source Plasma in an approved collection
program from a donor who is otherwise determined to be ineligible.
(C) The collection of a blood sample in accordance with Sec.
640.65(b)(1)(i) of this chapter.
(ii) The responsible physician, who may or may not be present when
these activities are performed, may delegate to a physician substitute
the following activities:
(A) Approval and signature for a plasmapheresis procedure as
provided in Sec. 640.65(b)(1)(ii) of this chapter; and
(B) Review and signature for accumulated laboratory data, the
calculated values of each component, and the collection records in
accordance with Sec. 640.65(b)(2)(i) of this chapter. However, the
responsible physician must not delegate the decision to reinstate the
deferred donor in accordance with that provision.
(2) Donor immunization. The responsible physician must not delegate
activities performed in accordance with Sec. 640.66 of this chapter,
except that:
(i) The responsible physician may delegate to a physician substitute
or other trained person the administration of an immunization other than
red blood cells to a donor in an approved collection program, provided
that the responsible physician or a physician substitute is on the
premises at the collection site when the immunization is administered.
(ii) The responsible physician may delegate to a physician
substitute the administration of red blood cells to a donor in an
approved collection program, provided that the responsible physician has
approved the procedure and is on the premises at the collection site
when the red blood cells are administered.
(3) Medical history, physical examination, informed consent, and
examination before immunization. Provided that such activities are
performed under the supervision of the responsible physician, the
responsible physician may delegate to a physician substitute the
activities described in Sec. 630.15(b)(1), (2), and (5). The
responsible physician is not required to be present at the collection
site when the physician substitute performs these activities under
supervision.
(4) Infrequent plasma donors. (i) For infrequent plasma donors other
than those described in paragraph (c)(4)(ii) of this section, the
responsible physician may delegate to a trained person the activities
listed in paragraphs
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(b)(1)(i) through (iii) and (b)(1)(v) of this section and the informed
consent requirements described in Sec. 630.15(b)(2). The responsible
physician or a physician substitute need not be present at the
collection site when any of these activities are performed, provided
that the responsible physician has delegated oversight of these
activities to a trained person who is not only adequately trained and
experienced in the performance of these activities but also adequately
trained and experienced in the recognition of and response to the known
adverse responses associated with blood collection procedures. However,
the responsible physician must not delegate:
(A) The examination and determination of the donor's health required
in Sec. 630.10(f)(2) for donors with blood pressure measurements
outside specified limits, or in Sec. 630.15(b)(7) for certain donors
who have experienced red blood cell loss; or
(B) The determination of the health of the donor required in Sec.
630.10(f)(4).
(ii) For infrequent plasma donors who are otherwise ineligible or
are participating in an approved immunization program, the responsible
physician may delegate only in accordance with paragraphs (c)(1) through
(3) of this section.
(d) Must rapid emergency medical services be available?
Establishments that collect blood or blood components must establish,
maintain, and follow standard operating procedures for obtaining rapid
emergency medical services for donors when medically necessary. In
addition, establishments must assure that an individual (responsible
physician, physician substitute, or trained person) who is currently
certified in cardiopulmonary resuscitation is located on the premises
whenever collections of blood or blood components are performed.
Sec. 630.10 General donor eligibility requirements.
(a) What factors determine the eligibility of a donor? You, an
establishment that collects blood or blood components, must not collect
blood or blood components before determining that the donor is eligible
to donate or before determining that an exception to this provision
applies. To be eligible, the donor must be in good health and free from
transfusion-transmitted infections as can be determined by the processes
in this subchapter. A donor is not eligible if the donor is not in good
health or if you identify any factor(s) that may cause the donation to
adversely affect:
(1) The health of the donor; or
(2) The safety, purity, or potency of the blood or blood component.
(b) What educational material must you provide to the donor before
determining eligibility? You must provide educational material
concerning relevant transfusion-transmitted infections to donors before
donation when donor education about that relevant transfusion-
transmitted infection, such as HIV, is necessary to assure the safety,
purity, and potency of blood and blood components. The educational
material must include an explanation of the readily identifiable risk
factors closely associated with exposure to the relevant transfusion-
transmitted infection. You must present educational material in an
appropriate form, such as oral, written or multimedia, and in a manner
designed to be understood by the donor. The educational material must
instruct the donor not to donate blood and blood components when a risk
factor is present. When providing educational material to donors under
this section, you may include in those materials the information
required to be provided to donors under paragraph (g)(2)(ii)(E) of this
section.
(c) When must you determine the eligibility of a donor? You must
determine donor eligibility on the day of donation, and before
collection. Except:
(1) When a donor is donating blood components that cannot be stored
for more than 24 hours, you may determine the donor's eligibility and
collect a sample for testing required under Sec. 610.40 of this
chapter, no earlier than 2 calendar days before the day of donation,
provided that your standard operating procedures address these
activities.
(2) In the event that, upon review, you find that a donor's
responses to the donor questions before collection were incomplete,
within 24 hours of the time of collection, you may clarify a donor's
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response or obtain omitted information required under paragraph (e) of
this section, provided that your standard operating procedures address
these activities.
(d) How must you determine the eligibility of a donor? You must
determine the donor's eligibility before collection of blood or blood
components, by the following procedures:
(1) You must consult the records of deferred donors maintained under
Sec. 606.160(e)(1) and (2) of this chapter. Exception: If pre-
collection review of the record described in Sec. 606.160(e)(2) of this
chapter is not feasible because you cannot consult the cumulative record
at the collection site, you must consult the cumulative record prior to
release of any blood or blood component prepared from the collection.
(2) Assure that the interval since the donor's last donation is
appropriate;
(3) Assess the donor's medical history; and
(4) Perform a physical assessment of the donor.
(e) How do you assess the donor's medical history? Before collection
you must conduct a medical history interview as described in this
section to determine if the donor is in good health; to identify risk
factors closely associated with exposure to, or clinical evidence of a
relevant transfusion-transmitted infection; and to determine if there
are other conditions that may adversely affect the health of the donor
or the safety, purity, or potency of the blood or blood components or
any product manufactured from the blood or blood components. Your
assessment must include each of the following factors:
(1) Factors that make the donor ineligible to donate because of an
increased risk for, or evidence of, a relevant transfusion-transmitted
infection. A donor is ineligible to donate when information provided by
the donor or other reliable evidence indicates possible exposure to a
relevant transfusion-transmitted infection if that risk of exposure is
still applicable at the time of donation. Information and evidence
indicating possible exposure to a relevant transfusion-transmitted
infection include:
(i) Behaviors associated with a relevant transfusion-transmitted
infection;
(ii) Receipt of blood or blood components or other medical
treatments and procedures associated with possible exposure to a
relevant transfusion-transmitted infection;
(iii) Signs and/or symptoms of a relevant transfusion-transmitted
infection;
(iv) Institutionalization for 72 hours or more consecutively in the
past 12 months in a correctional institution;
(v) Intimate contact with risk for a relevant transfusion-
transmitted infection; and
(vi) Nonsterile percutaneous inoculation.
(2) Other factors that make the donor ineligible to donate. A donor
is ineligible to donate when donating could adversely affect the health
of the donor, or when the safety, purity, or potency of the blood or
blood component could be affected adversely. Your assessment of the
donor must include each of the following factors:
(i) Symptoms of a recent or current illness;
(ii) Certain medical treatments or medications;
(iii) Travel to, or residence in, an area endemic for a transfusion-
transmitted infection, when such screening is necessary to assure the
safety, purity, and potency of blood and blood components due to the
risks presented by donor travel and the risk of transmission of that
transfusion-transmitted infection by such donors;
(iv) Exposure or possible exposure to an accidentally or
intentionally released disease or disease agent relating to a
transfusion-transmitted infection, if you know or suspect that such a
release has occurred;
(v) Pregnancy at the time of, or within 6 weeks prior to, donation;
(vi) Whether, in the opinion of the interviewer, the donor appears
to be under the influence of any drug, alcohol or for any reason does
not appear to be providing reliable answers to medical history
questions, or if the donor says that the purpose of donating is to
obtain test results for a relevant transfusion-transmitted infection;
and
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(vii) The donor is a xenotransplantation product recipient.
(f) How do you perform a physical assessment of the donor? You must
determine on the day of donation, and before collection that the donor
is in good health based on the following, at a minimum:
(1) Temperature. The donor's oral body temperature must not exceed
37.5 [deg]C (99.5 [deg]F), or the equivalent if measured at another body
site;
(2) Blood pressure. The donor's systolic blood pressure must not
measure above 180 mm of mercury, or below 90 mm of mercury, and the
diastolic blood pressure must not measure above 100 mm of mercury or
below 50 mms of mercury. A donor with measurements outside these limits
may be permitted to donate only when the responsible physician examines
the donor and determines and documents that the health of the donor
would not be adversely affected by donating.
(3) Hemoglobin or hematocrit determination. You must determine the
donor's hemoglobin level or hematocrit value by using a sample of blood
obtained by fingerstick, venipuncture, or by a method that provides
equivalent results. Blood obtained from the earlobe is not acceptable.
(i) Allogeneic donors must have a hemoglobin level or hematocrit
value that is adequate to assure donor safety and product potency. The
following minimum standards apply.
(A) Female allogeneic donors must have a hemoglobin level that is
equal to or greater than 12.5 grams of hemoglobin per deciliter of
blood, or a hematocrit value that is equal to or greater than 38
percent. Recognizing that lower levels are also within normal limits for
female donors, you may collect blood from female allogeneic donors who
have a hemoglobin level between 12.0 and 12.5 grams per deciliter of
blood, or a hematocrit value between 36 and 38 percent, provided that
you have taken additional steps to assure that this alternative standard
is adequate to ensure that the health of the donor will not be adversely
affected due to the donation, in accordance with a procedure that has
been found acceptable for this purpose by FDA.
(B) Male allogeneic donors must have a hemoglobin level that is
equal to or greater than 13.0 grams of hemoglobin per deciliter of
blood, or a hematocrit value that is equal to or greater than 39
percent.
(ii) An autologous donor must have a hemoglobin level no less than
11.0 grams of hemoglobin per deciliter of blood, or a hematocrit value
no less than 33 percent.
(4) Pulse. The donor's pulse must be regular and between 50 and 100
beats per minute. A donor with an irregular pulse or measurements
outside these limits may be permitted to donate only when the
responsible physician determines and documents that the health of the
donor would not be adversely affected by donating.
(5) Weight. The donor must weigh a minimum of 50 kilograms (110
pounds).
(6) Skin examination. (i) The donor's phlebotomy site must be free
of infection, inflammation, and lesions; and
(ii) The donor's arms and forearms must be free of punctures and
scars indicative of injected drugs of abuse.
(g) Are there additional requirements for determining the
eligibility of the donor? You must obtain the following from the donor
on the day of donation:
(1) Proof of identity and postal address. You must obtain proof of
identity of the donor and a postal address where the donor may be
contacted for 8 weeks after donation; and
(2) Donor's acknowledgement. (i) Prior to each donation, you must
provide information to the donor addressing the elements specified in
paragraphs (g)(2)(ii)(A) through (E) of this section and obtain the
donor's acknowledgement that the donor has reviewed the information. You
must establish procedures in accordance with Sec. 606.100 of this
chapter to assure that the donor has reviewed this material, and provide
for a signature or other documented acknowledgement.
(ii) The donor acknowledgement must not include any exculpatory
language through which the donor is made to waive or appear to waive any
of the donor's legal rights. It must, at a minimum clearly address the
following:
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(A) The donor has reviewed the educational material provided under
paragraph (b) of this section regarding relevant transfusion-transmitted
infections;
(B) The donor agrees not to donate if the donation could result in a
potential risk to recipients as described in the educational material;
(C) A sample of the donor's blood will be tested for specified
relevant transfusion-transmitted infections;
(D) If the donation is determined to be not suitable under Sec.
630.30(a) or if the donor is deferred from donation under Sec. 610.41
of this chapter, the donor's record will identify the donor as
ineligible to donate and the donor will be notified under Sec. 630.40
of the basis for the deferral and the period of deferral;
(E) The donor has been provided and reviewed information regarding
the risks and hazards of the specific donation procedure; and
(F) The donor has the opportunity to ask questions and withdraw from
the donation procedure.
(h) What must you do when a donor is not eligible? You must not
collect blood or blood components from a donor found to be ineligible
prior to collection based on criteria in Sec. Sec. 630.10 or 630.15, or
deferred under Sec. 610.41 of this chapter or Sec. 630.30(b)(2),
unless this subchapter provides an exception. You must defer donors
found to be ineligible and you must notify the donor of their deferral
under Sec. 630.40.
Sec. 630.15 Donor eligibility requirements specific to Whole Blood,
Red Blood Cells and Plasma collected by apheresis.
(a) What additional donor eligibility requirements apply when you,
an establishment that collects blood or blood components, collect Whole
Blood or Red Blood Cells by apheresis?
(1) Donation frequency must be consistent with protecting the health
of the donor.
(i) For a collection resulting in a single unit of Whole Blood or
Red Blood Cells collected by apheresis, donation frequency must be no
more than once in 8 weeks, and for apheresis collections resulting in
two units of Red Blood Cells, the donor must not donate more than once
in 16 weeks.
(ii) The limitations in paragraph (a)(1)(i) of this section apply
unless the responsible physician examines the donor at the time of
donation and one of the following conditions exists:
(A) The donation is for autologous use as prescribed by the donor's
physician and the responsible physician determines and documents that
the donation may proceed; or
(B) The donation is a dedicated donation based on the intended
recipient's documented exceptional medical need and the responsible
physician determines and documents that the health of the donor would
not be adversely affected by donating.
(2) Therapeutic phlebotomy. When a donor who is determined to be
eligible under Sec. 630.10 undergoes a therapeutic phlebotomy under a
prescription to promote the donor's health, you may collect from the
donor more frequently than once in 8 weeks for collections resulting in
a single unit of Whole Blood or Red Blood Cells, or once in 16 weeks for
apheresis collections resulting in two units of Red Blood Cells,
provided that the container label conspicuously states the disease or
condition of the donor that necessitated phlebotomy. However, no
labeling for the disease or condition is required under this section if:
(i) The donor meets all eligibility criteria;
(ii) The donor undergoes a therapeutic phlebotomy as prescribed by a
licensed health care provider treating the donor for:
(A) Hereditary hemochromatosis; or
(B) Another disease or condition, when the health of a donor with
that disease or condition will not be adversely affected by donating,
and the donor's disease or condition will not adversely affect the
safety, purity, and potency of the blood and blood components, or any
products manufactured from them, and the collection is in accordance
with a procedure that has been found acceptable for this purpose by FDA;
and
(iii) You perform without charge therapeutic phlebotomies for all
individuals with that disease or condition.
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(b) What additional donor eligibility requirements apply when you,
an establishment that collects blood or blood components, collect Source
Plasma or plasma by plasmapheresis?
(1) Medical history and physical examination. Except as provided in
Sec. 630.25:
(i) The responsible physician must conduct an appropriate medical
history and physical examination of the donor on the day of the first
donation or no more than 1 week before the first donation and at
subsequent intervals of no longer than 1 year.
(ii) The responsible physician must examine the donor for medical
conditions that would place the donor at risk from plasmapheresis. If
the donor is determined to be at risk, you must defer the donor from
donating.
(iii) The responsible physician must conduct a new medical history
and physical examination of a donor who does not return for 6 months.
(2) What requirements apply to obtaining informed consent?
(i) The responsible physician must obtain the informed consent of a
plasma donor on the first day of donation or no more than 1 week before
the first donation, and at subsequent intervals of no longer than 1
year.
(ii) The responsible physician must obtain the informed consent of a
plasma donor who does not return within 6 months of the last donation.
(iii) The responsible physician must explain the risks and hazards
of the procedure to the donor. The explanation must include the risks of
a hemolytic transfusion reaction if the donor is given the cells of
another donor and the risks involved if the donor is immunized. The
explanation must be made in such a manner that the donor may give their
consent and has a clear opportunity to refuse the procedure.
(iv) If a donor is enrolled in a new program, such as an
immunization or special collection program, the responsible physician
must again obtain an informed consent specific for that program.
(3) Weight. You must weigh a donor at each donation.
(4) Total protein level. You must determine the donor's total plasma
protein level before each plasmapheresis procedure. The donor must have
a total plasma protein level of no less than 6.0 grams per deciliter and
no more than 9.0 grams per deciliter in a plasma sample or a serum
sample.
(5) Examination before immunization. (i) No more than 1 week before
the first immunization injection for the production of high-titer
antibody plasma, the responsible physician must conduct an appropriate
medical history and physical examination, as described in paragraph
(b)(1) of this section, in addition to assessing the general donor
eligibility requirements under Sec. 630.10. It is not necessary to
repeat the medical history and physical examination requirement in
paragraph (b)(1) of this section, if the immunized donor's plasma is
collected within 3 weeks of the first immunization injection.
(ii) You are not required to repeat the medical history and physical
examination required under paragraph (b)(1) of this section for a donor
currently participating in a plasmapheresis collection program and
determined to be eligible under Sec. 630.10 unless the medical history
and physical examination are due under paragraph (b)(1)(i) or
(b)(1)(iii) of this section.
(6) Deferral of donors due to red blood cell loss. (i) You must
defer a donor from donating plasma by plasmapheresis for 8 weeks if the
donor has donated a unit of Whole Blood, or a single unit of Red Blood
Cells by apheresis. However, you may collect plasma by plasmapheresis
after a donation of Whole Blood or a single unit of Red Blood Cells by
apheresis after at least 2 calendar days have passed, provided that the
extracorporeal volume of the apheresis device is less than 100
milliliters.
(ii) You must defer a donor from donating plasma by plasmapheresis
for a period of 16 weeks if the donor donates two units of Red Blood
Cells during a single apheresis procedure;
(iii) You must defer a donor for 8 weeks or more if the cumulative
red blood cell loss in any 8 week period could adversely affect donor
health.
(7) Exceptions to deferral due to red blood cell loss. You are not
required to defer a Source Plasma donor from donating plasma by
plasmapheresis due
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to red blood cell loss if the following conditions are met:
(i) The responsible physician examines the donor at the time of the
current donation and determines and documents that the donor is in good
health and the donor's health permits the plasmapheresis;
(ii) The donor's plasma possesses a property, such as an antibody,
antigen, or protein deficiency that is transitory, of a highly unusual
or infrequent specificity, or of an unusually high titer;
(iii) The special characteristics of the donor's plasma and the need
for plasmapheresis of the donor under Sec. 630.20(b) are documented at
your establishment; and
(iv) The extracorporeal volume of the apheresis device is less than
100 milliliters.
(8) Malaria. Freedom from risk of malaria is not required for a
donor of Source Plasma.
(9) You must comply with other requirements for collection of plasma
in part 640 of this chapter and this part including restrictions on
frequency of collection as specified in Sec. Sec. 640.32 and 640.65 of
this chapter.
Sec. 630.20 Exceptions for certain ineligible donors.
After assessing donor eligibility under Sec. Sec. 630.10 and
630.15, an establishment may collect blood and blood components from a
donor who is determined to be not eligible to donate under any provision
of Sec. 630.10(e) and (f) or Sec. 630.15(a) if one of the following
sets of conditions are met:
(a) The donation is for autologous use only as prescribed by the
donor's physician, the donor has a hemoglobin level no less than 11.0
grams of hemoglobin per deciliter of blood or a hematocrit value no less
than 33 percent, and the responsible physician determines and documents
that the donor's health permits the collection procedure; or
(b) The donation is collected under a Source Plasma collection
program which has received prior written approval from the Director,
Center for Biologics Evaluation and Research, to collect plasma for
further manufacturing use into in vitro products for which there are no
alternative sources, the donor meets the criteria in Sec. 630.10(f)(1)
through (6), and the responsible physician determines and documents for
each donation that the donor's health permits the collection procedure,
and the collection takes place under the medical oversight specified in
the approved plasmapheresis program.
(c) The donation is restricted for use solely by a specific
transfusion recipient based on documented exceptional medical need, and
the responsible physician determines and documents that the donor's
health permits the collection procedure, and that the donation presents
no undue medical risk to the transfusion recipient.
Sec. 630.25 Exceptions from certain donor eligibility requirements for
infrequent plasma donors.
For an infrequent plasma donor who is not participating in an
immunization program, establishments are not required to:
(a) Perform a medical history and physical examination of the donor
under Sec. 630.15(b)(1);
(b) Perform a test for total protein under Sec. 630.15(b)(4);
(c) Determine the total plasma or serum protein and immunoglobulin
composition under Sec. 640.65(b)(1)(i) of this chapter; or
(d) Review the data and records as required in Sec. 640.65(b)(2)(i)
of this chapter.
Sec. 630.30 Donation suitability requirements.
(a) When is a donation suitable? A donation is suitable when:
(1) The donor is not currently deferred from donation as determined
by review of the records of deferred donors required under Sec.
606.160(e) of this chapter;
(2) The results in accordance with Sec. Sec. 630.10 through 630.25
indicate that the donor is in good health and procedures were followed
to ensure that the donation would not adversely affect the health of the
donor;
(3) The results in accordance with Sec. 630.10(e) indicate that the
donor is free from risk factors for, or evidence of, relevant
transfusion-transmitted infections and other factors that make the donor
ineligible to donate;
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(4) The donor's blood is tested in accordance with Sec. 610.40 of
this chapter, and is negative or nonreactive, unless an exception
applies under Sec. 610.40(h) of this chapter; and
(5) The donation meets other requirements in this subchapter.
(b) What must you do when the donation is not suitable? (1) You must
not release the donation for transfusion or further manufacturing use
unless it is an autologous donation, or an exception is provided in this
chapter.
(2) You must defer the donor when a donation is determined to be
unsuitable based on the criteria in paragraphs (a)(1) through (4) of
this section.
(3) You must defer the donor of bacterially contaminated platelets
when the contaminating organism is identified in accordance with Sec.
606.145(d) of this chapter as likely to be associated with a bacterial
infection that is endogenous to the bloodstream of the donor.
(4) You must notify the deferred donor in accordance with the
notification requirements in Sec. 630.40.
Sec. 630.35 Requalification of previously deferred donors.
Establishments may determine a deferred donor to be eligible as a
donor of blood and blood components if, at the time of the current
collection, the donor meets the eligibility criteria in this part,
except for the record of the previous deferral, and you determine that
the criteria that were the basis for the previous deferral are no longer
applicable. Criteria for the previous deferral are no longer applicable
if the following conditions are met:
(a) The previous deferral was for a defined period of time and that
time period has passed, or the deferral was otherwise temporary, such as
a deferral based on eligibility criteria described in Sec. Sec.
630.10(f)(1) through (5) or 630.15(b)(4); or
(b) For a donor deferred for reasons other than under Sec.
610.41(a) of this chapter, you determine that the donor has met criteria
for requalification by a method or process found acceptable for such
purpose by FDA.
Subpart C_Donor Notification
Source: 80 FR 29898, May 22, 2015, unless otherwise noted.
Sec. 630.40 Requirements for notifying deferred donors.
(a) Notification of donors. You, an establishment that collects
blood or blood components, must make reasonable attempts to notify any
donor, including an autologous donor, who has been deferred based on the
results of tests for evidence of infection with a relevant transfusion-
transmitted infection(s) as required by Sec. 610.41(a) of this chapter;
any donor who has been deferred as required under Sec. 630.30(b)(3)
because their donated platelets have been determined under Sec.
606.145(d) of this chapter to be contaminated with an organism that is
identified as likely to be associated with a bacterial infection that is
endogenous to the bloodstream of the donor; and any donor who has been
determined not to be eligible as a donor based on eligibility criteria
under Sec. Sec. 630.10 and 630.15. You must attempt to obtain the
results of further testing required under Sec. 610.40(e) of this
chapter prior to notifying a donor of the deferral. If notification
occurs prior to receipt of such results, you must also notify a deferred
donor of the results of the further testing. You must notify a donor as
described in paragraph (b) of this section.
(b) Content of notification. You must provide the following
information to a donor deferred or determined not to be eligible as a
donor as described in paragraph (a) of this section:
(1) That the donor is deferred or determined not to be eligible for
donation and the reason for that decision;
(2) Where appropriate, the types of donation of blood or blood
components that the donor should not donate in the future;
(3) Where applicable, the results of tests for evidence of infection
due to relevant transfusion-transmitted infection(s) that were a basis
for deferral under Sec. 610.41 of this chapter, including results of
further testing as required in Sec. 610.40(e) of this chapter; and,
(4) Where appropriate, information concerning medical followup and
counseling.
[[Page 94]]
(c) Time period for notification. You must make reasonable attempts
to notify the donor within 8 weeks after determining that the donor is
deferred or determined not to be eligible for donation as described in
paragraph (a) of this section. You must document that you have
successfully notified the donor or when you are unsuccessful that you
have made reasonable attempts to notify the donor.
(d) Autologous donors. (1) You also must provide the following
information to the referring physician of an autologous donor who is
deferred based on the results of tests for evidence of infection with a
relevant transfusion-transmitted infection(s) or whose platelets
indicate evidence of a bacterial infection that is endogenous to the
bloodstream of the donor as described in paragraph (a) of this section:
(i) Information that the autologous donor is deferred based on the
results of tests for evidence of infection due to relevant transfusion-
transmitted infection(s), as required under Sec. 610.41 of this
chapter, and the reason for that decision;
(ii) Where appropriate, the types of donation of blood or blood
components that the autologous donor should not donate in the future;
and
(iii) The results of tests for evidence of infection due to relevant
transfusion-transmitted infection(s), that were a basis for deferral
under Sec. 610.41 of this chapter, including results of further testing
as required in Sec. 610.40(e) of this chapter.
(2) You must make reasonable attempts to notify the autologous
donor's referring physician within 8 weeks after determining that the
autologous donor is deferred as described in paragraph (a) of this
section. You must document that you have successfully notified the
autologous donor's referring physician or when you are unsuccessful that
you have made reasonable attempts to notify the physician.
[66 FR 31176, June 11, 2001. Redesignated and amended at 80 FR 29898,
May 22, 2015]
PART 640_ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS-
-Table of Contents
Subpart A_Whole Blood
Sec.
640.1 Whole Blood.
640.2 General requirements.
640.4 Collection of the blood.
640.5 Testing the blood.
640.6 Modifications of Whole Blood.
Subpart B_Red Blood Cells
640.10 Red Blood Cells.
640.11 General requirements.
640.12 Eligibility of donor.
640.13 Collection of the blood.
640.14 Testing the blood.
640.15 Segments for testing.
640.16 Processing.
640.17 Modifications for specific products.
Subpart C_Platelets
640.20 Platelets.
640.21 Eligibility of donors.
640.22 Collection of source material.
640.23 Testing the blood.
640.24 Processing.
640.25 General requirements.
Subpart D_Plasma
640.30 Plasma.
640.31 Eligibility of donors.
640.32 Collection of source material.
640.33 Testing the blood.
640.34 Processing.
Subpart E [Reserved]
Subpart F_Cryoprecipitate
640.50 Cryoprecipitate AHF.
640.51 Eligibility of donors.
640.52 Collection of source material.
640.53 Testing the blood.
640.54 Processing.
640.55 U.S. Standard preparation.
640.56 Quality control test for potency.
Subpart G_Source Plasma
640.60 Source Plasma.
640.64 Collection of blood for Source Plasma.
640.65 Plasmapheresis.
640.66 Immunization of donors.
640.67 Laboratory tests.
640.68 Processing.
640.69 General requirements.
640.71 Manufacturing responsibility.
640.72 Records.
640.73 Reporting of fatal donor reactions.
640.74 Modification of Source Plasma.
[[Page 95]]
640.76 Products stored or shipped at unacceptable temperatures.
Subpart H_Albumin (Human)
640.80 Albumin (Human).
640.81 Processing.
640.82 Tests on final product.
640.83 General requirements.
640.84 Labeling.
Subpart I_Plasma Protein Fraction (Human)
640.90 Plasma Protein Fraction (Human).
640.91 Processing.
640.92 Tests on final product.
640.93 General requirements.
640.94 Labeling.
Subpart J_Immune Globulin (Human)
640.100 Immune Globulin (Human).
640.101 General requirements.
640.102 Manufacture of Immune Globulin (Human).
640.103 The final product.
640.104 Potency.
Subpart K [Reserved]
Subpart L_Alternative Procedures
640.120 Alternative procedures.
Subpart M_Definitions and Medical Supervision
640.125 Definitions.
640.130 Medical supervision.
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 U.S.C.
216, 262, 263, 263a, 264.
Source: 38 FR 32089, Nov. 20, 1973, unless otherwise noted.
Cross References: For U.S. Customs Service regulations relating to
viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal
Service regulations relating to the admissibility to the United States
mails see parts 124 and 125 of the Domestic Mail Manual, that is
incorporated by reference in 39 CFR part 111.
Subpart A_Whole Blood
Sec. 640.1 Whole Blood.
The proper name of this product shall be Whole Blood. Whole Blood is
defined as blood collected from human donors for transfusion to human
recipients.
[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985]
Sec. 640.2 General requirements.
(a) Manufacturing responsibility. All manufacturing of Whole Blood,
including donor examination, blood collection, laboratory tests,
labeling, storage and issue, shall be done under the supervision and
control of the same licensed establishment except that the Director,
Center for Biologics Evaluation and Research, may approve arrangements,
upon joint request of two or more licensed establishments, which he
finds are of such a nature as to assure compliance otherwise with the
provisions of this subchapter.
(b) Blood container. The blood container shall not be entered prior
to issue for any purpose except for blood collection or when the method
of processing requires use of a different container. The container shall
be uncolored and transparent to permit visual inspection of the contents
and any closure shall be such as will maintain a hermetic seal and
prevent contamination of the contents. The container material shall not
interact with the contents under the customary conditions of storage and
use, in such a manner as to have an adverse effect upon the safety,
purity, or potency of the blood.
(c) Reissue of blood. Blood that has been removed from storage
controlled by a licensed establishment shall not be reissued by a
licensed establishment unless the following conditions are observed:
(1) The container has a tamper-proof seal when originally issued and
this seal remains unbroken;
(2) A segment is properly attached and has not been removed, except
that blood lacking a properly attached segment may be reissued in an
emergency provided it is accompanied by instructions for sampling and
for use within 6 hours after entering the container for sampling;
(3) The blood has been stored continuously at 1 to 6 [deg]C and
shipped between 1 and 10 [deg]C;
[[Page 96]]
(4) The blood is held for observation until a significant inspection
consistent with the requirements of Sec. 640.5(e) can be made.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 4015, Jan. 28, 1976; 42
FR 59878, Nov. 22, 1977; 43 FR 34460, Aug. 4, 1978; 49 FR 15187, Apr.
18, 1984; 49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 1985; 53 FR
116, Jan. 5, 1988; 55 FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6,
1998; 64 FR 45371, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR
31165, June 11, 2001; 66 FR 40889, Aug. 6, 2001; 67 FR 9587, Mar. 4,
2002]
Sec. 640.4 Collection of the blood.
(a) [Reserved]
(b) The donor center. The pertinent requirements of Sec. Sec.
600.10 and 600.11 of this chapter shall apply at both the blood
establishment and at any other place where the bleeding is performed.
(c) Blood containers. Blood containers and donor sets shall be
pyrogen-free, sterile and identified by lot number. The amount of
anticoagulant required for the quantity of blood to be collected shall
be in the blood container when it is sterilized. In addition, all
container and donor set surfaces that come in contact with blood used in
the processing of Heparin Whole Blood shall be water repellent.
(d) The anticoagulant solution. The anticoagulant solution shall be
sterile and pyrogen-free. Anticoagulant solutions shall be compounded
and used according to a formula approved by the Director, Center for
Biologics Evaluation and Research.
(e) Donor identification. Each unit of blood shall be so marked or
identified by number or other symbol as to relate it to the individual
donor whose identity shall be established to the extent necessary for
compliance with Sec. 630.10 of this chapter.
(f) Prevention of contamination of the blood. The skin of the donor
at the site of phlebotomy shall be prepared thoroughly and carefully by
a method that gives maximum assurance of a sterile container of blood.
The blood shall be collected by aseptic methods in a sterile system
which may be closed or may be vented if the vent protects the blood
against contamination.
(g) Samples and segments for laboratory tests. Samples and segments
for laboratory tests shall meet the following standards:
(1) One or more segments shall be provided with each unit of blood
when issued or reissued except as provided in Sec. 640.2(c)(2) and all
segments shall be from the donor who is the source of the unit of blood.
(2) All samples for laboratory tests performed by the manufacturer
and all segments accompanying a unit of blood shall be collected at the
time of filling the original blood container.
(3) All containers for all samples shall bear the donor's
identification before collecting the samples.
(4) All segments accompanying a unit of blood shall be attached to
the whole blood container before blood collection, in a tamperproof
manner that will conspicuously indicate removal and reattachment.
(5) Segments for compatibility testing shall contain blood mixed
with the appropriate anticoagulant.
(h) Storage. Whole Blood must be placed in storage at a temperature
between 1 and 6 [deg]C immediately after collection unless the blood is
to be further processed into another component or the blood must be
transported from the donor center to the processing laboratory. If
transported, the blood must be placed in temporary storage having
sufficient refrigeration capacity to cool the blood continuously toward
a temperature range between 1 and 10 [deg]C until arrival at the
processing laboratory. At the processing laboratory, the blood must be
stored at a temperature between 1 and 6 [deg]C. Blood from which a
component is to be prepared must be held in an environment maintained at
a temperature range specified for that component in the directions for
use for the blood collecting, processing, and storage system approved
for such use by the Director, CBER.
[38 FR 32089, Nov. 20, 1973, as amended at 42 FR 59878, Nov. 22, 1977;
43 FR 34460, Aug. 4, 1978; 49 FR 23834, June 8, 1984; 50 FR 4138, Jan.
29, 1985; 55 FR 11013, Mar. 26, 1990; 64 FR 45372, Aug. 19, 1999; 66 FR
1836, Jan. 10, 2001; 66 FR 40889, Aug. 6, 2001; 72 FR 45887, Aug. 16,
2007; 73 FR 7464, Feb. 8, 2008; 80 FR 29904, May 22, 2015]
Sec. 640.5 Testing the blood.
All laboratory tests shall be made on a specimen of blood taken from
the
[[Page 97]]
donor, and these tests shall include the following:
(a) [Reserved]
(b) Determination of blood group. Each container of Whole Blood
shall be classified as to ABO blood group. At least two blood group
tests shall be made and the unit shall not be issued until grouping
tests by different methods or with different lots of antiserums are in
agreement. Only those Anti-A and Anti-B Blood Grouping Reagents licensed
under, or that otherwise meet the requirements of, the regulations of
this subchapter shall be used, and the technique used shall be that for
which the serum is specifically designed to be effective.
(c) Determination of the Rh factors. Each container of Whole Blood
shall be classified as to Rh type on the basis of tests done on the
sample. The label shall indicate the extent of typing and the results of
all tests performed. If the test, using Anti-D Blood Grouping Reagent,
is positive, the container may be labeled ``Rh Positive.'' If the test
is negative, the results shall be confirmed by further testing which
shall include tests for the ``weak D (formerly D\u\).'' Blood may be
labeled ``Rh Negative'' if further testing is negative. Units testing
positive after additional more specific testing shall be labeled as ``Rh
Positive.'' Only Anti-Rh Blood Grouping Reagents licensed under, or that
otherwise meet the requirements of, this subchapter shall be used, and
the technique used shall be that for which the reagent is specifically
designed to be effective.
(d) Sterility test. Whole Blood intended for transfusion shall not
be tested for sterility by a method that entails entering the final
container before the blood is used for transfusion.
(e) Inspection. Whole Blood shall be inspected visually during
storage and immediately prior to issue. If the color or physical
appearance is abnormal or there is any indication or suspicion of
microbial contamination the unit of Whole Blood shall not be issued for
transfusion.
(f) Test for relevant transfusion-transmitted infections. Whole
Blood shall be tested for evidence of infection due to relevant
transfusion-transmitted infections as required under Sec. 610.40 of
this chapter.
[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985; 53
FR 117, Jan. 5, 1988; 53 FR 12764, Apr. 19, 1988; 64 FR 45372, Aug. 19,
1999; 66 FR 1836, Jan. 10, 2001; 66 FR 31165, June 11, 2001; 66 FR
40889, Aug. 6, 2001; 80 FR 29904, May 22, 2015]
Sec. 640.6 Modifications of Whole Blood.
Upon approval by the Director, Center for Biologics Evaluation and
Research, of a supplement to the biologics license application for Whole
Blood a manufacturer may prepare Whole Blood from which the
antihemophilic factor has been removed, provided the Whole Blood meets
the applicable requirements of this subchapter and the following
conditions are met:
(a) The antihemophilic factor shall be removed in accordance with
paragraphs (a), (b), and (c) of Sec. 640.52.
(b) Although the closed system between the red blood cells and
plasma shall be maintained, the red blood cells shall be maintained
between 1 and 6 [deg]C at all times, including that time when the plasma
is being frozen for removal of the antihemophilic factor.
[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50
FR 4138, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept.
28, 1994; 64 FR 45372, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999]
Subpart B_Red Blood Cells
Sec. 640.10 Red Blood Cells.
The proper name of this product shall be Red Blood Cells. The
product is defined as red blood cells remaining after separating plasma
from human blood.
[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985]
Sec. 640.11 General requirements.
(a) Storage. Immediately after processing, the Red Blood Cells shall
be placed in storage and maintained at a temperature between 1 and 6
[deg]C.
(b) Inspection. The product shall be inspected immediately after
separation of the plasma, periodically during storage, and at the time
of issue. The product shall not be issued if there is any
[[Page 98]]
abnormality in color or physical appearance or if there is any
indication of microbial contamination.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 18292, May 3, 1976; 42
FR 59878, Nov. 11, 1977; 50 FR 4139, Jan. 29, 1985]
Sec. 640.12 Eligibility of donor.
Establishments must determine the eligibility of donors of the
source blood for Red Blood Cells in accordance with Sec. Sec. 630.10
and 630.15 of this chapter.
[80 FR 29904, May 22, 2015]
Sec. 640.13 Collection of the blood.
(a) The source blood shall be collected as prescribed in Sec.
640.4.
(b) Source blood may also be derived from Whole Blood manufactured
in accordance with applicable provisions of this subchapter.
[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4139, Jan. 29, 1985; 64
FR 45372, Aug. 19, 1999]
Sec. 640.14 Testing the blood.
Blood from which Red Blood Cells are prepared shall be tested as
prescribed in Sec. 610.40 of this chapter and Sec. 640.5 (b) and (c).
[53 FR 117, Jan. 5, 1988, as amended at 66 FR 31165, June 11, 2001; 80
FR 29904, May 22, 2015]
Sec. 640.15 Segments for testing.
Segments collected in integral tubing shall meet the following
standards:
(a) One or more segments shall be provided with each unit of Whole
Blood or Red Blood Cells when issued or reissued.
(b) Before they are filled, all segments shall be marked or
identified so as to relate them to the donor of that unit of red cells.
(c) All segments accompanying a unit of Red Blood Cells shall be
filled at the time the blood is collected or at the time the final
product is prepared.
[66 FR 40890, Aug. 6, 2001]
Sec. 640.16 Processing.
(a) Separation. Within the timeframe specified in the directions for
use for the blood collecting, processing, and storage system used, Red
Blood Cells may be prepared either by centrifugation, done in a manner
that will not tend to increase the temperature of the blood, or by
normal undisturbed sedimentation. A portion of the plasma sufficient to
insure optimal cell preservation shall be left with the red cells except
when a cryoprotective substance or additive solution is added for
prolonged storage.
(b) Sterile system. All surfaces that come in contact with the red
cells shall be sterile and pyrogen-free.
(c) Final containers. Final containers used for Red Blood Cells
shall be the original blood containers unless the method of processing
requires a different container. The final container shall meet the
requirements for blood containers prescribed in Sec. 640.2(c). At the
time of filing, if a different container is used, it shall be marked or
identified by number or other symbol so as to relate it to the donor of
that unit of red cells.
[38 FR 32089, Nov. 20, 1973, as amended at 43 FR 34460, Aug. 4, 1978; 50
FR 4139, Jan. 29, 1985; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10,
2001; 66 FR 40890, Aug. 6, 2001]
Sec. 640.17 Modifications for specific products.
Red Blood Cells Frozen: A cryophylactic substance may be added to
the Red Blood Cells for extended manufacturers' storage at -65 [deg]C or
colder, provided the manufacturer submits data considered by the
Director, Center for Biologics Evaluation and Research, as adequately
demonstrating through in vivo cell survival and other appropriate tests
that the addition of the substance, the materials used and the
processing methods results in a final product that meets the required
standards of safety, purity, and potency for Red Blood Cells, and that
the frozen product will maintain those properties for the prescribed
dating period. Section 640.11 (a) and (b) do not apply while a
cryophylactic substance is present.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 18292, May 3, 1976; 49
FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26,
1990; 63 FR 16685, Apr. 6, 1998]
[[Page 99]]
Subpart C_Platelets
Sec. 640.20 Platelets.
(a) Proper name and definition. The proper name of this product
shall be Platelets. The product is defined as platelets collected from
one unit of blood and resuspended in an appropriate volume of original
plasma, as prescribed in Sec. 640.24(d).
(b) Source. The source material for Platelets is plasma which may be
obtained by whole blood collection or by plateletpheresis.
[40 FR 4304, Jan. 29, 1975, as amended at 47 FR 49021, Oct. 29, 1982; 50
FR 4139, Jan. 29, 1985; 72 FR 45887, Aug. 16, 2007]
Sec. 640.21 Eligibility of donors.
(a) Establishments must determine the eligibility of donors of
platelets derived from Whole Blood and donors of platelets collected by
plateletpheresis in accordance with Sec. Sec. 630.10 and 630.15 of this
chapter, except as provided in this section.
(b) A plateletpheresis donor must not serve as the source of
platelets for transfusion if the donor has recently ingested a drug that
adversely affects platelet function.
(c) A Whole Blood donor must not serve as the source of platelets
for transfusion if the donor has recently ingested a drug that adversely
affects platelet function unless the unit is labeled to identify the
ingested drug that adversely affects platelet function.
(d) If you are collecting platelets by plateletpheresis, you must
assess and monitor the donor's platelet count.
(1) You must take adequate and appropriate steps to assure that the
donor's platelet count is at least 150,000 platelets per microliter (/
[micro]L) before plateletpheresis begins. Exception: If you do not have
records of a donor's platelet count from prior donations and you are not
able to assess the donor's platelet count either prior to or immediately
following the initiation of the collection procedure, you may collect
platelets by plateletpheresis, but you must not collect 9.0 x 10\11\ or
more platelets from that donor.
(2) You must defer from platelet donation a donor whose pre-donation
platelet count is less than 150,000 platelets/[micro]L until a
subsequent pre-donation platelet count indicates that the donor's
platelet count is at least 150,000 platelets/[micro]L; and
(3) You must take appropriate steps to assure that the donor's
intended post-donation platelet count will be no less than 100,000
platelets/[micro]L.
(e) Frequency of plateletpheresis collection. (1) The donor may
donate no more than a total of 24 plateletpheresis collections during a
12-month rolling period.
(2) When you collect fewer than 6 x 10\11\ platelets, you must wait
at least 2 calendar days before any subsequent plateletpheresis
collection. You must not attempt to collect more than 2 collections
within a 7 calendar day period.
(3) When you collect 6 x 10\11\ or more platelets, you must wait at
least 7 calendar days before any subsequent plateletpheresis collection.
(4) Exception. For a period not to exceed 30 calendar days, a donor
may serve as a dedicated plateletpheresis donor for a single recipient,
in accordance with Sec. 610.40(c)(1) of this chapter, as often as is
medically necessary, provided that the donor is in good health, as
determined and documented by the responsible physician, and the donor's
platelet count is at least 150,000 platelets/[micro]L, measured at the
conclusion of the previous donation or before initiating
plateletpheresis for the current donation.
(f) Deferral of plateletpheresis donors due to red blood cell loss.
(1) You must defer a donor from donating platelets by plateletpheresis
or a co-collection of platelets and plasma by apheresis for 8 weeks if
the donor has donated a unit of Whole Blood, or a single unit of Red
Blood Cells by apheresis unless at least 2 calendar days have passed and
the extracorporeal volume of the apheresis device is less than 100
milliliters.
(2) You must defer a donor from donating platelets for a period of
16 weeks if the donor donates two units of Red Blood Cells during a
single apheresis procedure.
(3) You must defer a donor for 8 weeks or more if the cumulative red
blood cell loss in any 8 week period could adversely affect donor
health.
(g) The responsible physician must obtain the informed consent of a
plateletpheresis donor on the first day
[[Page 100]]
of donation, and at subsequent intervals no longer than 1 year.
(1) The responsible physician must explain the risks and hazards of
the procedure to the donor; and
(2) The explanation must be made in such a manner that the donor may
give consent, and has a clear opportunity to refuse the procedure.
[80 FR 29904, May 22, 2015]
Sec. 640.22 Collection of source material.
(a) Whole blood used as the source of Platelets shall be collected
as prescribed in Sec. 640.4.
(b) [Reserved]
(c) If plateletpheresis is used, the procedure for collection must
be as prescribed in Sec. Sec. 640.21, 640.64 (except paragraph (c)),
and 640.65, or as described in an approved biologics license application
(BLA) or an approved supplement to a BLA.
(d) The phlebotomy shall be performed by a single uninterrupted
venipuncture with minimal damage to, and minimal manipulation of, the
donor's tissue.
[40 FR 4304, Jan. 29, 1975, as amended at 45 FR 27927, Apr. 25, 1980; 49
FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26,
1990; 59 FR 49351, Sept. 28, 1994; 64 FR 45372, Aug. 19, 1999; 64 FR
56453, Oct. 20, 1999; 72 FR 45887, Aug. 16, 2007; 80 FR 29904, May 22,
2015]
Sec. 640.23 Testing the blood.
(a) Blood from which plasma is separated for the preparation of
Platelets shall be tested as prescribed in Sec. 610.40 of this chapter
and Sec. 640.5 (b) and (c).
(b) The tests shall be performed on a sample of blood collected at
the time of collecting the source blood, and such sample container shall
be labeled with the donor's number before the container is filled.
[40 FR 4304, Jan. 29, 1975, as amended at 50 FR 4139, Jan. 29, 1985; 53
FR 117, Jan. 5, 1988; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10,
2001; 66 FR 31165, June 11, 2001; 80 FR 29904, May 22, 2015]
Sec. 640.24 Processing.
(a) Separation of plasma and platelets and resuspension of the
platelets must be in a closed system. Platelets must not be pooled
during processing unless the platelets are pooled as specified in the
directions for use for the blood collecting, processing, and storage
system approved for such use by the Director, Center for Biologics
Evaluation and Research.
(b) Immediately after collection, the whole blood or plasma shall be
held in storage between 20 and 24 [deg]C unless it must be transported
from the collection center to the processing laboratory. During such
transport, all reasonable methods shall be used to maintain the
temperature as close as possible to a range between 20 and 24 [deg]C
until it arrives at the processing laboratory where it shall be held
between 20 and 24 [deg]C until the platelets are separated. The platelet
concentrate shall be separated within 4 hours or within the timeframe
specified in the directions for use for the blood collecting,
processing, and storage system.
(c) The time and speed of centrifugation must have been demonstrated
to produce an unclumped product, without visible hemolysis, that yields
a count of not less than 5.5 x 10\10\ platelets per unit in at least 75
percent of the units tested.
(d) The volume of original plasma used for resuspension of the
platelets shall be determined by the maintenance of a pH of not less
than 6.2 during the storage period. The pH shall be measured on a sample
of platelets which has been stored for the maximum dating period at the
selected storage temperature. One of the following storage temperatures
shall be used continuously:
(1) 20 to 24 [deg]C.
(2) 1 to 6 [deg]C.
(e) Final containers used for Platelets shall be colorless and
transparent to permit visual inspection of the contents; any closure
shall maintain a hermetic seal and prevent contamination of the
contents. The container material shall not interact with the contents,
under the customary conditions of storage and use, in such a manner as
to have an adverse effect upon the safety, purity, potency, or efficacy
of the product. At the time of filling, the final container shall be
marked or identified
[[Page 101]]
by number so as to relate it to the donor.
[40 FR 4304, Jan. 29, 1975, as amended at 42 FR 10983, Feb. 25, 1977; 47
FR 49021, Oct. 29, 1982; 50 FR 4139, Jan. 29, 1985; 63 FR 16685, Apr. 6,
1998; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR
40890, Aug. 6, 2001; 72 FR 45887, Aug. 16, 2007; 73 FR 7464, Feb. 8,
2008]
Sec. 640.25 General requirements.
(a) Storage. Immediately after resuspension, Platelets shall be
placed in storage at the selected temperature range. If stored at 20 to
24 [deg]C, a continuous gentle agitation of the platelet concentrate
shall be maintained throughout the storage period. Agitation is optional
if stored at a temperature between 1 and 6 [deg]C.
(b) Quality control testing. Each month four units prepared from
different donors shall be tested at the end of the storage period as
follows:
(1) Platelet count.
(2) pH of not less than 6.2 measured at the storage temperature of
the unit.
(3) Measurement of actual plasma volume.
(4) If the results of the quality control testing indicate that the
product does not meet the prescribed requirements, immediate corrective
action shall be taken and a record maintained of such action.
(c) Manufacturing responsibility. All manufacturing of Platelets
shall be performed at the same licensed establishment, except that the
quality control testing under paragraph (b) of this section may be
performed by a clinical laboratory which meets the standards of the
Clinical Laboratories Improvement Amendments of 1988 (CLIA) (42 U.S.C.
263a) and is qualified to perform platelet counts. Such arrangements
must be approved by the Director, Center for Biologics Evaluation and
Research, Food and Drug Administration. Such testing shall not be
considered as divided manufacturing, as described in Sec. 610.63 of
this chapter, provided the following conditions are met:
(1) The results of each test are received within 10 days of the
preparation of the platelet concentrate, and are maintained by the
establishment licensed for Platelets so that they may be reviewed by an
authorized representative of the Food and Drug Administration.
(2) The licensed Platelets manufacturer has obtained a written
agreement that the testing laboratory will permit an authorized
representative of the Food and Drug Administration to inspect its
testing procedures and facilities during reasonable business hours.
(3) The testing laboratory will participate in any proficiency
testing programs undertaken by the Center for Biologics Evaluation and
Research, Food and Drug Administration.
[40 FR 4304, Jan. 29, 1975, as amended at 47 FR 49021, Oct. 29, 1982; 49
FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26,
1990; 66 FR 1836, Jan. 10, 2001; 72 FR 45888, Aug. 16, 2007]
Subpart D_Plasma
Sec. 640.30 Plasma.
(a) Proper name and definition. The proper name of this component is
Plasma. The component is defined as:
(1) The fluid portion of one unit of human blood intended for
intravenous use which is collected in a closed system, stabilized
against clotting, and separated from the red cells; or
(2) The fluid portion of human blood intended for intravenous use
which is prepared by apheresis methods as specified in the directions
for use for the blood collecting, processing, and storage system
including closed and open systems.
(b) Source. (1) Plasma shall be obtained by separating plasma from
blood collected from blood donors or by plasmapheresis.
(2) Plasma may be obtained from a unit of Whole Blood collected by
another licensed establishment.
[42 FR 59878, Nov. 22, 1977; 48 FR 13026, Mar. 29, 1983, as amended at
50 FR 4139, Jan. 29, 1985; 72 FR 45888, Aug. 16, 2007]
Sec. 640.31 Eligibility of donors.
(a) Whole Blood donors must meet the criteria for donor eligibility
prescribed in Sec. Sec. 630.10 and 630.15 of this chapter.
[[Page 102]]
(b) Collection establishments must determine the eligibility of
plasmapheresis donors in accordance with Sec. Sec. 630.10 and 630.15 of
this chapter.
[80 FR 29904, May 22, 2015]
Sec. 640.32 Collection of source material.
(a) Whole Blood must be collected, transported, and stored as
prescribed in Sec. 640.4. When whole blood is intended for Plasma,
Fresh Frozen Plasma, and Liquid Plasma, until the plasma is removed, the
whole blood must be maintained at a temperature between 1 and 6 [deg]C
or as specified in the directions for use for the blood collecting,
processing, and storage system approved for such use by the Director,
Center for Biologics Evaluations and Research. Whole blood intended for
Platelet Rich Plasma must be maintained as prescribed in Sec. 640.24
until the plasma is removed. The red blood cells must be placed in
storage at a temperature between 1 and 6 [deg]C immediately after the
plasma is separated.
(b) Plasma obtained by plasmapheresis shall be collected as
prescribed in Sec. 640.64 (except that paragraph (c)(3) of Sec. 640.64
shall not apply), and Sec. 640.65.
[42 FR 59878, Nov. 22, 1977, as amended at 45 FR 27927, Apr. 25, 1980;
50 FR 4139, Jan. 29, 1985; 64 FR 45372, Aug. 19, 1999; 72 FR 45888, Aug.
16, 2007; 80 FR 29905, May 22, 2015]
Sec. 640.33 Testing the blood.
(a) Blood from which plasma is separated shall be tested as
prescribed in Sec. 610.40 of this chapter and Sec. 640.5 (b) and (c).
(b) Manufacturers of Plasma collected by plasmapheresis shall have
testing and recordkeeping responsibilities equivalent to those
prescribed in Sec. Sec. 640.71 and 640.72.
[42 FR 59878, Nov. 22, 1977, as amended at 44 FR 17658, Mar. 23, 1979;
50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 66 FR 31165, June
11, 2001; 80 FR 29905, May 22, 2015]
Sec. 640.34 Processing.
(a) Plasma. Plasma shall be separated from the red blood cells and
shall be stored at -18 [deg]C or colder within 6 hours after transfer to
the final container or within the timeframe specified in the directions
for use for the blood collecting, processing, and storage system unless
the product is to be stored as Liquid Plasma.
(b) Fresh Frozen Plasma. Fresh frozen plasma shall be prepared from
blood collected by a single uninterrupted venipuncture with minimal
damage to and minimal manipulation of the donor's tissue. The plasma
must be separated from the red blood cells or collected by an apheresis
procedure, and placed in a freezer within 8 hours or within the
timeframe specified in the directions for use for the blood collecting,
processing, and storage system, and stored at -18 [deg]C or colder.
(c) Liquid Plasma. Liquid Plasma shall be separated from the red
blood cells and shall be stored at a temperature of 1 to 6 [deg]C within
4 hours after filling the final container or within the timeframe
specified in the directions for use for the blood collecting,
processing, and storage system.
(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
[[Page 103]]
``Fresh Frozen Plasma,'' if frozen within 6 hours after filling the
final container or within the timeframe specified in the directions for
use for the blood collecting, processing, and storage system.
(2) Cryoprecipitated AHF shall be removed as prescribed in subpart F
of part 640. The remaining plasma shall be labeled ``Plasma,
Cryoprecipitate Reduced.''
(3) Plasma remaining after both Platelets and Cryoprecipitated AHF
have been removed may be labeled ``Plasma, Cryoprecipitate Reduced.''
(f) The final container. (1) The final container shall have no color
added to the plastic and shall be transparent to permit visual
inspection of the contents; any closure shall maintain a hermetic seal
and prevent contamination of the contents.
(2) The final container material shall not interact with the
contents, under the customary conditions of storage and use, in such a
manner as to have an adverse effect upon the safety, purity, potency,
and effectiveness of the product.
(3) Prior to filling, the final container shall be identified by
number so as to relate it to the donor.
(g) The final product. (1) The final product shall be inspected
immediately after separation of the plasma and shall not be issued for
transfusion if there is (i) any abnormality in color or physical
appearance, or (ii) any indication of contamination.
(2) With the exception of Platelet Rich Plasma and Liquid Plasma the
final product shall be inspected for evidence of thawing or breakage at
the time of issuance, however, the containers need not be stored in a
manner that shows evidence of thawing if records of continuous
monitoring of the storage temperature establish that the temperature
remained at -18 [deg]C or colder. If continuous monitoring of the
product is not available, the final product shall be stored in a manner
that will show evidence of thawing and shall not be issued if there is
any evidence of thawing.
(3) No preservative shall be added to the final product.
[42 FR 59878, Nov. 22, 1977, as amended at 43 FR 34460, Aug. 4, 1978; 48
FR 13026, Mar. 29, 1983; 50 FR 4139, Jan. 29, 1985; 64 FR 45373, Aug.
19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001; 72 FR
45888, Aug. 16, 2007]
Subpart E [Reserved]
Subpart F_Cryoprecipitate
Sec. 640.50 Cryoprecipitated AHF.
(a) Proper name and definition. The proper name of this product
shall be Cryoprecipitated AHF. The product is defined as a preparation
of antihemophilic factor, which is obtained from a single unit of plasma
collected and processed in a closed system.
(b) Source. The source material for Cryoprecipitated AHF shall be
plasma which may be obtained by whole blood collection or by
plasmapheresis.
[42 FR 21774, Apr. 29, 1977; 48 FR 13026, Mar. 29, 1983, as amended at
50 FR 4139, Jan. 29, 1985]
Sec. 640.51 Eligibility of donors.
(a) Whole blood donors must meet the criteria for eligibility
prescribed in Sec. Sec. 630.10 and 630.15 of this chapter.
(b) Collection establishments must determine the eligibility of
plasmapheresis donors in accordance with Sec. Sec. 630.10 and 630.15 of
this chapter.
[80 FR 29905, May 22, 2015]
Sec. 640.52 Collection of source material.
(a) Whole blood used as a source of Cryoprecipitated AHF shall be
collected as prescribed in Sec. 640.4. Whole blood from which both
Platelets and Cryoprecipitated AHF is derived shall be maintained as
required under Sec. 640.24 until the platelets are removed.
(b) If plasmapheresis is used, the procedure for collection shall be
as prescribed in Sec. 640.64 (except that paragraph (c)(3) of that
section shall not apply), and 640.65.
[42 FR 21774, Apr. 29, 1977, as amended at 50 FR 4139, Jan. 29, 1985; 64
FR 45373, Aug. 19, 1999; 80 FR 29905, May 22, 2015]
[[Page 104]]
Sec. 640.53 Testing the blood.
(a) Blood from which plasma is separated for the preparation of
Cryoprecipitated AHF shall be tested as prescribed in Sec. 610.40 of
this chapter and Sec. 640.5 (b) and (c).
(b) The tests shall be performed on a sample of blood collected at
the time of collecting the source blood, and such sample container shall
be labeled with the donor's number before the container is filled.
(c) Manufacturers of Cryoprecipitated AHF obtained from plasma
collected by plasmapheresis shall have testing and record-keeping
responsibilities equivalent to those prescribed in Sec. Sec. 640.71 and
640.72.
[42 FR 21774, Apr. 29, 1977, as amended at 42 FR 37546, July 22, 1977;
42 FR 43063, Aug. 26, 1977; 50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan.
5, 1988; 66 FR 31165, June 11, 2001; 80 FR 29905, May 22, 2015]
Sec. 640.54 Processing.
(a) Processing the plasma. (1) The plasma shall be separated from
the red blood cells by centrifugation to obtain essentially cell-free
plasma.
(2) The plasma shall be placed in a freezer within 8 hours after
blood collection or within the timeframe specified in the directions for
use for the blood collecting, processing, and storage system. A
combination of dry ice and organic solvent may be used for freezing:
Provided, That the procedure has been shown not to cause the solvent to
penetrate the container or leach plasticizer from the container into the
plasma.
(3) Immediately after separation and freezing of the plasma, the
plasma shall be stored and maintained at -18 [deg]C or colder until
thawing of the plasma for further processing to remove the
Cryoprecipitated AHF.
(b) Processing the final product. (1) The Cryoprecipitated AHF shall
be separated from the plasma by a procedure that has been shown to
produce an average of no less than 80 units of antihemophilic factor per
final container.
(2) No diluent shall be added to the product by the manufacturer
prior to freezing.
(3) The final container used for Cryoprecipitated AHF shall be
colorless and transparent to permit visual inspection of the contents;
any closure shall maintain a hermetic seal and prevent contamination of
the contents. The container material shall not interact with the
contents under customary conditions of storage and use in such a manner
as to have an adverse effect upon the safety, purity, potency and
effectiveness of the product. At the time of filling, the final
container shall be identified by a number so as to relate it to the
donor.
[42 FR 21774, Apr. 29, 1977, as amended at 47 FR 15330, Apr. 9, 1982; 50
FR 4139, Jan. 29, 1985; 64 FR 45373, Aug. 19, 1999; 66 FR 1837, Jan. 10,
2001; 66 FR 40890, Aug. 6, 2001]
Sec. 640.55 U.S. Standard preparation.
A U.S. Standard Antihemophilic Factor (Factor VIII) preparation may
be obtained from the Center for Biologics Evaluation and Research, (HFM-
407) (see mailing addresses in Sec. 600.2 of this chapter) for use in
the preparation of a working reference to be employed in a quality
control potency test of Cryoprecipitated AHF.
[42 FR 21774, Apr. 29, 1977, as amended at 49 FR 23834, June 8, 1984; 50
FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 70 FR 14985, Mar.
24, 2005]
Sec. 640.56 Quality control test for potency.
(a) Quality control tests for potency of antihemophilic factor shall
be conducted each month on at least four representative containers of
Cryoprecipitated AHF.
(b) The results of each test are received by the establishment
licensed for Cryoprecipitated AHF within 30 days of the preparation of
the cryoprecipitated antihemophilic factor and are maintained at that
establishment so that they may be reviewed by an authorized
representative of the Food and Drug Administration.
(c) The quality control test for potency may be performed by a
clinical laboratory which meets the standards of the Clinical
Laboratories Improvement Amendments of 1988 (CLIA) (42 U.S.C. 263a) and
is qualified to perform potency tests for antihemophilic factor. Such
arrangements must be approved by the Director, Center for Biologics
Evaluation and Research, Food
[[Page 105]]
and Drug Administration. Such testing shall not be considered as divided
manufacturing, as described in Sec. 610.63 of this chapter, provided
the following conditions are met:
(1) The establishment licensed for Cryoprecipitated AHF has obtained
a written agreement that the testing laboratory will permit an
authorized representative of the Food and Drug Administration to inspect
its testing procedures and facilities during reasonable business hours.
(2) The testing laboratory will participate in any proficiency
testing programs undertaken by the Center for Biologics Evaluation and
Research, Food and Drug Administration.
(d) If the average potency level of antihemophilic factor in the
containers tested is less than 80 units of antihemophilic factor per
container, immediate corrective actions shall be taken and a record
maintained of such action.
[42 FR 21774, Apr. 29, 1977, as amended at 49 FR 23834, June 8, 1984; 50
FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 64 FR 45373, Aug.
19, 1999; 66 FR 1837, Jan. 10, 2001]
Subpart G_Source Plasma
Sec. 640.60 Source Plasma.
The proper name of the product shall be Source Plasma. The product
is defined as the fluid portion of human blood collected by
plasmapheresis and intended as source material for further manufacturing
use. The definition excludes single donor plasma products intended for
intravenous use.
[41 FR 10768, Mar. 12, 1976, as amended at 50 FR 4140, Jan. 29, 1985]
Sec. 640.64 Collection of blood for Source Plasma.
(a) [Reserved]
(b) Blood containers. Blood containers and donor sets must be
pyrogen-free, sterile, and identified by lot number.
(c) The anticoagulant solution. The anticoagulant solution must be
sterile and pyrogen-free. Anticoagulant solutions must be compounded and
used according to a formula that has been approved for the applicant by
the Director, Center for Biologics Evaluation and Research.
(d) Donor identification. Each unit of blood and plasma shall be so
marked or identified by number or other symbol so as to relate it
directly to the donor.
(e) Prevention of contamination of the blood and plasma. The skin of
the donor at the site of phlebotomy shall be prepared thoroughly and
carefully by a method that gives maximum assurance of a sterile
container of blood. The blood shall be collected, the plasma separated,
and the cells returned to the donor by aseptic methods in a sterile
system which may be closed, or may be vented if the vent protects the
blood cells and plasma against contamination.
[38 FR 32089, Nov. 20, 1973; 39 FR 13632, Apr. 16, 1974, as amended at
41 FR 10768, Mar. 12, 1976; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan.
29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 63 FR
16685, Apr. 6, 1998; 64 FR 56453, Oct. 20, 1999; 72 FR 45888, Aug. 16,
2007; 80 FR 29905, May 22, 2015]
Sec. 640.65 Plasmapheresis.
(a) Procedure-general. The plasmapheresis procedure is a procedure
in which, during a single visit to the establishment, blood is removed
from a donor, the plasma separated from the formed elements, and at
least the red blood cells returned to the donor. This procedure shall be
described in detail in the biologics license application.
(b) Procedures-specific requirements. The plasmapheresis procedure
shall meet the following requirements:
(1)(i) Except as provided under Sec. 630.25 of this chapter, the
responsible physician must draw a sample of blood from each donor on the
day of the initial physical examination or plasmapheresis, whichever
comes first, and at least every 4 months thereafter. A serologic test
for syphilis, a total plasma or serum protein determination, and a
plasma or serum protein electrophoresis or quantitative immuno-diffusion
test or an equivalent test to determine immunoglobulin composition of
the plasma or serum shall be performed on the sample.
(ii) A repeat donor who does not return for plasmapheresis at the
time the 4-month sample is due to be collected may be plasmapheresed on
the day he appears: Provided, That no longer than 6 months has elapsed
since the last
[[Page 106]]
sample was collected, and the responsible physician approves the
plasmapheresis procedure and so indicates by signing the donor's record
before such procedure is performed. The sample for the 4-month tests
shall be collected on the day of the donor's return.
(iii) A repeat donor from whom the plasmapheresis center is unable
to obtain a sample for testing as prescribed in paragraph (b)(1)(i) of
this section for a total period exceeding 6 months shall be processed as
a new donor.
(2)(i) Except as provided under Sec. 630.25 of this chapter, the
responsible physician must review the accumulated laboratory data,
including any tracings of the plasma or serum protein electrophoresis
pattern, the calculated values of the protein composition of each
component, and the collection records within 14 calendar days after the
sample is drawn to determine whether or not the donor should be deferred
from further donation. If a determination is not made within 14 calendar
days, the donor must be deferred pending such a determination. The
responsible physician must sign the review. If the protein composition
is not within normal limits established by the testing laboratory, or if
the total protein level is less than 6.0 grams per deciliter or more
than 9.0 grams per deciliter in a plasma sample or serum sample, the
donor must be deferred from donation until the protein composition
returns to acceptable levels. Reinstatement of the donor into the
plasmapheresis program when the donor's protein composition values have
returned to an acceptable level must first be approved by the
responsible physician.
(ii) A donor with a reactive serologic test for syphilis shall not
be plasmapheresed again until the donor's serum is tested and found to
be nonreactive to a serologic test for syphilis, except as provided in
paragraph (b)(2) (iii) and (iv) of this section.
(iii) A donor whose serum is determined to have a biologic false-
positive reaction to a serologic test for syphilis may be
plasmapheresed: Provided, That the donor's file identifies the serologic
test for syphilis and results used to confirm the biologic false-
positive reaction and indicates that the responsible physician has
determined the false-positive reaction is not the result of an
underlying disorder that would disqualify the donor from participation
in the plasmapheresis program. If the serologic test for syphilis is
performed at a facility other than the plasmapheresis center, all
applicable provisions of Sec. 640.71 shall be met.
(iv) A donor with a reactive serologic test for syphilis may be
plasmapheresed only to obtain plasma to be used for further
manufacturing into control serum for the serologic test for syphilis:
Provided, That the responsible physician approves the donation, the
donor's file contains a signed statement from a physician or clinic
establishing that treatment for syphilis has been initiated and that
continuance in the plasmapheresis program will not interfere with or
jeopardize the treatment of the syphilitic donor.
(3) A donor identification system shall be established that
positively identifies each donor and relates such 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.
[[Page 107]]
(6) No more than 500 milliliters of whole blood shall be removed
from a donor at one time, unless the donor's weight is 175 pounds or
greater, in which case no more than 600 milliliters of whole blood shall
be removed from the donor at one time.
(7) The plasma shall be separated from the red blood cells
immediately after blood collection. The maximum feasible volume of red
blood cells shall be returned to the donor before another unit is
collected.
(8) The volume of plasma collected during an automated
plasmapheresis collection procedure shall be consistent with the volumes
specifically approved by the Director, Center for Biologics Evaluation
and Research, and collection shall not occur less than 2 days apart or
more frequently than twice in a 7-day period.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976;
64 FR 45373, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999; 80 FR 29905, May
22, 2015]
Sec. 640.66 Immunization of donors.
If specific immunization of a donor is to be performed, the
selection, scheduling and administration of the antigen, and the
evaluation of each donor's clinical response, shall be by the
responsible physician. Any material used for immunization shall be
either a product licensed under section 351 of the Public Health Service
Act for such purpose or one specifically approved by the Director,
Center for Biologics Evaluation and Research, Food and Drug
Administration. Immunization procedures shall be on file at each
plasmapheresis center where immunizations are performed.
[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 55
FR 11013, Mar. 26, 1990; 80 FR 29905, May 22, 2015]
Sec. 640.67 Laboratory tests.
Each unit of Source Plasma shall be tested for evidence of infection
due to relevant transfusion-transmitted infections as required under
Sec. 610.40 of this chapter.
[66 FR 31165, June 11, 2001, as amended at 80 FR 29905, May 22, 2015]
Sec. 640.68 Processing.
(a) Sterile system. All administration and transfer sets inserted
into blood containers used for processing Source Plasma intended for
manufacturing into injectable or noninjectable products and all interior
surfaces of plasma containers used for processing Source Plasma intended
for manufacturing into injectable products shall be sterile, pyrogen-
free, nontoxic, and compatible with the contents under normal conditions
of use. Only Sodium Chloride Injection USP shall be used as a red blood
cell diluent. If the method of separation of the plasma intended for
injectable products involves a system in which an airway must be
inserted into the plasma container, the airway shall be sterile and
constructed so as to exclude microorganisms and maintain a sterile
system.
(b) Final containers. Final containers used for Source Plasma,
whether integrally attached or separated from the original blood
container, shall not be entered prior to issuance for any purpose except
for filling with the plasma. Such containers shall be uncolored and
hermetically sealed, and shall permit clear visibility of the contents.
Final containers and their components shall not interact with the plasma
contents under conditions of storage and use so as to alter the safety,
quality, purity, or potency of the plasma and shall provide adequate
protection against external factors that may cause deterioration or
contamination. Prior to filling, the final container shall be marked or
identified by number or other symbol which will relate it directly to
the donor.
(c) Preservative. Source Plasma shall not contain a preservative.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976;
50 FR 4140, Jan. 29, 1985]
Sec. 640.69 General requirements.
(a) Pooling. Two units of Source Plasma from the same donor may be
pooled if such units are collected during one plasmapheresis procedure:
Provided, That the pooling is done by a procedure that does not
introduce a risk of contamination of the red blood cells and, for plasma
intended for injectable
[[Page 108]]
products, gives maximum assurance of a sterile container of plasma.
(1) The pooling of plasma from two or more donors is not permitted
in the manufacture of Source Plasma intended for manufacturing into
injectable products.
(2) The pooling of plasma from two or more donors by the
manufacturer of Source Plasma intended for manufacturing into
noninjectable products is permitted: Provided, That the plasma from two
or more donors is pooled after the plasma has been removed from the red
blood cells, and after the red blood cell containers are sealed.
(b) Storage. Immediately after filling, plasma intended for
manufacturing into injectable products shall be stored at a temperature
not warmer than -20 [deg]C, except for plasma collected as provided in
Sec. 640.74. Plasma intended for manufacturing into noninjectable
products may be stored at temperatures appropriate for the intended use
of the final product, provided these temperatures are included in the
Source Plasma license application.
(c) Inspection. Source Plasma intended for manufacturing into
injectable products shall be inspected for evidence of thawing at the
time of issuance, except that inspection of individual plasma containers
need not be made if the records of continuous monitoring of the storage
temperature establish that the temperature remained at -20 [deg]C or
colder. If there is evidence that the storage temperature has not been
maintained at -20 [deg]C or colder, the plasma may be relabeled and
issued as provided in Sec. 640.76(a).
(d) Samples. If samples are provided, they shall meet the following
standards:
(1) Prior to filling, all samples shall be marked or identified so
as to relate them directly to the donor of that unit of plasma.
(2) All samples shall be filled at the time the final product is
prepared by the person who prepares the final product.
(3) All samples shall be representative of the contents of the final
product or be collected from the donor at the time of filling the
collection container.
(4) All samples shall be collected in a manner that does not
contaminate the contents of the final container.
(e) Restrictions on distribution. Establishments must ensure that
Source Plasma donated by paid donors not be used for further
manufacturing into injectable products until the donor has a record of
being found eligible to donate in accordance with Sec. 630.10 of this
chapter and a record of negative test results on all tests required
under Sec. 610.40(a) of this chapter on two occasions in the past 6
months.
(f) Hold. Source Plasma donated by paid donors determined to be
suitable for further manufacturing into injectable products must be held
in quarantine for a minimum of 60 calendar days before it is released
for further manufacturing. If, after placing a donation in quarantine
under this section, the donor is subsequently deferred under Sec.
610.41 of this chapter, or you subsequently determine a donor to be
ineligible under Sec. 630.10 of this chapter due to risk factors
closely associated with exposure to, or clinical evidence of, infection
due to a relevant transfusion-transmitted infection, you must not
distribute quarantined donations from that donor for further
manufacturing use to make an injectable product.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976;
41 FR 14367, Apr. 5, 1976; 50 FR 4140, Jan. 29, 1985; 63 FR 16685, Apr.
6, 1998; 64 FR 45374, Aug. 19, 1999; 80 FR 29905, May 22, 2015]
Sec. 640.71 Manufacturing responsibility.
(a) All steps in the manufacturing of Source Plasma, including donor
examination, blood collection, plasmapheresis, laboratory testing,
labeling, storage, and issuing shall be performed by personnel of the
establishment licensed to manufacture Source Plasma, except that testing
performed in accordance with Sec. 610.40 of this chapter and Sec.
640.65(b) may be performed by personnel of an establishment licensed for
blood and blood derivatives under section 351(a) of the Public Health
Service Act, or by a clinical laboratory that meets the standards of the
Clinical Laboratories Improvement Amendments of 1988 (CLIA) (42 U.S.C.
263a): Provided, The establishment or clinical
[[Page 109]]
laboratory is qualified to perform the assigned test(s).
(b) Such testing shall not be considered divided manufacturing,
which requires two biologics licenses for Source Plasma: Provided, That
(1) The results of such tests are maintained by the licensed
manufacturer of the Source Plasma whereby such results may be reviewed
by a responsible physician as required in Sec. 640.65(b)(2) of this
chapter and by an authorized representative of the Food and Drug
Administration.
(2) The Source Plasma manufacturer has obtained a written agreement
that the testing laboratory will permit authorized representatives of
the Food and Drug Administration to inspect its testing procedures and
facilities during reasonable business hours.
(3) The testing laboratory will participate in any proficiency
testing programs undertaken by the Center for Biologics Evaluation and
Research, Food and Drug Administration.
[41 FR 10770, Mar. 12, 1976, as amended at 49 FR 23834, June 8, 1984; 50
FR 4140, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 55 FR 11013, Mar. 26,
1990; 64 FR 45374, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999; 66 FR
1837, Jan. 10, 2001; 80 FR 29905, May 22, 2015]
Sec. 640.72 Records.
(a) In addition to the recordkeeping requirements of this
subchapter, the following records shall be maintained:
(1) Documentation shall be available to ensure that the shipping
temperature requirements of Sec. 600.15 of this title and of Sec.
640.74(b)(2) are being met for Source Plasma intended for manufacture
into injectable products.
(2)(i) For each donor, establishments must maintain records
including a separate and complete record of initial and periodic
examinations, tests, laboratory data, and interviews, etc., as required
in Sec. Sec. 630.10 and 630.15 of this chapter and Sec. Sec. 640.65,
640.66, and 640.67, except as provided in paragraph (a)(2)(ii) of this
section.
(ii) Negative results for testing for evidence of infection due to
relevant transfusion-transmitted infections required in Sec. 610.40 of
this chapter, and the volume or weight of plasma withdrawn from a donor
need not be recorded on the individual donor record if such information
is maintained on the premises of the plasmapheresis center where the
donor's plasma has been collected.
(3) The original or a clear copy or other durable record which may
be electronic of the donor's consent for participation in the
plasmapheresis program or for immunization.
(4) Records of the medical history and physical examination of the
donor conducted in accordance with Sec. 630.15(b)(1) of this chapter
and, where applicable, Sec. 630.15(b)(5) of this chapter must document
the eligibility of the donor as a plasmapheresis donor and, when
applicable, as an immunized donor.
(5) If plasma that is reactive to a serologic test for syphilis is
issued as prescribed in Sec. 640.65(b)(2)(iv), the distribution records
shall indicate by number those units that are reactive.
(b) Each donor record must be directly cross-referenced to the
unit(s) of Source Plasma associated with the donor.
(c) If a repeat donor is rejected or a donor's plasma is found
unsuitable, the donor's record shall contain a full explanation for the
rejection.
(d) If a donor has a reaction while on the plasmapheresis premises,
or a donor reaction is reported to the center after the donor has left
the premises, the donor's record shall contain a full explanation of the
reaction, including the measures taken to assist the donor and the
outcome of the incident.
[41 FR 10770, Mar. 12, 1976, as amended at 50 FR 4140, Jan. 29, 1985; 53
FR 117, Jan. 5, 1988; 64 FR 45374, Aug. 19, 1999; 67 FR 9587, Mar. 4,
2002; 80 FR 29905, May 22, 2015]
Sec. 640.73 Reporting of fatal donor reactions.
If a donor has a fatal reaction which, in any way, may be associated
with plasmapheresis the Director of the Center for Biologics Evaluation
and Research shall be notified by telephone as soon as possible. If the
facility is located outside of the continental United States,
notification by cable or telegram shall be acceptable.
[41 FR 10770, Mar. 12, 1976, as amended at 49 FR 23834, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
[[Page 110]]
Sec. 640.74 Modification of Source Plasma.
(a) Upon approval by the Director, Center for Biologics Evaluation
and Research, Food and Drug Administration, of a supplement to the
biologics license application for Source Plasma, a manufacturer may
prepare Source Plasma as a liquid product for a licensed blood
derivative manufacturer who has indicated a need for a liquid product.
(b) Source Plasma Liquid shall meet all standards of the frozen
Source Plasma except:
(1) Source Plasma Liquid shall be stored in nonleachable containers
so that the containers and their components will not interact with the
plasma contents under conditions of storage and use so as to alter the
safety, quality, purity, or potency of the plasma and shall provide
adequate protection against external factors that may cause
deterioration or contamination.
(2) Source Plasma Liquid shall be shipped, stored and labeled for
storage at a temperature of 10 [deg]C or colder. An exception to the
shipping or storage temperature shall be approved by the Director,
Center for Biologics Evaluation and Research, Food and Drug
Administration, based upon his receipt of substantial evidence to
support another temperature. Such evidence may be submitted by either
the licensed manufacturer of the Source Plasma Liquid or the
manufacturer of the final blood derivative product who has requested the
Source Plasma Liquid.
(3) The label for the Source Plasma Liquid shall be easily
distinguished from that of the frozen product. Color coding shall not be
used for this purpose.
(4) The label affixed to each container of Source Plasma Liquid
shall contain, in addition to the information required by Sec. 606.121
of this chapter, but excluding Sec. 606.121(e)(5)(ii) of this chapter,
the name of the manufacturer of the final blood derivative product for
whom it was prepared.
(5) Source Plasma Liquid shall be inspected immediately prior to
issuance. If the color or physical appearance is abnormal, or there is
any indication or suspicion of microbial contamination, the unit of
Source Plasma Liquid shall not be issued.
[38 FR 32089, Nov. 20, 1973. Redesignated and amended at 41 FR 10770,
Mar. 12, 1976; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55
FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 63 FR 16685, Apr.
6, 1998; 64 FR 56454, Oct. 20, 1999; 77 FR 18, Jan. 3, 2012]
Sec. 640.76 Products stored or shipped at unacceptable temperatures.
(a) Storage temperature. (1) Except as provided in paragraph (a)(2)
of this section, Source Plasma intended for manufacture into injectable
products that is inadvertently exposed (i.e., an unforeseen occurrence
in spite of compliance with good manufacturing practice) to a storage
temperature warmer than -20 [deg]C and colder than + 10 [deg]C may be
issued only if labeled as ``Source Plasma Salvaged.'' The label shall be
revised before issuance, and 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
[[Page 111]]
compliance with good manufacturing practice) to a shipping temperature
warmer than -5 [deg]C and colder than + 10 [deg]C, the plasma derivative
manufacturer shall label it ``Source Plasma Salvaged.'' Appropriate
records shall be maintained identifying the units involved, describing
their disposition, and explaining fully the conditions that caused the
inadvertent temperature exposure.
(c) Relabeling. If Source Plasma is required to be relabeled as
``Source Plasma Salvaged'' under paragraph (a)(1) or (b) of this
section, the person responsible for the relabeling shall cover the
original label with either (1) a complete new label containing the
appropriate information or (2) a partial label affixed to the original
label and containing the appropriate new information, which covers the
incorrect information regarding storage temperature.
[45 FR 80501, Dec. 5, 1980, as amended at 50 FR 4140, Jan. 29, 1985]
Subpart H_Albumin (Human)
Sec. 640.80 Albumin (Human).
(a) Proper name and definition. The proper name of the product shall
be Albumin (Human). The product is defined as a sterile solution of the
albumin derived from human plasma.
(b) Source material. The source material of Albumin (Human) shall be
plasma recovered from Whole Blood prepared as prescribed in Sec. Sec.
640.1 through 640.5, or Source Plasma prepared as prescribed in
Sec. Sec. 640.60 through 640.76.
(c) Additives in source material. Source material shall not contain
an additive unless it is shown that the processing method yields a final
product free of the additive to such extent that the continued safety,
purity, potency, and effectiveness of the final product will not be
adversely affected.
[42 FR 27582, May 31, 1977, as amended at 50 FR 4140, Jan. 29, 1985; 64
FR 26286, May 14, 1999]
Sec. 640.81 Processing.
(a) Date of manufacture. The date of manufacture shall be the date
of final sterile filtration of a uniform pool of bulk solution.
(b) Processing method. The processing method shall not affect the
integrity of the product, and shall have been shown to yield
consistently a product which is safe for intravenous injection.
(c) Microbial contamination. All processing steps shall be conducted
in a manner to minimize the risk of contamination from microorganisms,
pyrogens, or other impurities. Preservatives to inhibit growth of
microorganisms shall not be used during processing.
(d) Storage of bulk fraction. Bulk concentrate to be held more than
1 week prior to further processing shall be stored in clearly identified
closed vessels at a temperature of -5 [deg]C or colder. Any other bulk
form of the product, exclusive of the sterile bulk solution, to be held
more than 1 week prior to further processing shall be stored in 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
[[Page 112]]
shall be identified as to genus, and the material from such containers
shall not be used for further manufacturing.
[42 FR 27582, May 31, 1977, as amended at 50 FR 4140, Jan. 29, 1985; 64
FR 26286, May 14, 1999; 65 FR 13679, Mar. 14, 2000; 65 FR 52018, Aug.
28, 2000]
Sec. 640.82 Tests on final product.
Tests shall be performed on the final product to determine that it
meets the following standards:
(a) Protein concentration. Final product shall conform to one of the
following concentrations: 4.0 0.25 percent; 5.0
0.30 percent; 20.0 1.2
percent; and 25.0 1.5 percent solution of protein.
(b) Protein composition. At least 96 percent of the total protein in
the final product shall be albumin, as determined by a method that has
been approved for each manufacturer by the Director, Center for
Biologics Evaluation and Research, Food and Drug Administration.
(c) pH. The pH shall be 6.9 0.5 when measured
in a solution of the final product diluted to a concentration of 1
percent protein with 0.15 molar sodium chloride.
(d) Sodium concentration. The sodium concentration of the final
product shall be 130 to 160 milliequivalents per liter.
(e) Potassium concentration. The potassium concentration of the
final product shall not exceed 2 milliequivalents per liter.
(f) Heat stability. A final container sample of Albumin (Human)
shall remain unchanged, as determined by visual inspection, after
heating at 57 [deg]C for 50 hours, when compared to its control
consisting of a sample, from the same lot, which has not undergone this
heating.
[42 FR 27582, May 31, 1977, as amended at 49 FR 23834, June 8, 1984; 50
FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 64 FR 26286, May 14,
1999]
Sec. 640.83 General requirements.
(a) Preservative. The final product shall not contain a
preservative.
(b) Storage of bulk solution. After all processing steps have been
completed, the sterile bulk solution shall be stored in a manner that
will ensure the continued sterility of the product, and at a temperature
that shall not exceed the recommended storage temperature of the final
product prescribed in Sec. 610.53 of this chapter.
[42 FR 27582, May 31, 1977]
Sec. 640.84 Labeling.
In addition to the labeling requirements of Sec. Sec. 610.60,
610.61, and 610.62 of this chapter, the container and package labels
shall contain the following information:
(a) The osmotic equivalent in terms of plasma, and the sodium
concentration in terms of a value or a range in milliequivalents per
liter;
(b) The cautionary statement placed in a prominent position on the
label, ``Do Not Use if Turbid. Do Not Begin Administration More Than 4
Hours After the Container Has Been Entered.'';
(c) The need for additional fluids when 20 percent or 25 percent
albumin is administered to a patient with marked dehydration;
(d) The protein concentration, expressed as a 4 percent, 5 percent,
20 percent, or 25 percent solution.
[42 FR 27582, May 31, 1977, as amended at 49 FR 2244, Jan. 19, 1984; 64
FR 26286, May 14, 1999]
Subpart I_Plasma Protein Fraction (Human)
Source: 42 FR 27583, May 31, 1977, unless otherwise noted.
Sec. 640.90 Plasma Protein Fraction (Human).
(a) Proper name and definition. The proper name of the product shall
be Plasma Protein Fraction (Human). The product is defined as a sterile
solution of protein composed of albumin and globulin, derived from human
plasma.
(b) Source material. The source material of Plasma Protein Fraction
(Human) shall be plasma recovered from Whole Blood prepared as
prescribed in Sec. Sec. 640.1 through 640.5, or Source Plasma prepared
as prescribed in Sec. Sec. 640.60 through 640.76.
(c) Additives in source material. Source material shall not contain
an additive unless it is shown that the processing method yields a final
product free of
[[Page 113]]
the additive to such extent that the continued safety, purity, potency,
and effectiveness of the final product will not be adversely affected.
[42 FR 27583, May 31, 1977, as amended at 64 FR 26286, May 14, 1999]
Sec. 640.91 Processing.
(a) Date of manufacture. The date of manufacture shall be the date
of final sterile filtration of a uniform pool of bulk solution.
(b) Processing method. The processing method shall not affect the
integrity of the product, and shall have been shown to yield
consistently a product which:
(1) After the heating prescribed in paragraph (e) of this section
does not show an increase in the components with electrophoretic
mobility similar to that of alpha globulin that amounts to more than 5
percent of the total protein.
(2) Contains less than 5 percent protein with a sedimentation
coefficient greater than 7.0 S.
(3) Is safe for intravenous injection.
(c) Microbial contamination. All processing steps shall be conducted
in a manner to minimize the risk of contamination from microorganisms,
pyrogens, or other impurities. Preservatives to inhibit growth of
microorganisms shall not be used during processing.
(d) Storage of bulk fraction. Bulk concentrate to be held more than
1 week prior to further processing shall be stored in clearly identified
closed vessels at a temperature of -5 [deg]C or colder. Any other bulk
form of the product (exclusive of the sterile bulk solution) to be held
more than 1 week prior to further processing, shall be stored in clearly
identified closed vessels at a temperature of 5 [deg]C or colder. Any
bulk fraction to be held one week or less prior to further processing
shall be stored in clearly identified closed vessels at a temperature of
5 [deg]C or colder.
(e) Heat treatment. Heating of the final containers of Plasma
Protein Fraction (Human) shall begin within 24 hours after completion of
filling. Heat treatment shall be conducted so that the solution is
heated continuously for not less than 10 or more than 11 hours at an
attained temperature of 600.5 [deg]C.
(f) Stabilizer. Either 0.080.016 millimole
sodium caprylate, or 0.080.016 millimole sodium
acetyltryptophanate and 0.080.016 millimole sodium
caprylate per gram of protein shall be present as a stabilizer(s).
Calculations of the stabilizer concentration may employ the labeled
value 5 percent for the protein concentration of the product.
(g) Incubation. All final containers of Plasma Protein Fraction
(Human) shall be incubated at 20 to 35 [deg]C for at least 14 days
following the heat treatment prescribed in paragraph (e) of this
section. At the end of this incubation period, each final container
shall be examined and all containers showing any indication of turbidity
or microbial contamination shall not be issued. The contents of turbid
final containers 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