[Title 21 CFR I]
[Code of Federal Regulations (annual edition) - April 1, 1996 Edition]
[Title 21 - FOOD AND DRUGS]
[Chapter I - FOOD AND DRUG ADMINISTRATION,]
[From the U.S. Government Publishing Office]
21
FOOD AND DRUGS
7
1996-04-01
1996-04-01
false
FOOD AND DRUG ADMINISTRATION,
I
CHAPTER I
FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION,
SUBCHAPTER F--BIOLOGICS
PART 600--BIOLOGICAL PRODUCTS: GENERAL--Table of Contents
Subpart A--General Provisions
Sec.
600.3 Definitions.
Subpart B--Establishment Standards
600.10 Personnel.
600.11 Physical establishment, equipment, animals, and care.
600.12 Records.
600.13 Retention samples.
600.14 Reporting of errors.
600.15 Temperatures during shipment.
Subpart C--Establishment Inspection
600.20 Inspectors.
600.21 Time of inspection.
600.22 Duties of inspector.
Subpart D--Reporting of Adverse Experiences
600.80 Postmarketing reporting of adverse experiences.
600.81 Distribution reports.
600.90 Waivers.
Authority: Secs. 201, 501, 502, 503, 505, 510, 519, 701, 704 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355,
360, 360i, 371, 374); secs. 215, 351, 352, 353, 361, 2125 of the Public
Health Service Act (42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25).
Cross References: For U.S. Customs Service regulations relating to
viruses, serums, and toxins, see 19 CFR 12.21--12.23. For U.S. Postal
Service regulations relating to the admissibility to the United States
mails see parts 124 and 125 of the Domestic Mail Manual, that is
incorporated by reference in 39 CFR part 111.
Subpart A--General Provisions
Sec. 600.3 Definitions.
As used in this subchapter:
(a) Act means the Public Health Service Act (58 Stat. 682), approved
July 1, 1944.
(b) Secretary means the Secretary of Health and Human Services and
any other officer or employee of the Department of Health and Human
Services to whom the authority involved has been delegated.
(c) Commissioner of Food and Drugs means the Commissioner of the
Food and Drug Administration.
(d) Center for Biologics Evaluation and Research means Center for
Biologics Evaluation and Research of the Food and Drug Administration.
(e) State means a State or the District of Columbia, Puerto Rico, or
the Virgin Islands.
(f) Possession includes among other possessions, Puerto Rico and the
Virgin Islands.
(g) Products includes biological products and trivalent organic
arsenicals.
(h) Biological product means any virus, therapeutic serum, toxin,
antitoxin, or analogous product applicable to the prevention, treatment
or cure of diseases or injuries of man:
(1) A virus is interpreted to be a product containing the minute
living cause of an infectious disease and includes but is not limited to
filterable viruses, bacteria, rickettsia, fungi, and protozoa.
(2) A therapeutic serum is a product obtained from blood by removing
the clot or clot components and the blood cells.
(3) A toxin is a product containing a soluble substance poisonous to
laboratory animals or to man in doses of 1 milliliter or less (or
equivalent in weight) of the product, and having the property, following
the injection of non-fatal doses into an animal, of causing to be
produced therein another soluble substance which specifically
neutralizes the poisonous substance and which is demonstrable in the
serum of the animal thus immunized.
(4) An antitoxin is a product containing the soluble substance in
serum or other body fluid of an immunized animal which specifically
neutralizes the toxin against which the animal is immune.
(5) A product is analogous:
(i) To a virus if prepared from or with a virus or agent actually or
potentially infectious, without regard to the degree of virulence or
toxicogenicity of the specific strain used.
(ii) To a therapeutic serum, if composed of whole blood or plasma or
[[Page 6]]
containing some organic constituent or product other than a hormone or
an amino acid, derived from whole blood, plasma, or serum.
(iii) To a toxin or antitoxin, if intended, irrespective of its
source of origin, to be applicable to the prevention, treatment, or cure
of disease or injuries of man through a specific immune process.
(i) Trivalent organic arsenicals means arsphenamine and its
derivatives (or any other trivalent organic arsenic compound) applicable
to the prevention, treatment, or cure of diseases or injuries of man.
(j) A product is deemed applicable to the prevention, treatment, or
cure of diseases or injuries of man irrespective of the mode of
administration or application recommended, including use when intended
through administration or application to a person as an aid in
diagnosis, or in evaluating the degree of susceptibility or immunity
possessed by a person, and including also any other use for purposes of
diagnosis if the diagnostic substance so used is prepared from or with
the aid of a biological product.
(k) Proper name, as applied to a product, means the name designated
in the license for use upon each package of the product.
(l) Dating period means the period beyond which the product cannot
be expected beyond reasonable doubt to yield its specific results.
(m) Expiration date means the calendar month and year, and where
applicable, the day and hour, that the dating period ends.
(n) The word standards means specifications and procedures
applicable to an establishment or to the manufacture or release of
products, which are prescribed in this subchapter and which are designed
to insure the continued safety, purity and potency of such products.
(o) The word continued as applied to the safety, purity and potency
of products is interpreted to apply to the dating period.
(p) The word safety means the relative freedom from harmful effect
to persons affected, directly or indirectly, by a product when prudently
administered, taking into consideration the character of the product in
relation to the condition of the recipient at the time.
(q) The word sterility is interpreted to mean freedom from viable
contaminating microorganisms, as determined by the tests prescribed in
Sec. 610.12 of this chapter.
(r) Purity means relative freedom from extraneous matter in the
finished product, whether or not harmful to the recipient or deleterious
to the product. Purity includes but is not limited to relative freedom
from residual moisture or other volatile substances and pyrogenic
substances.
(s) The word potency is interpreted to mean the specific ability or
capacity of the product, as indicated by appropriate laboratory tests or
by adequately controlled clinical data obtained through the
administration of the product in the manner intended, to effect a given
result.
(t) Manufacturer means any legal person or entity engaged in the
manufacture of a product subject to license under the act.
(u) Manufacture means all steps in propagation or manufacture and
preparation of products and includes but is not limited to filling,
testing, labeling, packaging, and storage by the manufacturer.
(v) Location includes all buildings, appurtenances, equipment and
animals used, and personnel engaged by a manufacturer within a
particular area designated by an address adequate for identification.
(w) Establishment includes all locations.
(x) Lot means that quantity of uniform material identified by the
manufacturer as having been thoroughly mixed in a single vessel.
(y) A filling refers to a group of final containers identical in all
respects, which have been filled with the same product from the same
bulk lot without any change that will affect the integrity of the
filling assembly.
(z) Process refers to a manufacturing step that is performed on the
product itself which may affect its safety, purity or potency, in
contrast to such manufacturing steps which do not affect intrinsically
the safety, purity or potency of the product.
[[Page 7]]
(aa) Selling agent or distributor means any person engaged in the
unrestricted distribution, other than by sale at retail, of products
subject to license.
(bb) Container (referred to also as ``final container'') is the
immediate unit, bottle, vial, ampule, tube, or other receptacle
containing the product as distributed for sale, barter, or exchange.
(cc) Package means the immediate carton, receptacle, or wrapper,
including all labeling matter therein and thereon, and the contents of
the one or more enclosed containers. If no package, as defined in the
preceding sentence, is used, the container shall be deemed to be the
package.
(dd) Label means any written, printed, or graphic matter on the
container or package or any such matter clearly visible through the
immediate carton, receptacle, or wrapper.
(ee) Radioactive biological product means a biological product which
is labeled with a radionuclide or intended solely to be labeled with a
radionuclide.
[38 FR 32048, Nov. 20, 1973, as amended at 40 FR 31313, July 25, 1975;
55 FR 11014, Mar. 26, 1990]
Subpart B--Establishment Standards
Sec. 600.10 Personnel.
(a) Responsible head. A person shall be designated as the
responsible head who shall exercise control of the establishment in all
matters relating to compliance with the provisions of this subchapter,
with authority to represent the manufacturer in all pertinent matters
with the Center for Biologics Evaluation and Research, and with
authority to enforce or to direct the enforcement of discipline and the
performance of assigned functions by employees engaged in the
manufacture of products. The responsible head shall have an
understanding of the scientific principles and the techniques involved
in the manufacture of products. The responsible head shall have the
responsibility for the training of employees in manufacturing methods
and for their being informed concerning the application of the pertinent
provisions of this subchapter to their respective functions.
(b) Other personnel. Personnel shall have capabilities commensurate
with their assigned functions, a thorough understanding of the
manufacturing operations which they perform, the necessary training and
experience relating to individual products, and adequate information
concerning the application of the pertinent provisions of this
subchapter to their respective functions. Personnel shall include such
professionally trained persons as are necessary to insure the competent
performance of all manufacturing processes.
(c) Restrictions on personnel--(1) Specific duties. Persons whose
presence can affect adversely the safety and purity of a product shall
be excluded from the room where the manufacture of a product is in
progress.
(2) Sterile operations. Personnel performing sterile operations
shall wear clean or sterilized protective clothing and devices to the
extent necessary to protect the product from contamination.
(3) Pathogenic viruses and spore-bearing organisms. Persons working
with viruses pathogenic for man or with spore-bearing microorganisms,
and persons engaged in the care of animals or animal quarters, shall be
excluded from areas where other products are manufactured, or such
persons shall change outer clothing, including shoes, or wear protective
covering prior to entering such areas.
(4) Live vaccine work areas. Persons may not enter a live vaccine
processing area after having worked with other infectious agents in any
other laboratory during the same working day. Only persons actually
concerned with propagation of the culture, production of the vaccine,
and unit maintenance, shall be allowed in live vaccine processing areas
when active work is in progress. Casual visitors shall be excluded from
such units at all times and all others having business in such areas
shall be admitted only under supervision. Street clothing, including
shoes, shall be replaced or covered by suitable laboratory clothing
before entering a live vaccine processing unit. Persons caring for
animals used in the manufacture of live vaccines shall be excluded from
other animal quarters and from
[[Page 8]]
contact with other animals during the same working day.
[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55
FR 11014, Mar. 26, 1990]
Sec. 600.11 Physical establishment, equipment, animals, and care.
(a) Work areas. All rooms and work areas where products are
manufactured or stored shall be kept orderly, clean, and free of dirt,
dust, vermin and objects not required for manufacturing. Precautions
shall be taken to avoid clogging and back-siphonage of drainage systems.
Precautions shall be taken to exclude extraneous infectious agents from
manufacturing areas. Work rooms shall be well lighted and ventilated.
The ventilation system shall be arranged so as to prevent the
dissemination of microorganisms from one manufacturing area to another
and to avoid other conditions unfavorable to the safety of the product.
Filling rooms, and other rooms where open, sterile operations are
conducted, shall be adequate to meet manufacturing needs and such rooms
shall be constructed and equipped to permit thorough cleaning and to
keep air-borne contaminants at a minimum. If such rooms are used for
other purposes, they shall be cleaned and prepared prior to use for
sterile operations. Refrigerators, incubators and warm rooms shall be
maintained at temperatures within applicable ranges and shall be free of
extraneous material which might affect the safety of the product.
(b) Equipment. Apparatus for sterilizing equipment and the method of
operation shall be such as to insure the destruction of contaminating
microorganisms. The effectiveness of the sterilization procedure shall
be no less than that achieved by an attained temperature of 121.5 deg. C
maintained for 20 minutes by saturated steam or by an attained
temperature of 170 deg. C maintained for 2 hours with dry heat.
Processing and storage containers, filters, filling apparatus, and other
pieces of apparatus and accessory equipment, including pipes and tubing,
shall be designed and constructed to permit thorough cleaning and, where
possible, inspection for cleanliness. All surfaces that come in contact
with products shall be clean and free of surface solids, leachable
contaminants, and other materials that will hasten the deterioration of
the product or otherwise render it less suitable for the intended use.
For products for which sterility is a factor, equipment shall be
sterile, unless sterility of the product is assured by subsequent
procedures.
(c) Laboratory and bleeding rooms. Rooms used for the processing of
products, including bleeding rooms, shall be effectively fly-proofed and
kept free of flies and vermin. Such rooms shall be so constructed as to
insure freedom from dust, smoke and other deleterious substances and to
permit thorough cleaning and disinfection. Rooms for animal injection
and bleeding, and rooms for smallpox vaccine animals, shall be
disinfected and be provided with the necessary water, electrical and
other services.
(d) Animal quarters and stables. Animal quarters, stables and food
storage areas shall be of appropriate construction, fly-proofed,
adequately lighted and ventilated, and maintained in a clean, vermin-
free and sanitary condition. No manure or refuse shall be stored as to
permit the breeding of flies on the premises, nor shall the
establishment be located in close proximity to off-property manure or
refuse storage capable of engendering fly breeding.
(e) Restrictions on building and equipment use--(1) Work of a
diagnostic nature. Laboratory procedures of a clinical diagnostic nature
involving materials that may be contaminated, shall not be performed in
space used for the manufacture of products except that manufacturing
space which is used only occasionally may be used for diagnostic work
provided spore-bearing pathogenic microorganisms are not involved and
provided the space is thoroughly cleaned and disinfected before the
manufacture of products is resumed.
(2) Spore-bearing organisms for supplemental sterilization procedure
control test. Spore-bearing organisms used as an additional control in
sterilization procedures may be introduced into areas used for the
manufacture of products, only for the purposes of the test and only
immediately before use for such
[[Page 9]]
purposes: Provided, That (i) the organism is not pathogenic for man or
animals and does not produce pyrogens or toxins, (ii) the culture is
demonstrated to be pure, (iii) transfer of test cultures to culture
media shall be limited to the sterility test area or areas designated
for work with spore-bearing organisms, (iv) each culture be labeled with
the name of the microorganism and the statement ``Caution: microbial
spores. See directions for storage, use and disposition.'', and (v) the
container of each culture is designed to withstand handling without
breaking.
(3) Work with spore-bearing organisms. Except as provided in the
previous paragraph, all work with spore-bearing microorganisms shall be
done in an entirely separate building: Provided, That such work may be
done in a portion of a building used in the manufacture of products not
containing spore-bearing microorganisms if such portion is completely
walled-off and is constructed so as to prevent contamination of other
areas and if entrances to such portion are independent of the remainder
of the building. All vessels, apparatus and equipment used for spore-
bearing microorganisms shall be permanently identified and reserved
exclusively for use with those organisms. Materials destined for further
manufacturing may be removed from such an area only under conditions
which will prevent the introduction of spores into other manufacturing
areas.
(4) Live vaccine processing. Space used for processing a live
vaccine shall not be used for any other purpose during the processing
period for that vaccine and such space shall be decontaminated prior to
initiation of the processing. Live vaccine processing areas shall be
isolated from and independent of any space used for any other purpose by
being either in a separate building, in a separate wing of a building,
or in quarters at the blind end of a corridor and shall include adequate
space and equipment for all processing steps up to filling into final
containers. Test procedures which potentially involve the presence of
microorganisms other than the vaccine strains, or the use of tissue
culture cell lines other than primary cultures, shall not be conducted
in space used for processing live vaccine.
(5) Equipment and supplies--contamination. Equipment and supplies
used in work on or otherwise exposed to any pathogenic or potentially
pathogenic agent shall be kept separated from equipment and supplies
used in the manufacture of products to the extent necessary to prevent
cross-contamination.
(f) Animals used in manufacture--(1) Care of animals used in
manufacturing. Caretakers and attendants for animals used for the
manufacture of products shall be sufficient in number and have adequate
experience to insure adequate care. Animal quarters and cages shall be
kept in sanitary condition. Animals on production shall be inspected
daily to observe response to production procedures. Animals that become
ill for reasons not related to production shall be isolated from other
animals and shall not be used for production until recovery is complete.
Competent veterinary care shall be provided as needed.
(2) Quarantine of animals--(i) General. No animal shall be used in
processing unless kept under competent daily inspection and preliminary
quarantine for a period of at least 7 days before use, or as otherwise
provided in this subchapter. Only healthy animals free from detectable
communicable diseases shall be used. Animals must remain in overt good
health throughout the quarantine periods and particular care shall be
taken during the quarantine periods to reject animals of the equine
genus which may be infected with glanders and animals which may be
infected with tuberculosis.
(ii) Quarantine of monkeys. In addition to observing the pertinent
general quarantine requirements, monkeys used as a source of tissue in
the manufacture of vaccine shall be maintained in quarantine for at
least 6 weeks prior to use, except when otherwise provided in this part.
Only monkeys that have reacted negatively to tuberculin at the start of
the quarantine period and again within 2 weeks prior to use shall be
used in the manufacture of vaccine. Due precaution shall be taken to
prevent cross-infection from any infected or potentially infected
monkeys on the
[[Page 10]]
premises. Monkeys to be used in the manufacture of a live vaccine shall
be maintained throughout the quarantine period in cages closed on all
sides with solid materials except the front which shall be screened,
with no more than two monkeys housed in one cage. Cage mates shall not
be interchanged.
(3) Immunization against tetanus. Horses and other animals
susceptible to tetanus, that are used in the processing steps of the
manufacture of biological products, shall be treated adequately to
maintain immunity to tetanus.
(4) Immunization and bleeding of animals used as a source of
products. Toxins or other nonviable antigens administered in the
immunization of animals used in the manufacture of products shall be
sterile. Viable antigens, when so used, shall be free of contaminants,
as determined by appropriate tests prior to use. Injections shall not be
made into horses within 6 inches of bleeding site. Horses shall not be
bled for manufacturing purposes while showing persistent general
reaction or local reaction near the site of bleeding. Blood shall not be
used if it was drawn within 5 days of injecting the animals with viable
microorganisms. Animals shall not be bled for manufacturing purposes
when they have an intercurrent disease. Blood intended for use as a
source of a biological product shall be collected in clean, sterile
vessels. When the product is intended for use by injection, such vessels
shall also be pyrogen-free.
(5) [Reserved]
(6) Reporting of certain diseases. In cases of actual or suspected
infection with foot and mouth disease, glanders, tetanus, anthrax, gas
gangrene, equine infectious anemia; equine encephalomyelitis, or any of
the pock diseases among animals intended for use or used in the
manufacture of products, the manufacturer shall immediately notify the
Director, Center for Biologics Evaluation and Research.
(7) Monkeys used previously for experimental or test purposes.
Monkeys that have been used previously for experimental or test purposes
with live microbiological agents shall not be used as a source of kidney
tissue for the manufacture of vaccine. Except as provided otherwise in
this subchapter, monkeys that have been used previously for other
experimental or test purposes may be used as a source of kidney tissue
upon their return to a normal condition, provided all quarantine
requirements have been met.
(8) Necropsy examination of monkeys. Each monkey used in the
manufacture of vaccine shall be examined at necropsy under the direction
of a qualified pathologist, physician, or veterinarian having experience
with diseases of monkeys, for evidence of ill health, particularly for
(i) evidence of tuberculosis, (ii) presence of herpes-like lesions,
including eruptions or plaques on or around the lips, in the buccal
cavity or on the gums, and (iii) signs of conjunctivitis. If there are
any such signs or other significant gross pathological lesions, the
tissue shall not be used in the manufacture of vaccine.
(g) Filling procedures. Filling procedures shall be such as will not
affect adversely the safety, purity or potency of the product.
(h) Containers and closures. All final containers and closures shall
be made of material that will not hasten the deterioration of the
product or otherwise render it less suitable for the intended use. All
final containers and closures shall be clean and free of surface solids,
leachable contaminants and other materials that will hasten the
deterioration of the product or otherwise render it less suitable for
the intended use. After filling, sealing shall be performed in a manner
that will maintain the integrity of the product during the dating
period. In addition, final containers and closures for products intended
for use by injection shall be sterile and free from pyrogens. Except as
otherwise provided in the regulations of this subchapter, final
containers for products intended for use by injection shall be colorless
and sufficiently transparent to permit visual examination of the
contents under normal light. As soon as possible after filling final
containers shall be labeled as prescribed in Sec. 610.60 et seq. of this
chapter, except that final containers may be stored without such
prescribed labeling provided they are stored in a sealed receptacle
labeled both inside and outside with at least the name of the product,
[[Page 11]]
the lot number, and the filling identification.
[38 FR 32048, Nov. 20, 1973, as amended at 41 FR 10428, Mar. 11, 1976;
49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990]
Sec. 600.12 Records.
(a) Maintenance of records. Records shall be made, concurrently with
the performance, of each step in the manufacture and distribution of
products, in such a manner that at any time successive steps in the
manufacture and distribution of any lot may be traced by an inspector.
Such records shall be legible and indelible, shall identify the person
immediately responsible, shall include dates of the various steps, and
be as detailed as necessary for clear understanding of each step by one
experienced in the manufacture of products.
(b) Records retention--(1) General. Records shall be retained for
such interval beyond the expiration date as is necessary for the
individual product, to permit the return of any clinical report of
unfavorable reactions. The retention period shall be no less than five
years after the records of manufacture have been completed or six months
after the latest expiration date for the individual product, whichever
represents a later date.
(2) Records of recall. Complete records shall be maintained
pertaining to the recall from distribution of any product upon
notification by the Director, Center for Biologics Evaluation and
Research, to recall for failure to conform with the standards prescribed
in the regulations of this subchapter, because of deterioration of the
product or for any other factor by reason of which the distribution of
the product would constitute a danger to health.
(3) Suspension of requirement for retention. The Director, Center
for Biologics Evaluation and Research, may authorize the suspension of
the requirement to retain records of a specific manufacturing step upon
a showing that such records no longer have significance for the purposes
for which they were made: Provided, That a summary of such records shall
be retained.
(c) Records of sterilization of equipment and supplies. Records
relating to the mode of sterilization, date, duration, temperature and
other conditions relating to each sterilization of equipment and
supplies used in the processing of products shall be made by means of
automatic recording devices or by means of a system of recording which
gives equivalent assurance of the accuracy and reliability of the
record. Such records shall be maintained in a manner that permits an
identification of the product with the particular manufacturing process
to which the sterilization relates.
(d) Animal necropsy records. A necropsy record shall be kept on each
animal from which a biological product has been obtained and which dies
or is sacrificed while being so used.
(e) Records in case of divided manufacturing responsibility. If two
or more establishments participate in the manufacture of a product, the
records of each such establishment must show plainly the degree of its
responsibility. In addition, each participating manufacturer shall
furnish to the manufacturer who prepares the product in final form for
sale, barter or exchange, a copy of all records relating to the
manufacturing operations performed by such participating manufacturer
insofar as they concern the safety, purity and potency of the lots of
the product involved, and the manufacturer who prepares the product in
final form shall retain a complete record of all the manufacturing
operations relating to the product.
[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Sec. 600.13 Retention samples.
Manufacturers shall retain for a period of at least 6 months after
the expiration date, unless a different time period is specified in
additional standards, a quantity of representative material of each lot
of each product, sufficient for examination and testing for safety and
potency, except Whole Blood, Cryoprecipitated AHF, Platelets, Red Blood
Cells, Plasma, and Source Plasma and Allergenic Products prepared to a
physician's prescription. Samples so retained shall be selected at
random from either final container material, or from bulk and final
containers, provided they include at least one final container as a
final package,
[[Page 12]]
or package-equivalent of such filling of each lot of the product as
intended for distribution. Such sample material shall be stored at
temperatures and under conditions which will maintain the identity and
integrity of the product. Samples retained as required in this section
shall be in addition to samples of specific products required to be
submitted to the Center for Biologics Evaluation and Research.
Exceptions may be authorized by the Director, Center for Biologics
Evaluation and Research, when the lot yields relatively few final
containers and when such lots are prepared by the same method in large
number and in close succession.
[41 FR 10428, Mar. 11, 1976, as amended at 49 FR 23833, June 8, 1984; 50
FR 4133, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990]
Sec. 600.14 Reporting of errors.
(a) The Director, Office of Compliance, Center for Biologics
Evaluation and Research (HFB-100), 8800 Rockville Pike, Bethesda, MD
20892, shall be notified promptly of errors or accidents in the
manufacture of products that may affect the safety, purity, or potency
of any product.
(b) Manufacturers of licensed in vitro diagnostic products, and
manufacturers of unlicensed in vitro diagnostic products which are
required to be registered under part 607 of this chapter, shall notify
the Director in accordance with paragraph (a) of this section.
Manufacturers of other in vitro diagnostic products which are required
to be registered under part 807 of this chapter, shall report in
accordance with part 803 of this chapter.
[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 49
FR 36348, Sept. 14, 1984; 55 FR 11014, Mar. 26, 1990]
Sec. 600.15 Temperatures during shipment.
The following products shall be maintained during shipment at the
specified temperatures:
(a) Products.
------------------------------------------------------------------------
Product Temperature
------------------------------------------------------------------------
Cryoprecipitated AHF...................... -18 C or colder.
Measles and Rubella Virus Vaccine Live.... 10 C or colder.
Measles Live and Smallpox Vaccine......... Do.
Measles, Mumps, and Rubella Virus Vaccine Do.
Live.
Measles and Mumps Virus Vaccine Live...... Do.
Measles Virus Vaccine Live................ Do.
Mumps Virus Vaccine Live.................. Do.
Fresh Frozen Plasma....................... -18 C or colder.
Liquid Plasma............................. 1 to 10C.
Plasma.................................... -18 C or colder.
Platelet Rich Plasma...................... Between 1 and 10 C if the
label indicates storage
between 1 and 6 C, or all
reasonable methods to
maintain the temperature as
close as possible to a
range between 20 and 24 C,
if the label indicates
storage between 20 and 24
C.
Platelets................................. Between 1 and 10 C if the
label indicates storage
between 1 and 6 C, or all
reasonable methods to
maintain the temperature as
close as possible to a
range between 20 to 24 C,
if the label indicates
storage between 20 and 24
C.
Poliovirus Vaccine Live Oral Trivalent.... 0 C or colder.
Poliovirus Vaccine Live Oral Type I....... Do.
Poliovirus Vaccine Live Oral Type II...... Do.
Poliovirus Vaccine Live Oral Type III..... Do.
Red Blood Cells (liquid product).......... Between 1 and 10 C.
Red Blood Cells Frozen.................... -65 C or colder.
Rubella and Mumps Virus Vaccine Live...... 10 C or colder.
Rubella Virus Vaccine Live................ Do.
Smallpox Vaccine (Liquid Product)......... 0 C or colder.
Source Plasma............................. -5 C or colder.
Source Plasma Liquid...................... 10 C or colder.
Whole Blood............................... Blood that is transported
from the collecting
facility to the processing
facility shall be
transported in an
environment capable of
continuously cooling the
blood toward a temperature
range of 1 to 10 C, or at
a temperature as close as
possible to 20 to 24 C for
a period not to exceed 6
hours. Blood transported
from the storage facility
shall be placed in an
appropriate environment to
maintain a temperature
range between 1 to 10 C
during shipment.
Yellow Fever Vaccine...................... 0 C or colder.
------------------------------------------------------------------------
(b) Exemptions. Exemptions or modifications shall be made only upon
written approval, in the form of a
[[Page 13]]
supplement of the product license, issued by the Director, Center for
Biologics Evaluation and Research.
[39 FR 39872, Nov. 12, 1974, as amended at 49 FR 23833, June 8, 1984; 50
FR 4133, Jan. 29, 1985; 50 FR 9000, Mar. 6, 1985; 55 FR 11013, Mar. 26,
1990; 59 FR 49351, Sept. 28, 1994]
Subpart C--Establishment Inspection
Sec. 600.20 Inspectors.
Inspections shall be made by an officer of the Food and Drug
Administration having special knowledge of the methods used in the
manufacture and control of products and designated for such purposes by
the Commissioner of Food and Drugs, or by any officer, agent, or
employee of the Department of Health and Human Services specifically
designated for such purpose by the Secretary.
[38 FR 32048, Nov. 20, 1973]
Sec. 600.21 Time of inspection.
The inspection of an establishment for which a license is pending
need not be made until the establishment is in operation and is
manufacturing the complete product for which a product license is
desired. In case the license is denied following inspection for the
original license, no reinspection need be made until assurance has been
received that the faulty conditions which were the basis of the denial
have been corrected. An inspection of each licensed establishment and
its additional location(s) shall be made at least once every 2 years.
Inspections may be made with or without notice, and shall be made during
regular business hours unless otherwise directed.
[38 FR 32048, Nov. 20, 1973, as amended at 48 FR 26314, June 7, 1983]
Sec. 600.22 Duties of inspector.
The inspector shall:
(a) Call upon the active head of the establishment, stating the
object of his visit,
(b) Interrogate the proprietor or other personnel of the
establishment as he may deem necessary,
(c) Examine the details of location, construction, equipment and
maintenance, including stables, barns, warehouses, manufacturing
laboratories, bleeding clinics maintained for the collection of human
blood, shipping rooms, record rooms, and any other structure or
appliance used in any part of the manufacture of a product,
(d) Investigate as fully as he deems necessary the methods of
propagation, processing, testing, storing, dispensing, recording, or
other details of manufacture and distribution of each licensed product,
or product for which a license has been requested, including observation
of these procedures in actual operation,
(e) Obtain and cause to be sent to the Director, Center for
Biologics Evaluation and Research, adequate samples for the examination
of any product or ingredient used in its manufacture,
(f) Bring to the attention of the manufacturer any fault observed in
the course of inspection in location, construction, manufacturing
methods, or administration of a licensed establishment which might lead
to impairment of a product,
(g) Inspect and copy, as circumstances may require, any records
required to be kept pursuant to Sec. 600.12,
(h) Certify as to the condition of the establishment and of the
manufacturing methods followed and make recommendations as to action
deemed appropriate with respect to any application for license or any
license previously issued.
[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Subpart D--Reporting of Adverse Experiences
Source: 59 FR 54042, Oct. 27, 1994, unless otherwise noted.
Sec. 600.80 Postmarketing reporting of adverse experiences.
(a) Definitions. The following definitions of terms apply to this
section:
Adverse experience means any adverse event associated with the use
of a biological product in humans, whether or not considered product
related, including the following: an adverse event occurring in the
course of the use of a biological product in professional practice; an
adverse event occurring from
[[Page 14]]
overdose of the product, whether accidental or intentional; an adverse
event occurring from abuse of the product; an adverse event occurring
from withdrawal of the product; and any failure of expected
pharmacological action.
Blood Component for this purpose has the same meaning as defined in
Sec. 606.3(c) of this chapter.
Increased frequency means an increase in the rate of occurrence of a
particular adverse biological product experience, e.g., an increased
number of reports of a particular adverse biological product experience
after appropriate adjustment for biological product exposure.
Serious means an adverse experience associated with the use of a
biological product that is fatal or life-threatening, is permanently
disabling, requires inpatient hospitalization, or is a congenital
anomaly, cancer, or overdose.
Unexpected means an adverse biological product experience that is
not listed in the current labeling for the product and includes an event
that may be symptomatically and pathophysiologically related to an event
listed in the labeling, but differs from the event because of greater
severity or specificity. For example, under this definition, hepatic
necrosis would be unexpected (by virtue of greater severity) if the
labeling only referred to elevated hepatic enzymes or hepatitis.
Similarly, cerebral thromboembolism and cerebral vasculitis would be
unexpected (by virtue of greater specificity) if the labeling only
listed cerebral vascular accidents.
(b) Review of adverse experiences. Any person having a product
license under Sec. 601.20 of this chapter shall promptly review all
adverse experience information pertaining to its product obtained or
otherwise received by the licensed manufacturer from any source, foreign
or domestic, including information derived from commercial marketing
experience, postmarketing clinical investigations, postmarketing
epidemiological/surveillance studies, reports in the scientific
literature, and unpublished scientific papers.
(c) Reporting requirements. The licensed manufacturer shall report
to FDA adverse experience information, as described in this section. The
licensed manufacturer shall submit two copies of each report described
in this section for nonvaccine biological products, to the Center for
Biologics Evaluation and Research (HFM-210), Food and Drug
Administration, 1401 Rockville Pike, suite 200 N., Rockville, MD 20852-
1448. Submit all vaccine adverse experience reports to: Vaccine Adverse
Event Reporting System (VAERS), P.O. Box 1100, Rockville, MD 20849-1100.
FDA may waive the requirement for the second copy in appropriate
instances.
(1) Fifteen-day Alert reports. (i) The licensed manufacturer shall
report each adverse experience that is both serious and unexpected,
regardless of source, as soon as possible but in any case within 15
working days of initial receipt of the information. These reports are
required to be submitted, for nonvaccine biological products, on a form
designated by FDA or a suitable format containing all of the data
elements in the FDA designated reporting form, and, for vaccines on a
VAERS form. The licensed manufacturer shall promptly investigate all
adverse experiences that are the subject of these 15-day Alert reports
and shall submit followup reports within 15 working days of receipt of
new information or as requested by FDA. If additional information is not
obtainable, a followup report may be required that describes briefly the
steps taken to seek additional information and the reasons why it could
not be obtained. These 15-day Alert reports and followups to them are
required to be submitted under separate cover and may not be included,
except for summary or tabular purposes, in a periodic report.
(ii) The licensed manufacturer shall review periodically (at least
as often as the periodic reporting cycle) the frequency of reports of
adverse biological product experiences that are both serious and
expected and reports of therapeutic failure (lack of effect), regardless
of source, and report any significant increase in frequency as soon as
possible but in any case within 15 working days of determining that a
significant increase in frequency exists. Upon written notice, FDA may
require that licensed manufacturers
[[Page 15]]
review the frequency of reports of serious, expected adverse biological
product experiences at intervals different than the periodic reporting
cycle. Reports of a significant increase in frequency are required to be
submitted in narrative form (including the time period on which the
increased frequency is based, the method of analysis, and the
interpretation of the results), rather than using the form designated by
FDA. Fifteen-day Alert reports based on increased frequency are required
to be submitted under separate cover and may not be included, except for
summary purposes, in a periodic report.
(iii) The requirements of paragraphs (c)(1)(i) and (c)(1)(ii) of
this section, concerning the submission of Fifteen-day Alert reports,
shall also apply to any person other than the licensed manufacturer of
the final product whose name appears on the label of a licensed
biological product as a manufacturer, packer, distributor, shared
manufacturer, joint manufacturer, or any other participant involved in
divided manufacturing. In order to avoid unnecessary duplication in the
initial and followup submission of reports to FDA, the obligations of a
manufacturer other than the licensed manufacturer, may be met by
submitting all reports to the licensed manufacturer of the final
product. If a manufacturer other than the licensed manufacturer elects
to submit reports to the licensed manufacturer rather than to FDA, it
shall submit each report to the licensed manufacturer within 3 working
days of its receipt, and the licensed manufacturer shall then comply
with the requirements of this section. Under this circumstance, the
manufacturer shall maintain a record of this action which shall include:
(A) A copy of all adverse biological product experience reports
submitted to the licensed manufacturer,
(B) Date the report was received by the manufacturer,
(C) Date the report was submitted to the licensed manufacturer,
(D) Name and address of the licensed manufacturer.
(iv) Each report submitted under this paragraph shall bear prominent
identification as to its contents, i.e., ``15-day Alert report'' or
``15-day Alert report--followup.''
(2) Periodic adverse experience reports. (i) The licensed
manufacturer shall report each adverse experience not reported under
paragraph (c)(1)(i) of this section at quarterly intervals, for 3 years
from the date of issuance of the product license, and then at annual
intervals. The licensed manufacturer shall submit each quarterly report
within 30 days of the close of the quarter (the first quarter beginning
on the date of issuance of the product license) and each annual report
within 60 days of the anniversary date of the issuance of the product
license. Upon written notice, FDA may extend or reestablish the
requirement that a licensed manufacturer submit quarterly reports, or
require that the licensed manufacturer submit reports under this section
at different times than those stated. Followup information to adverse
experiences submitted in a periodic report may be submitted in the next
periodic report.
(ii) Each periodic report shall contain:
(A) A narrative summary and analysis of the information in the
report and an analysis of the 15-day Alert reports submitted during the
reporting interval (all 15-day Alert reports being appropriately
referenced by the licensed manufacturer's patient identification number,
adverse reaction term(s), and date of submission to FDA);
(B) A form designated for Adverse Experience Reporting by FDA for
each adverse experience not reported under paragraph (c)(1)(i) of this
section (with an index consisting of a line listing of the licensed
manufacturer's patient identification number and adverse reaction
term(s)); and
(C) A history of actions taken since the last report because of
adverse experiences (for example, labeling changes or studies
initiated).
(iii) Periodic reporting, except for information regarding 15-day
Alert reports, does not apply to adverse experience information obtained
from postmarketing studies (whether or not conducted under an
investigational new drug application), from reports in the scientific
literature, and from foreign marketing experience.
[[Page 16]]
(d) Scientific literature. (1) A 15-day Alert report based on
information from the scientific literature shall be accompanied by a
copy of the published article. The 15-day Alert reporting requirements
in paragraph (c)(1)(i) of this section (i.e., serious, unexpected
adverse experiences) apply only to reports found in scientific and
medical journals either as case reports or as the result of a formal
clinical trial. The 15-day Alert reporting requirements in paragraph
(c)(1)(ii) of this section (i.e., a significant increase in frequency of
a serious, expected adverse experience or of a therapeutic failure)
apply only to reports found in scientific and medical journals either as
the result of a formal clinical trial, or from epidemiologic studies or
analyses of experience in a monitored series of patients.
(2) As with all reports submitted under paragraph (c)(1)(i) of this
section, reports based on the scientific literature shall be submitted
on the reporting form designated by FDA or comparable format as
prescribed by paragraph (f) of this section. In cases where the licensed
manufacturer believes that preparing the form designated by FDA
constitutes an undue hardship, the licensed manufacturer may arrange
with the Division of Biostatistics and Epidemiology (HFM-210) for an
acceptable alternative reporting format.
(e) Postmarketing studies. (1) Licensed manufacturers are not
required to submit a 15-day Alert report under paragraph (c) of this
section for an adverse experience obtained from a postmarketing clinical
study (whether or not conducted under a biological investigational new
drug application) unless the licensed manufacturer concludes that there
is a reasonable possibility that the product caused the adverse
experience.
(2) The licensed manufacturer shall separate and clearly mark
reports of adverse experiences that occur during a postmarketing study
as being distinct from those experiences that are being reported
spontaneously to the licensed manufacturer.
(f) Reporting forms. (1) Except as provided in paragraphs
(c)(1)(ii), and (f)(3) of this section, the licensed manufacturer shall
complete the reporting form designated by FDA (FDA-3500A, or, for
vaccines, a VAERS form) for each report of an adverse experience.
(2) Each completed form should refer only to an individual patient
or single attached publication.
(3) Instead of using a designated reporting form, a licensed
manufacturer may use a computer-generated form or other alternative
format (e.g., a computer-generated tape or tabular listing) provided
that:
(i) The content of the alternative format is equivalent in all
elements of information to those specified in the form designated by
FDA; and
(ii) the format is approved in advance by MEDWATCH: The FDA Medical
Products Reporting Program; or, for alternatives to the VAERS Form, by
the Division of Biostatistics and Epidemiology.
(4) Copies of the reporting form designated by FDA (FDA-3500A) for
nonvaccine biological products may be obtained from the Center for
Biologics Evaluation and Research (address above). Additional supplies
of the form may be obtained from the Consolidated Forms and Publications
Distribution Center, 3222 Hubbard Rd., Landover, MD 20785. Supplies of
the VAERS form may be obtained from VAERS by calling 1-800-822-7967.
(g) Multiple reports. A licensed manufacturer should not include in
reports under this section any adverse experiences that occurred in
clinical trials if they were previously submitted in the product license
application. If a report refers to more than one biological product
marketed by a licensed manufacturer, the licensed manufacturer should
submit the report to the license for the product listed first in the
report.
(h) Patient privacy. For nonvaccine biological products, a licensed
manufacturer should not include in reports under this section the names
and addresses of individual patients; instead, the licensed manufacturer
should assign a unique code number to each report, preferably not more
than eight characters in length. The licensed manufacturer should
include the name of the reporter from whom the information was received.
The names of patients, health care professionals,
[[Page 17]]
hospitals, and geographical identifiers in adverse experience reports
are not releasable to the public under FDA's public information
regulations in part 20 this of chapter. For vaccine adverse experience
reports, these data will become part of the CDC Privacy Act System 09-
20-0136, ``Epidemiologic Studies and Surveillance of Disease Problems.''
Information identifying the person who received the vaccine or that
person's legal representative will not be made available to the public,
but may be available to the vaccinee or legal representative.
(i) Recordkeeping. The licensed manufacturer shall maintain for a
period of 10 years records of all adverse experiences known to the
licensed manufacturer, including raw data and any correspondence
relating to the adverse experiences.
(j) Guideline. FDA has prepared a guideline for the submission of
reports of adverse experiences and suggested followup investigation of
reports.
(k) Revocation of license. If a licensed manufacturer fails to
establish and maintain records and make reports required under this
section with respect to a licensed biological product, FDA may revoke
the product license for such a product in accordance with the procedures
of Sec. 601.5 of this chapter.
(l) Exemptions. Manufacturers of the following listed products are
not required to submit adverse experience reports under this section:
(1) Whole blood or components of whole blood.
(2) In vitro diagnostic products, including assay systems for the
detection of antibodies or antigens to retroviruses. These products are
subject to the reporting requirements for devices.
(m) Disclaimer. A report or information submitted by a licensed
manufacturer under this section (and any release by FDA of that report
or information) does not necessarily reflect a conclusion by the
licensed manufacturer or FDA that the report or information constitutes
an admission that the biological product caused or contributed to an
adverse effect. A licensed manufacturer need not admit, and may deny,
that the report or information submitted under this section constitutes
an admission that the biological product caused or contributed to an
adverse effect. For purposes of this provision, this paragraph also
includes any person reporting under paragraph (c)(1)(iii) of this
section.
Sec. 600.81 Distribution reports.
The licensed manufacturer shall submit information about the
quantity of the product distributed under the product license, including
the quantity distributed to distributors. The interval between
distribution reports shall be 6 months. Upon written notice, FDA may
require that the licensed manufacturer submit distribution reports under
this section at times other than every 6 months. The distribution report
shall consist of the bulk lot number (from which the final container was
filled), the fill lot numbers for the total number of dosage units of
each strength or potency distributed (e.g., fifty thousand per 10-
milliliter vials), the label lot number (if different from fill lot
number), labeled date of expiration, number of doses in fill lot/label
lot, date of release of fill lot/label lot for distribution at that
time. If any significant amount of a fill lot/label lot is returned,
include this information. Disclosure of financial or pricing data is not
required. As needed, FDA may require submission of more detailed product
distribution information. Upon written notice, FDA may require that the
licensed manufacturer submit reports under this section at times other
than those stated. Requests by a licensed manufacturer to submit reports
at times other than those stated should be made as a request for a
waiver under Sec. 600.90.
Sec. 600.90 Waivers.
(a) A licensed manufacturer may ask the Food and Drug Administration
to waive under this section any requirement that applies to the licensed
manufacturer under Secs. 600.80 and 600.81. A waiver request under this
section is required to be submitted with supporting documentation. The
waiver request is required to contain one of the following:
(1) An explanation why the licensed manufacturer's compliance with
the
[[Page 18]]
requirement is unnecessary or cannot be achieved,
(2) A description of an alternative submission that satisfies the
purpose of the requirement, or
(3) Other information justifying a waiver.
(b) FDA may grant a waiver if it finds one of the following:
(1) The licensed manufacturer's compliance with the requirement is
unnecessary or cannot be achieved,
(2) The licensed manufacturer's alternative submission satisfies the
requirement, or
(3) The licensed manufacturer's submission otherwise justifies a
waiver.
PART 601--LICENSING--Table of Contents
Subpart A--General Provisions
Sec.
601.1 Two forms of licenses.
601.2 Applications for establishment and product licenses; procedure
for filing.
601.3 License forms.
601.4 Issuance and denial of license.
601.5 Revocation of license.
601.6 Suspension of license.
601.7 Procedure for hearings.
601.8 Publication of revocation.
601.9 Licenses; reissuance.
Subpart B--Establishment Licensing
601.10 Establishment licenses; issuance and conditions.
601.12 Changes to be reported.
Subpart C--Product Licensing
601.20 Product licenses; issuance and conditions.
601.21 Products under development.
601.22 Products in short supply; initial manufacturing at other than
licensed establishment.
601.25 Review procedures to determine that licensed biological products
are safe, effective, and not misbranded under prescribed,
recommended, or suggested conditions of use.
601.26 Reclassification procedures to determine that licensed
biological products are safe, effective, and not misbranded
under prescribed, recommended, or suggested conditions of use.
Subpart D--Licensing of Foreign Establishments and Products
601.30 Licenses required; products for controlled investigation only.
601.31 Procedure.
601.32 Form of license.
601.33 Samples for each importation.
Subpart E--Accelerated Approval of Biological Products for Serious or
Life-Threatening Illnesses
601.40 Scope.
601.41 Approval based on a surrogate endpoint or on an effect on a
clinical endpoint other than survival or irreversible
morbidity.
601.42 Approval with restrictions to assure safe use.
601.43 Withdrawal procedures.
601.44 Postmarketing safety reporting.
601.45 Promotional materials.
601.46 Termination of requirements.
Subpart F--Confidentiality of Information
601.50 Confidentiality of data and information in an investigational
new drug notice for a biological product.
601.51 Confidentiality of data and information in applications for
establishment and product licenses.
Authority: Secs. 201, 501, 502, 503, 505, 510, 513-516, 518-520,
701, 704, 721, 801 of the Federal Food, Drug, and Cosmetic Act (21
U.S.C. 321, 351, 352, 353, 355, 360, 360c-360f, 360h-360j, 371, 374,
379e, 381); secs. 215, 301, 351, 352 of the Public Health Service Act
(42 U.S.C. 216, 241, 262, 263); secs. 2-12 of the Fair Packaging and
Labeling Act (15 U.S.C. 1451-1461).
Source: 38 FR 32052, Nov. 20, 1973, unless otherwise noted.
Cross References: For U.S. Customs Service regulations relating to
viruses, serums, and toxins, see 19 CFR 12.21--12.23. For U.S. Postal
Service regulations relating to the admissibility to the United States
mails see parts 124 and 125 of the Domestic Mail Manual, that is
incorporated by reference in 39 CFR part 111.
Subpart A--General Provisions
Sec. 601.1 Two forms of licenses.
There shall be two forms of licenses: establishment and product.
Sec. 601.2 Applications for establishment and product licenses; procedures for filing.
(a) General. To obtain a license for any establishment or product,
the manufacturer shall make application to the Director, Center for
Biologics Evaluation and Research, on forms prescribed for such
purposes, and in the case of an application for a product license, shall
submit data derived from
[[Page 19]]
nonclinical laboratory and clinical studies which demonstrate that the
manufactured product meets prescribed standards of safety, purity, and
potency; with respect to each nonclinical laboratory study, either a
statement that the study was conducted in compliance with the
requirements set forth in part 58 of this chapter, or, if the study was
not conducted in compliance with such regulations, a brief statement of
the reason for the noncompliance; statements regarding each clinical
investigation involving human subjects contained in the application,
that it either was conducted in compliance with the requirements for
institutional review set forth in part 56 of this chapter or was not
subject to such requirements in accordance with Sec. 56.104 or
Sec. 56.105, and was conducted in compliance with requirements for
informed consent set forth in part 50 of this chapter; a full
description of manufacturing methods; data establishing stability of the
product through the dating period; sample(s) representative of the
product to be sold, bartered, or exchanged or offered, sent, carried or
brought for sale, barter, or exchange; summaries of results of tests
performed on the lot(s) represented by the submitted sample(s); and
specimens of the labels, enclosures, and containers proposed to be used
for the product. An application for license shall not be considered as
filed until all pertinent information and data have been received from
the manufacturer by the Center for Biologics Evaluation and Research.
The applicant shall also include either a claim for categorical
exclusion under Sec. 25.24 of this chapter or an environmental
assessment under Sec. 25.31 of this chapter. In lieu of the procedures
described in this paragraph, applications for radioactive biological
products shall be handled as set forth in paragraph (b) of this section.
(b) Radioactive biological products. In lieu of submitting an
establishment and product license for the manufacture of a radioactive
biological product, as defined in Sec. 600.3(ee) of this chapter, the
manufacturer of such a product shall submit a new drug application to
the Director, Division of Medical Imaging, Surgical, and Dental Products
(HFD-160), Center for Drug Evaluation and Research, Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857, consistent with
the procedures set forth in Sec. 314.50 of this chapter. For such
products, the approval of the new drug application will be in lieu of
issuing a product and an establishment license. Compliance with the
provisions of part 314 of this chapter shall be deemed to constitute
compliance with the provisions of Subchapter F of this chapter unless
the Commissioner makes a determination that a particular regulation from
Subchapter F shall be applicable to radioactive drugs containing a
biological product, e.g., Sec. 610.2 of this chapter.
[40 FR 31313, July 25, 1975, as amended at 46 FR 8955, Jan. 27, 1981; 47
FR 6618, Feb. 16, 1982; 49 FR 23833, June 8, 1984; 50 FR 7518, Feb. 22,
1985; 50 FR 16669, Apr. 26, 1985; 55 FR 11013 and 11014, Mar. 26, 1990]
Sec. 601.3 License forms.
(a) Establishment license. The establishment license form shall be
prescribed by the Director, Center for Biologics Evaluation and Research
and shall include:
(1) The name and address of the manufacturer.
(2) The name and address of the establishment.
(3) The names and addresses of all locations of the establishment.
(4) The license number.
(5) The date of issuance.
(b) Product license. The product license form shall be prescribed by
the Director, Center for Biologics Evaluation and Research and shall
include:
(1) The name and address of the manufacturer.
(2) The name and address of the establishment.
(3) The name and address of each location at which the product is
manufactured.
(4) The license number of the establishment.
(5) The proper name of the product, with additional specifications,
if any, which may be approved or required for additional labeling
purposes.
[38 FR 32052, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
[[Page 20]]
Sec. 601.4 Issuance and denial of license.
(a) An establishment or product license shall be issued upon a
determination by the Director, Center for Biologics Evaluation and
Research that the establishment or the product, as the case may be,
meets the applicable standards established in this chapter. Licenses
shall be valid until suspended or revoked.
(b) If the Commissioner determines that the establishment or product
does not meet the standards established in this chapter, he shall deny
the application and inform the applicant of the grounds for, and of an
opportunity for a hearing on, his decision. If the applicant so
requests, the Commissioner shall issue a notice of opportunity for
hearing on the matter pursuant to Sec. 12.21(b) of this chapter.
[42 FR 4718, Jan. 25, 1977, as amended at 42 FR 15676, Mar. 22, 1977; 42
FR 19142, Apr. 12, 1977; 49 FR 23833, June 8, 1984; 55 FR 11013, Mar.
26, 1990]
Sec. 601.5 Revocation of license.
(a) An establishment or product license shall be revoked upon
application of the manufacturer giving notice of intention to
discontinue the manufacture of all products or to discontinue the
manufacture of a particular product for which a license is held, and
waiving an opportunity for a hearing on the matter.
(b) If the Commissioner finds that (1) authorized Food and Drug
Administration employees after reasonable efforts have been unable to
gain access to an establishment or a location for the purpose of
carrying out the inspection required under Sec. 600.21 of this chapter,
(2) manufacturing of products or of a product has been discontinued to
an extent that a meaningful inspection or evaluation cannot be made, (3)
the manufacturer has failed to report a change as required by
Sec. 601.12, (4) the establishment or any location thereof, or the
product for which the license has been issued, fails to conform to the
applicable standards established in the license and in this chapter
designed to ensure the continued safety, purity, and potency of the
manufactured product, (5) the establishment or the manufacturing methods
have been so changed as to require a new showing that the establishment
or product meets the standards established in this chapter in order to
protect the public health, or (6) the licensed product is not safe and
effective for all of its intended uses or is misbranded with respect to
any such use, he shall notify the licensee of his intention to revoke
the license, setting forth the grounds for, and offering an opportunity
for a hearing on, the proposed revocation. Except as provided in
Sec. 601.6 or in cases involving willfulness, the notification required
in this paragraph shall provide a reasonable period for the licensee to
demonstrate or achieve compliance with the requirements of this chapter,
before proceedings will be instituted for the revocation of the license.
If compliance is not demonstrated or achieved and the licensee does not
waive the opportunity for a hearing, the Commissioner shall issue a
notice of opportunity for hearing on the matter pursuant to
Sec. 12.21(b) of this chapter.
[42 FR 4718, Jan. 25, 1977, as amended at 42 FR 15676, Mar. 22, 1977; 42
FR 19143, Apr. 12, 1977; 49 FR 23833, June 8, 1984]
Sec. 601.6 Suspension of license.
(a) Whenever the Commissioner has reasonable grounds to believe that
any of the grounds for revocation of a license exist and that by reason
thereof there is a danger to health, he may notify the licensee that his
license for the establishment or the product is suspended and require
that the licensee (1) notify the selling agents and distributors to whom
such product or products have been delivered of such suspension, and (2)
furnish to the Director, Center for Biologics Evaluation and Research,
complete records of such deliveries and notice of suspension.
(b) Upon suspension of a license, the Commissioner shall either (1)
proceed pursuant to the provisions of Sec. 601.5(b) to revoke the
license, or (2) if the licensee agrees, hold revocation in abeyance
pending resolution of the matters involved.
[42 FR 4718, Jan. 25, 1977 as amended at 49 FR 23833, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Sec. 601.7 Procedure for hearings.
(a) A notice of opportunity for hearing, notice of appearance and
request
[[Page 21]]
for hearing, and grant or denial of hearing for a biological drug
pursuant to this part, for which the exemption from the Federal Food,
Drug, and Cosmetic Act in Sec. 310.4 of this chapter has been revoked,
shall be subject to the provisions of Sec. 314.200 of this chapter
except to the extent that the notice of opportunity for hearing on the
matter issued pursuant to Sec. 12.21(b) of this chapter specifically
provides otherwise.
(b) Hearings pursuant to Secs. 601.4 through 601.6 shall be governed
by part 12 of this chapter.
(c) When a license has been suspended pursuant to Sec. 601.6 and a
hearing request has been granted, the hearing shall proceed on an
expedited basis.
[42 FR 4718, Jan. 25, 1977, as amended at 42 FR 15676, Mar. 22, 1977; 42
FR 19143, Apr. 12, 1977]
Sec. 601.8 Publication of revocation.
Notice of revocation of a license, with statement of the cause
therefor, shall be issued by the Commissioner and published in the
Federal Register.
[42 FR 4718, Jan. 25, 1977]
Sec. 601.9 Licenses; reissuance.
(a) Compliance with standards. An establishment or product license,
previously suspended or revoked, may be reissued or reinstated upon a
showing of compliance with required standards and upon such inspection
and examination as may be considered necessary by the Director, Center
for Biologics Evaluation and Research.
(b) Exclusion of noncomplying location. An establishment or product
license, excluding a location or locations that fail to comply with
required standards, may be issued without further application and
concurrently with the suspension or revocation of the license for
noncompliance at the excluded location or locations.
[42 FR 4718, Jan. 25, 1977, as amemded at 49 FR 23833, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Subpart B--Establishment Licensing
Sec. 601.10 Establishment licenses; issuance and conditions.
(a) Inspection--compliance with standards. An establishment license
shall be issued only after inspection of the establishment and upon a
determination that the establishment complies with the applicable
standards prescribed in the regulations in this subchapter.
(b) Availability of product; simultaneous request for and issuance
of product license. No establishment license shall be issued unless (1)
a product intended for sale, barter or exchange or intended to be
offered, sent, carried or brought for sale, barter or exchange is
available for examination, (2) such product is available for inspection
during all phases of manufacture and (3) a product license is requested
and issued simultaneously with the establishment license.
(c) One establishment license to cover all locations. One
establishment license shall be issued to cover all locations meeting the
establishment standards.
Sec. 601.12 Changes to be reported.
(a) General. Important proposed changes in location, equipment,
management and responsible personnel, or in manufacturing methods and
labeling, of any product for which a license is in effect or for which
an application for license is pending, shall be reported to the
Director, Center for Biologics Evaluation and Research, by the
manufacturer, and unless in case of an emergency, not less than 30 days
in advance of the time such changes are intended to be made.
(b) Manufacturing methods and labeling. Proposed changes in
manufacturing methods and labeling may not become effective until
notification of acceptance is received from the Director, Center for
Biologics Evaluation and Research.
[38 FR 32052, Nov. 20, 1973. Redesignated and amended at 42 FR 4718,
Jan. 25, 1977; 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990]
[[Page 22]]
Subpart C--Product Licensing
Sec. 601.20 Product licenses; issuance and conditions.
(a) Examination--compliance with standards. A product license shall
be issued only upon examination of the product and upon a determination
that the product complies with the standards prescribed in the
regulations in this subchapter: Provided, That no product license shall
be issued except upon a determination that the establishment complies
with the establishment standards prescribed in the regulations contained
in this subchapter, applicable to the manufacture of such product.
(b) Manufacturing process--impairment of assurances. No product
shall be licensed if any part of the process of or relating to the
manufacture of such product, in the judgment of the Commissioner of Food
and Drugs, would impair the assurances of continued safety, purity and
potency as provided by the regulations contained in this subchapter.
Sec. 601.21 Products under development.
A biological product undergoing development, but not yet ready for a
product license, may be shipped or otherwise delivered from one State or
possession into another State or possession provided such shipment or
delivery is not for sale, barter, or exchange, except as provided in
section 505(i) of the Federal Food, Drug, and Cosmetic Act, as amended,
and the regulations thereunder (21 CFR part 312).
[45 FR 73923, Nov. 7, 1980, as amended at 55 FR 11014, Mar. 26, 1990]
Sec. 601.22 Products in short supply; initial manufacturing at other than licensed establishment.
Licenses issued to a manufacturer for an establishment shall
authorize persons other than such manufacturer to conduct at places
other than such establishment the initial, and partial manufacturing of
a product for shipment solely to such manufacturer only to the extent
that the names of such persons and places are registered with the
Commissioner of Food and Drugs and he finds upon application of such
manufacturer, that (a) the product is in short supply due either to the
peculiar growth requirements of the organism involved or to the scarcity
of the animal required for manufacturing purposes, and (b) such
manufacturer has established with respect to such persons and places
such procedures, inspections, tests or other arrangements as will assure
full compliance with the applicable regulations of this subchapter
related to continued safety, purity, and potency. Such persons and
places shall be subject to all regulations of this subchapter except
Secs. 601.1 to 601.6, 601.9, 601.10, 601.20, 601.21, 601.30 to 601.33,
and Secs. 610.60 to 610.65 of this chapter. Failure of such manufacturer
to maintain such procedures, inspections, tests, or other arrangements,
or failure of any person conducting such partial manufacturing to comply
with applicable regulations shall constitute a ground for suspension or
revocation of the authority conferred pursuant to this section on the
same basis as provided in Secs. 601.6 to 601.8 with respect to the
suspension and the revocation of licenses.
[42 FR 4718, Jan. 25, 1977]
Sec. 601.25 Review procedures to determine that licensed biological products are safe, effective, and not misbranded under prescribed, recommended, or
suggested conditions of use.
For purposes of reviewing biological products that have been
licensed prior to July 1, 1972, to determine that they are safe and
effective and not misbranded, the following regulations shall apply.
Prior administrative action exempting biological products from the
provisions of the Federal Food, Drug, and Cosmetic Act is superseded to
the extent that these regulations result in imposing requirements
pursuant to provisions therein for a designated biological product or
category of products.
(a) Advisory review panels. The Commissioner of Food and Drugs shall
appoint advisory review panels (1) to evaluate the safety and
effectiveness of biological products for which a license has been issued
pursuant to section 351 of the Public Health Service Act, (2) to review
the labeling of such biological products, and (3) to advise him on
[[Page 23]]
which of the biological products under review are safe, effective, and
not misbranded. An advisory review panel shall be established for each
designated category of biological product. The members of a panel shall
be qualified experts, appointed by the Commissioner, and shall include
persons from lists submitted by organizations representing professional,
consumer, and industry interests. Such persons shall represent a wide
divergence of responsible medical and scientific opinion. The
Commissioner shall designate the chairman of each panel, and summary
minutes of all meetings shall be made.
(b) Request for data and views. (1) The Commissioner of Food and
Drugs will publish a notice in the Federal Register requesting
interested persons to submit, for review and evaluation by an advisory
review panel, published and unpublished data and information pertinent
to a designated category of biological products.
(2) Data and information submitted pursuant to a published notice,
and falling within the confidentiality provisions of 18 U.S.C. 1905, 5
U.S.C. 552(b), or 21 U.S.C. 331(j), shall be handled by the advisory
review panel and the Food and Drug Administration as confidential until
publication of a proposed evaluation of the biologics under review and
the full report or reports of the panel. Thirty days thereafter such
data and information shall be made publicly available and may be viewed
at the Dockets Management Branch of the Food and Drug Administration,
except to the extent that the person submitting it demonstrates that it
still falls within the confidentiality provisions of one or more of
those statutes.
(3) To be considered, 12 copies of the submission on any marketed
biological product within the class shall be submitted, preferably
bound, indexed, and on standard sized paper, approximately 8\1/2\ x 11
inches. The time allotted for submissions will be 60 days, unless
otherwise indicated in the specific notice requesting data and views for
a particular category of biological products. When requested,
abbreviated submissions should be sent. All submissions shall be in the
following format, indicating ``none'' or ``not applicable'' where
appropriate, unless changed in the Federal Register notice:
Biological Products Review Information
I. Label or labels and all other labeling (preferably mounted.
Facsimile labeling is acceptable in lieu of actual container labeling),
including labeling for export.
II. Representative advertising used during the past 5 years.
III. The complete quantitative composition of the biological
product.
IV. Animal safety data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
C. Finished biological product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
V. Human safety data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a
determination as to the safety of each individual active component.
5. Pertinent medical and scientific literature.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a
determination as to the safety of combinations of the individual active
components.
5. Pertinent medical and scientific literature.
C. Finished biological product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a
determination as to the safety of the finished biological product.
5. Pertinent medical and scientific literature.
VI. Efficacy data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
[[Page 24]]
4. Pertinent marketing experiences that may influence a
determination on the efficacy of each individual active component.
5. Pertinent medical and scientific literature.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a
determination as to the effectiveness of combinations of the individual
active components.
5. Pertinent medical and scientific literature.
C. Finished biological product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a
determination as to the effectiveness of the finished biological
product.
5. Pertinent medical and scientific literature.
VII. A summary of the data and views setting forth the medical
rational and purpose (or lack thereof) for the biological product and
its components and the scientific basis (or lack thereof) for the
conclusion that the biological product, including its components, has
been proven safe and effective and is properly labeled for the intended
use or uses. If there is an absence of controlled studies in the
materials submitted, an explanation as to why such studies are not
considered necessary or feasible shall be included.
VIII. If the submission is by a licensee, a statement signed by the
responsible head (as defined in Sec. 600.10 of this chapter) of the
licensee shall be included, stating that to the best of his knowledge
and belief, it includes all information, favorable and unfavorable,
pertinent to an evaluation of the safety, effectiveness, and labeling of
the product, including information derived from investigation,
commercial marketing, or published literature. If the submission is by
an interested person other than a licensee, a statement signed by the
person responsible for such submission shall be included, stating that
to the best of his knowledge and belief, it fairly reflects a balance of
all the information, favorable and unfavorable, available to him
pertinent to an evaluation of the safety, effectiveness, and labeling of
the product.
(c) Deliberations of an advisory review panel. An advisory review
panel will meet as often and for as long as is appropriate to review the
data submitted to it and to prepare a report containing its conclusions
and recommendations to the Commissioner of Food and Drugs with respect
to the safety, effectiveness, and labeling of the biological products in
the designated category under review.
(1) A panel may also consult any individual or group.
(2) Any interested person may request in writing an opportunity to
present oral views to the panel. Such written requests for oral
presentations should include a summarization of the data to be presented
to the panel. Such request may be granted or denied by the panel.
(3) Any interested person may present written data and views which
shall be considered by the panel. This information shall be presented to
the panel in the format set forth in paragraph (b)(3) of this section
and within the time period established for the biological product
category in the notice for review by a panel.
(d) Standards for safety, effectiveness, and labeling. The advisory
review panel, in reviewing the submitted data and preparing the panel's
conclusions and recommendations, and the Commissioner of Food and Drugs,
in reviewing and implementing the conclusions and recommendations of the
panel, shall apply the following standards to determine that a
biological product is safe and effective and not misbranded.
(1) Safety means the relative freedom from harmful effect to persons
affected, directly or indirectly, by a product when prudently
administered, taking into consideration the character of the product in
relation to the condition of the recipient at the time. Proof of safety
shall consist of adequate tests by methods reasonably applicable to show
the biological product is safe under the prescribed conditions of use,
including results of significant human experience during use.
(2) Effectiveness means a reasonable expectation that, in a
significant proportion of the target population, the pharmacological or
other effect of the biological product, when used under adequate
directions, for use and warnings against unsafe use, will serve a
clinically significant function in the diagnosis, cure, mitigation,
treatment, or prevention of disease in man. Proof of effectiveness shall
consist of controlled clinical investigations as
[[Page 25]]
defined in Sec. 314.126 of this chapter, unless this requirement is
waived on the basis of a showing that it is not reasonably applicable to
the biological product or essential to the validity of the
investigation, and that an alternative method of investigation is
adequate to substantiate effectiveness. Alternate methods, such as
serological response evaluation in clinical studies and appropriate
animal and other laboratory assay evaluations may be adequate to
substantiate effectiveness where a previously accepted correlation
between data generated in this way and clinical effectiveness already
exists. Investigations may be corroborated by partially controlled or
uncontrolled studies, documented clinical studies by qualified experts,
and reports of significant human experience during marketing. Isolated
case reports, random experience, and reports lacking the details which
permit scientific evaluation will not be considered.
(3) The benefit-to-risk ratio of a biological product shall be
considered in determining safety and effectiveness.
(4) A biological product may combine two or more safe and effective
active components: (i) When each active component makes a contribution
to the claimed effect or effects; (ii) when combining of the active
ingredients does not decrease the purity, potency, safety, or
effectiveness of any of the individual active components; and (iii) if
the combination, when used under adequate directions for use and
warnings against unsafe use, provides rational concurrent preventive
therapy or treatment for a significant proportion of the target
population.
(5) Labeling shall be clear and truthful in all respects and may not
be false or misleading in any particular. It shall comply with section
351 of the Public Health Service Act and sections 502 and 503 of the
Federal Food, Drug, and Cosmetic Act, and in particular with the
applicable requirements of Secs. 610.60 through 610.65 and subpart D of
part 201 of this chapter.
(e) Advisory review panel report to the Commissioner. An advisory
review panel shall submit to the Commissioner of Food and Drugs a report
containing the panel's conclusions and recommendations with respect to
the biological products falling within the category covered by the
panel. Included within this report shall be:
(1) A statement which designates those biological products
determined by the panel to be safe and effective and not misbranded.
This statement may include any condition relating to active components,
labeling, tests required prior to release of lots, product standards, or
other conditions necessary or appropriate for their safety and
effectiveness.
(2) A statement which designates those biological products
determined by the panel to be unsafe or ineffective, or to be
misbranded. The statement shall include the panel's reasons for each
such determination.
(3) A statement which designates those biological products
determined by the panel not to fall within either paragraph (e) (1) or
(2) of this section on the basis of the panel's conclusion that the
available data are insufficient to classify such biological products,
and for which further testing is therefore required. The report shall
recommend with as must specificity as possible the type of further
testing required and the time period within which it might reasonably be
concluded. The report shall also recommend whether the product license
should or should not be revoked, thus permitting or denying continued
manufacturing and marketing of the biological product pending completion
of the testing. This recommendation will be based on an assessment of
the present evidence of the safety and effectiveness of the product and
the potential benefits and risks likely to result from the continued use
of the product for a limited period of time while the questions raised
concerning the product are being resolved by further study.\2\
---------------------------------------------------------------------------
\2\ As of November 4, 1982, the provisions under paragraphs (e)(3)
and (f)(3) of this section for the interim marketing of certain
biological products pending completion of additional studies have been
superseded by the review and reclassification procedures under
Sec. 601.26 of this chapter. The superseded text is included for the
convenience of the user only.
---------------------------------------------------------------------------
(f) Proposed order. After reviewing the conclusions and
recommendations of the advisory review panel, the
[[Page 26]]
Commissioner of Food and Drugs shall publish in the Federal Register a
proposed order containing:
(1) A statement designating the biological products in the category
under review that are determined by the Commissioner of Food and Drugs
to be safe and effective and not misbranded. This statement may include
any condition relating to active components, labeling, tests required
prior to release of lots, product standards, or other conditions
necessary or appropriate for their safety and effectiveness, and may
propose corresponding amendments in other regulations under this
subchapter F.
(2) A statement designating the biological products in the category
under review that are determined by the Commissioner of Food and Drugs
to be unsafe or ineffective, or to be misbranded, together with the
reasons therefor. All licenses for such products shall be proposed to be
revoked.
(3) A statement designating the biological products not included in
either of the above two statements on the basis of the Commissioner of
Food and Drugs determination that the available data are insufficient to
classify such biological products under either paragraph (f) (1) or (2)
of this section. Licenses for such products may be proposed to be
revoked or to remain in effect on an interim basis. Where the
Commissioner determines that the potential benefits outweigh the
potential risks, the proposed order shall provide that the product
license for any biological product, falling within this paragraph will
not be revoked but will remain in effect on an interim basis while the
data necessary to support its continued marketing are being obtained for
evaluation by the Food and Drug Administration. The tests necessary to
resolve whatever safety or effectiveness questions exist shall be
described.\2\
---------------------------------------------------------------------------
\2\ As of November 4, 1982, the provisions under paragraphs (e)(3)
and (f)(3) of this section for the interim marketing of certain
biological products pending completion of additional studies have been
superseded by the review and reclassification procedures under
Sec. 601.26 of this chapter. The superseded text is included for the
convenience of the user only.
---------------------------------------------------------------------------
(4) The full report or reports of the panel to the Commissioner of
Food and Drugs.
The summary minutes of the panel meeting or meetings shall be made
available to interested persons upon request. Any interested person may
within 90 days after publication of the proposed order in the Federal
Register, file with the Hearing Clerk of the Food and Drug
Administration written comments in quintuplicate. Comments may be
accompanied by a memorandum or brief in support thereof. All comments
may be reviewed at the office of the Dockets Management Branch during
regular working hours, Monday through Friday.
(g) Final order. After reviewing the comments, the Commissioner of
Food and Drugs shall publish in the Federal Register a final order on
the matters covered in the proposed order. The final order shall become
effective as specified in the order.
(h) [Reserved]
(i) Court Appeal. The final order(s) published pursuant to paragraph
(g) of this section, and any notice published pursuant to paragraph (h)
of this section, constitute final agency action from which appeal lies
to the courts. The Food and Drug Administration will request
consolidation of all appeals in a single court. Upon court appeal, the
Commissioner of Food and Drugs may, at his discretion, stay the
effective date for part or all of the final order or notice, pending
appeal and final court adjudication.
[38 FR 32052, Nov. 20, 1973, as amended at 39 FR 11535, Mar. 29, 1974;
40 FR 13498, Mar. 27, 1975; 43 FR 44838, Sept. 29, 1978; 47 FR 44071,
Oct. 5, 1982; 47 FR 50211, Nov. 5, 1982; 51 FR 15607, Apr. 25, 1986; 55
FR 11014, Mar. 26, 1990]
Sec. 601.26 Reclassification procedures to determine that licensed biological products are safe, effective, and not misbranded under prescribed, recommended,
or suggested conditions of use.
This regulation establishes procedures for the reclassification of
all biological products that have been classified into Category IIIA. A
Category IIIA biological product is one for which an advisory review
panel has recommended under Sec. 601.25(e)(3), the Commissioner of Food
and Drugs (Commissioner) has proposed under Sec. 601.25(f)(3), or the
Commissioner has finally
[[Page 27]]
decided under Sec. 601.25(g) that available data are insufficient to
determine whether the product license should be revoked or affirmed and
which may be marketed pending the completion of further testing. All of
these Category IIIA products will either be reclassified into Category I
(safe, effective, and not misbranded) or Category II (unsafe,
ineffective, or misbranded) in accordance with the procedures set forth
below.
(a) Advisory review panels. The Commissioner will appoint advisory
review panels and use existing advisory review panels to (1) evaluate
the safety and effectiveness of all Category IIIA biological products;
(2) review the labeling of such products; and (3) advise the
Commissioner on which Category IIIA biological products are safe,
effective, and not misbranded. These advisory review panels will be
established in accordance with procedures set forth in Sec. 601.25(a).
(b) Deliberations of advisory review panels. The deliberations of
advisory review panels will be conducted in accordance with
Sec. 601.25(d).
(c) Advisory review panel report to the Commissioner. An advisory
review panel shall submit to the Commissioner a report containing the
panel's conclusions and recommendations with respect to the biological
products falling within the category of products reviewed by the panel.
The panel report shall include:
(1) A statement designating the biological products in the category
under review in accordance with either Sec. 601.25(e)(1) or
Sec. 601.25(e)(2).
(2) A statement identifying those biological products designated
under Sec. 601.25(e)(2) that the panel recommends should be designated
as safe and presumptively effective and should remain on the market
pending completion of further testing because there is a compelling
medical need and no suitable alternative therapeutic, prophylactic, or
diagnostic agent that is available in sufficient quantities to meet
current medical needs. For the products or categories of products so
recommended, the report shall include: (i) A description and evaluation
of the available evidence concerning effectiveness and an explanation
why the evidence shows that the product has any benefit; and (ii) a
description of the alternative therapeutic, prophylactic, or diagnostic
agents considered and a statement of why such alternatives are not
suitable. In making this recommendation the panel shall also take into
account the seriousness of the condition intended to be treated,
prevented, or diagnosed by the product, the risks involved in the
continued use of the product, and the likelihood that, based upon
existing data, the effectiveness of the product can eventually be
established by further testing and new test development. The report
shall also recommend with as much specificity as possible the type of
further testing required and the time period within which it might
reasonably be concluded.
(d) Proposed order. After reviewing the conclusions and
recommendations of the advisory review panels, the Commissioner shall
publish in the Federal Register a proposed order containing:
(1) A statement designating the biological products in the category
under review in accordance with either Sec. 601.25(e)(1) or
601.25(e)(2);
(2) A notice of availability of the full panel report or reports.
The full panel report or reports shall be made publicly available at the
time of publication of the proposed order.
(3) A proposal to accept or reject the findings of the advisory
review panel required by Sec. 601.26(c)(2)(i) and (ii).
(4) A statement identifying those biological products that the
Commissioner proposes should be designated as safe and presumptively
effective under Sec. 601.26(c)(2) and should be permitted to remain on
the market pending completion of further testing because there is a
compelling medical need and no suitable alternative therapeutic,
prophylactic, or diagnostic agent for the product that is available in
sufficient quantities to meet current medical needs. In making this
proposal, the Commissioner shall take into account the seriousness of
the condition to be treated, prevented, or diagnosed by the product, the
risks involved in the continued use of the product, and the likelihood
that, based upon existing data, the effectiveness of the product can
eventually be established by further testing.
[[Page 28]]
(e) Final order. After reviewing the comments on the proposed order,
the Commissioner shall publish in the Federal Register a final order on
the matters covered in the proposed order. Where the Commissioner
determines that there is a compelling medical need and no suitable
alternative therapeutic, prophylactic, or diagnostic agent for any
biological product that is available in sufficient quantities to meet
current medical needs, the final order shall provide that the product
license for that biological product will not be revoked, but will remain
in effect on an interim basis while the data necessary to support its
continued marketing are being obtained for evaluation by the Food and
Drug Administration. The final order shall describe the tests necessary
to resolve whatever effectiveness questions exist.
(f) Additional studies and labeling. (1) Within 60 days following
publication of the final order, each licensee for a biological product
designated as requiring further study to justify continued marketing on
an interim basis, pursuant to paragraph (e) of this section, shall
submit to the Commissioner a written statement intended to show that
studies adequate and appropriate to resolve the questions raised about
the product have been undertaken. The Federal Government may undertake
the studies. Any study involving a clinical investigation that involves
human subjects shall be conducted in compliance with the requirements
for informed consent under part 50 of this chapter. Such a study is also
subject to the requirements for institutional review under part 56 of
this chapter unless exempt under Sec. 56.104 or Sec. 56.105. The
Commissioner may extend this 60-day period if necessary, either to
review and act on proposed protocols or upon indication from the
licensee that the studies will commence at a specified reasonable time.
If no such commitment is made, or adequate and appropriate studies are
not undertaken, the product license or licenses shall be revoked.
(2) A progress report shall be filed on the studies by January 1 and
July 1 until completion. If the progress report is inadequate or if the
Commissioner concludes that the studies are not being pursued promptly
and diligently, or if interim results indicate the product is not a
medical necessity, the product license or licenses shall be revoked.
(3) Promptly upon completion of the studies undertaken on the
product, the Commissioner will review all available data and will either
retain or revoke the product license or licenses involved. In making
this review the Commissioner may again consult the advisory review panel
which prepared the report on the product, or other advisory committees,
professional organizations, or experts. The Commissioner shall take such
action by notice published in the Federal Register.
(4) Labeling and promotional material for those biological products
requiring additional studies shall bear a box statement in the following
format:
Based on a review by the (insert name of appropriate advisory review
panel) and other information, the Food and Drug Administration has
directed that further investigation be conducted before this product is
conclusively determined to be effective for labeled indication(s).
(5) A written informed consent shall be obtained from participants
in any additional studies required under paragraph (f)(1) of this
section, explaining the nature of the product and the investigation. The
explanation shall consist of such disclosure and be made so that
intelligent and informed consent be given and that a clear opportunity
to refuse is presented.
(g) Court appeal. The final order(s) published pursuant to paragraph
(e) of this section constitute final agency action from which appeal
lies to the courts. The Food and Drug Administration will request
consolidation of all appeals in a single court. Upon court appeal, the
Commissioner of Food and Drugs may, at the Commissioner's discretion,
stay the effective date for part or all of the final order or notice,
pending appeal and final court adjudication.
(h) [Reserved]
(i) Institutional review and informed consent. Information and data
submitted under this section after July 27, 1981, shall include
statements regarding each clinical investigation involving human
subjects, that it was conducted in compliance with the requirements for
informed consent under part
[[Page 29]]
50 of this chapter. Such a study is also subject to the requirements for
institutional review under part 56 of this chapter, unless exempt under
Sec. 56.104 or Sec. 56.105.
[47 FR 44071, Oct. 5, 1982]
Subpart D--Licensing of Foreign Establishments and Products
Sec. 601.30 Licenses required; products for controlled investigation only.
Any biological or trivalent organic arsenical manufactured in any
foreign country and intended for sale, barter, or exchange shall be
refused entry by collectors of customs unless manufactured in an
establishment holding an unsuspended and unrevoked establishment license
and license for the product. Unlicensed products that are not imported
for sale, barter, or exchange and that are intended solely for purposes
of controlled investigation are admissible only if the investigation is
conducted in accordance with section 505 of the Federal Food, Drug, and
Cosmetic Act and the requirements set forth in parts 50, 56 unless
exempted under Sec. 56.104 as granted a waiver under Sec. 56.105, parts
58 and 312 of this chapter.
[46 FR 8956, Jan. 27, 1981]
Sec. 601.31 Procedure.
Except as otherwise provided in this subchapter, licenses for
foreign establishments and products shall be issued, suspended, and
revoked in the same manner as licenses for domestic establishments and
products. Each foreign establishment holding a license and sending,
carrying, or bringing any licensed product into any State or possession
for sale, barter, or exchange shall file with the Director, Center for
Biologics Evaluation and Research, the name and address of each person
to whom such a product is thus sent, carried, or brought. Foreign
licensees shall notify each person in the United States to whom such a
product is thus sent, carried, or brought, to keep such records of
distribution as are required of domestic licensed establishments.
Failure to give such notice to maintain records shall constitute ground
for revocation of license.
[38 FR 32052, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Sec. 601.32 Form of license.
Licenses for establishments located in foreign countries shall be in
form similar to that for domestic establishments except that they shall
authorize manufacture for sending, carrying, or bringing for sale,
barter or exchange from the foreign country designated in the license
into any State or possession of the United States and shall specify that
it is issued upon the condition that the licensee will permit the
inspection during all reasonable hours of the establishment by any
officer, agent, or employee of the Department of Health and Human
Services authorized by the Secretary for such purpose.
Sec. 601.33 Samples for each importation.
Random samples of each importation, obtained by the District
Director of Customs and forwarded to the Director, Center for Biologics
Evaluation and Research, shall be at least two final containers of each
lot of product. A copy of the associated documents which describe and
identify the shipment shall accompany the shipment for forwarding with
the samples to the Director, Center for Biologics Evaluation and
Research. For shipments of 20 or less final containers, samples need not
be forwarded, provided a copy of an official release from the Center for
Biologics Evaluation and Research accompanies each shipment.
[38 FR 32052, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Subpart E--Accelerated Approval of Biological Products for Serious or
Life-Threatening Illnesses
Source: 57 FR 58959, Dec. 11, 1992, unless otherwise noted.
Sec. 601.40 Scope.
This subpart applies to certain biological products that have been
studied for their safety and effectiveness in
[[Page 30]]
treating serious or life-threatening illnesses and that provide
meaningful therapeutic benefit to patients over existing treatments
(e.g., ability to treat patients unresponsive to, or intolerant of,
available therapy, or improved patient response over available therapy).
Sec. 601.41 Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity.
FDA may grant marketing approval for a biological product on the
basis of adequate and well-controlled clinical trials establishing that
the biological product has an effect on a surrogate endpoint that is
reasonably likely, based on epidemiologic, therapeutic,
pathophysiologic, or other evidence, to predict clinical benefit or on
the basis of an effect on a clinical endpoint other than survival or
irreversible morbidity. Approval under this section will be subject to
the requirement that the applicant study the biological product further,
to verify and describe its clinical benefit, where there is uncertainty
as to the relation of the surrogate endpoint to clinical benefit, or of
the observed clinical benefit to ultimate outcome. Postmarketing studies
would usually be studies already underway. When required to be
conducted, such studies must also be adequate and well-controlled. The
applicant shall carry out any such studies with due diligence.
Sec. 601.42 Approval with restrictions to assure safe use.
(a) If FDA concludes that a biological product shown to be effective
can be safely used only if distribution or use is restricted, FDA will
require such postmarketing restrictions as are needed to assure safe use
of the biological product, such as:
(1) Distribution restricted to certain facilities or physicians with
special training or experience; or
(2) Distribution conditioned on the performance of specified medical
procedures.
(b) The limitations imposed will be commensurate with the specific
safety concerns presented by the biological product.
Sec. 601.43 Withdrawal procedures.
(a) For biological products approved under Secs. 601.40 and 601.42,
FDA may withdraw approval, following a hearing as provided in part 15 of
this chapter, as modified by this section, if:
(1) A postmarketing clinical study fails to verify clinical benefit;
(2) The applicant fails to perform the required postmarketing study
with due diligence;
(3) Use after marketing demonstrates that postmarketing restrictions
are inadequate to ensure safe use of the biological product;
(4) The applicant fails to adhere to the postmarketing restrictions
agreed upon;
(5) The promotional materials are false or misleading; or
(6) Other evidence demonstrates that the biological product is not
shown to be safe or effective under its conditions of use.
(b) Notice of opportunity for a hearing. The Director of the Center
for Biologics Evaluation and Research will give the applicant notice of
an opportunity for a hearing on the Center's proposal to withdraw the
approval of an application approved under Sec. 601.40 or Sec. 601.41.
The notice, which will ordinarily be a letter, will state generally the
reasons for the action and the proposed grounds for the order.
(c) Submission of data and information. (1) If the applicant fails
to file a written request for a hearing within 15 days of receipt of the
notice, the applicant waives the opportunity for a hearing.
(2) If the applicant files a timely request for a hearing, the
agency will publish a notice of hearing in the Federal Register in
accordance with Secs. 12.32(e) and 15.20 of this chapter.
(3) An applicant who requests a hearing under this section must,
within 30 days of receipt of the notice of opportunity for a hearing,
submit the data and information upon which the applicant intends to rely
at the hearing.
(d) Separation of functions. Separation of functions (as specified
in Sec. 10.55 of this chapter) will not apply at any point in withdrawal
proceedings under this section.
(e) Procedures for hearings. Hearings held under this section will
be conducted in accordance with the
[[Page 31]]
provisions of part 15 of this chapter, with the following modifications:
(1) An advisory committee duly constituted under part 14 of this
chapter will be present at the hearing. The committee will be asked to
review the issues involved and to provide advice and recommendations to
the Commissioner of Food and Drugs.
(2) The presiding officer, the advisory committee members, up to
three representatives of the applicant, and up to three representatives
of the Center may question any person during or at the conclusion of the
person's presentation. No other person attending the hearing may
question a person making a presentation. The presiding officer may, as a
matter of discretion, permit questions to be submitted to the presiding
officer for response by a person making a presentation.
(f) Judicial review. The Commissioner's decision constitutes final
agency action from which the applicant may petition for judicial review.
Before requesting an order from a court for a stay of action pending
review, an applicant must first submit a petition for a stay of action
under Sec. 10.35 of this chapter.
Sec. 601.44 Postmarketing safety reporting.
Biological products approved under this program are subject to the
postmarketing recordkeeping and safety reporting applicable to all
approved biological products.
Sec. 601.45 Promotional materials.
For biological products being considered for approval under this
subpart, unless otherwise informed by the agency, applicants must submit
to the agency for consideration during the preapproval review period
copies of all promotional materials, including promotional labeling as
well as advertisements, intended for dissemination or publication within
120 days following marketing approval. After 120 days following
marketing approval, unless otherwise informed by the agency, the
applicant must submit promotional materials at least 30 days prior to
the intended time of initial dissemination of the labeling or initial
publication of the advertisement.
Sec. 601.46 Termination of requirements.
If FDA determines after approval that the requirements established
in Sec. 601.42, Sec. 601.43, or Sec. 601.45 are no longer necessary for
the safe and effective use of a biological product, it will so notify
the applicant. Ordinarily, for biological products approved under
Sec. 601.41, these requirements will no longer apply when FDA determines
that the required postmarketing study verifies and describes the
biological product's clinical benefit and the biological product would
be appropriate for approval under traditional procedures. For biological
products approved under Sec. 601.42, the restrictions would no longer
apply when FDA determines that safe use of the biological product can be
assured through appropriate labeling. FDA also retains the discretion to
remove specific postapproval requirements upon review of a petition
submitted by the sponsor in accordance with Sec. 10.30.
Subpart F--Confidentiality of Information
Sec. 601.50 Confidentiality of data and information in an investigational new drug notice for a biological product.
(a) The existence of an IND notice for a biological product will not
be disclosed by the Food and Drug Administration unless it has
previously been publicly disclosed or acknowledged.
(b) The availability for public disclosure of all data and
information in an IND file for a biological product shall be handled in
accordance with the provisions established in Sec. 601.51.
(c) Notwithstanding the provisions of Sec. 601.51, the Food and Drug
Administration shall disclose upon request to an individual on whom an
investigational biological product has been used a copy of any adverse
reaction report relating to such use.
[39 FR 44656, Dec. 24, 1974]
Sec. 601.51 Confidentiality of data and information in applications for establishment and product licenses.
(a) For purposes of this section the biological product file
includes all data and information submitted with or incorporated by
reference in any
[[Page 32]]
application for an establishment or product license, IND's incorporated
into any such application, master files, and other related submissions.
The availability for public disclosure of any record in the biological
product file shall be handled in accordance with the provisions of this
section.
(b) The existence of a biological product file will not be disclosed
by the Food and Drug Administration before a product license has been
sent to the applicant, unless it has previously been publicly disclosed
or acknowledged. The Director of the Center for Biologics Evaluation and
Research will maintain a list available for public disclosure of
biological products for which a license has been issued.
(c) If the existence of a biological product file has not been
publicly disclosed or acknowledged, no data or information in the
biological product file is available for public disclosure.
(d) If the existence of a biological product file has been publicly
disclosed or acknowledged before a license has been issued, no data or
information contained in the file is available for public disclosure
before such license is issued, but the Commissioner may, in his
discretion, disclose a summary of such selected portions of the safety
and effectiveness data as are appropriate for public consideration of a
specific pending issue, e.g., at an open session of a Food and Drug
Administration advisory committee or pursuant to an exchange of
important regulatory information with a foreign government.
(e) After a license has been issued, the following data and
information in the biological product file are immediately available for
public disclosure unless extraordinary circumstances are shown:
(1) All safety and effectiveness data and information.
(2) A protocol for a test or study, unless it is shown to fall
within the exemption established for trade secrets and confidential
commercial or financial information in Sec. 20.61 of this chapter.
(3) Adverse reaction reports, product experience reports, consumer
complaints, and other similar data and information, after deletion of:
(i) Names and any information that would identify the person using
the product.
(ii) Names and any information that would identify any third party
involved with the report, such as a physician or hospital or other
institution.
(4) A list of all active ingredients and any inactive ingredients
previously disclosed to the public, as defined in Sec. 20.81 of this
chapter.
(5) An assay method or other analytical method, unless it serves no
regulatory or compliance purpose and it is shown to fall within the
exemption established in Sec. 20.61 of this chapter.
(6) All correspondence and written summaries of oral discussions
relating to the biological product file, in accordance with the
provisions of part 20 of this chapter.
(7) All records showing the manufacturer's testing of a particular
lot, after deletion of data or information that would show the volume of
the drug produced, manufacturing procedures and controls, yield from raw
materials, costs, or other material falling within Sec. 20.61 of this
chapter.
(8) All records showing the testing of and action on a particular
lot by the Food and Drug Administration.
(f) The following data and information in a biological product file
are not available for public disclosure unless they have been previously
disclosed to the public as defined in Sec. 20.81 of this chapter or they
relate to a product or ingredient that has been abandoned and they no
longer represent a trade secret or confidential commercial or financial
information as defined in Sec. 20.61 of this chapter:
(1) Manufacturing methods or processes, including quality control
procedures.
(2) Production, sales, distribution, and similar data and
information, except that any compilation of such data and information
aggregated and prepared in a way that does not reveal data or
information which is not available for public disclosure under this
provision is available for public disclosure.
(3) Quantitative or semiquantitative formulas.
(g) For purposes of this regulation, safety and effectiveness data
include
[[Page 33]]
all studies and tests of a biological product on animals and humans and
all studies and tests on the drug for identity, stability, purity,
potency, and bioavailability.
[39 FR 44656, Dec. 24, 1974, as amended at 42 FR 15676, Mar. 22, 1977;
49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990]
PART 606--CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND BLOOD COMPONENTS--Table of Contents
Subpart A--General Provisions
Sec.
606.3 Definitions.
Subpart B--Organization and Personnel
606.20 Personnel.
Subpart C--Plant and Facilities
606.40 Facilities.
Subpart D--Equipment
606.60 Equipment.
606.65 Supplies and reagents.
Subpart E--[Reserved]
Subpart F--Production and Process Controls
606.100 Standard operating procedures.
606.110 Plateletpheresis, leukapheresis, and plasmapheresis.
Subpart G--Finished Product Control
606.120 Labeling, general requirements.
606.121 Container label.
606.122 Instruction circular.
Subpart H--Laboratory Controls
606.140 Laboratory controls.
606.151 Compatibility testing.
Subpart I--Records and Reports
606.160 Records.
606.165 Distribution and receipt; procedures and records.
606.170 Adverse reaction file.
Authority: Secs. 201, 301, 501, 502, 505, 510, 520, 701, 704 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 355,
360, 360j, 371, 374); secs. 215, 351, 353, 361 of the Public Health
Service Act (42 U.S.C. 216, 262, 263a, 264).
Source: 40 FR 53532, Nov. 18, 1975, unless otherwise noted.
Subpart A--General Provisions
Sec. 606.3 Definitions.
As used in this part:
(a) Blood means whole blood collected from a single donor and
processed either for transfusion or further manufacturing.
(b) Unit means the volume of blood or one of its components in a
suitable volume of anticoagulant obtained from a single collection of
blood from one donor.
(c) Component means that part of a single-donor unit of blood
separated by physical or mechanical means.
(d) Plasma for further manufacturing means that liquid portion of
blood separated and used as material to prepare another product.
(e) Plasmapheresis means the procedure in which blood is removed
from the donor, the plasma is separated from the formed elements and at
least the red blood cells are returned to the donor. This process may be
immediately repeated, once.
(f) Plateletpheresis means the procedure in which blood is removed
from the donor, a platelet concentrate is separated, and the remaining
formed elements and residual plasma are returned to the donor.
(g) Leukapheresis means the procedure in which blood is removed from
the donor, a leukocyte concentrate is separated, and the remaining
formed elements and residual plasma are returned to the donor.
(h) Facilities means any area used for the collection, processing,
compatibility testing, storage or distribution of blood and blood
components.
(i) Processing means any procedure employed after collection and
before compatibility testing of blood and includes the identification of
a unit of donor blood, the preparation of components from such unit of
donor blood, serological testing, labeling and associated recordkeeping.
(j) Compatibility testing means the in vitro serological tests
performed on donor and recipient blood samples to establish the
serological matching of a
[[Page 34]]
donor's blood or blood components with that of a potential recipient.
Subpart B--Organization and Personnel
Sec. 606.20 Personnel.
(a) A blood establishment shall be under the direction of a
designated, qualified person who shall exercise control of the
establishment in all matters relating to compliance with the provisions
of this subchapter. This person shall also have the authority to
represent the establishment in all pertinent matters with the Center for
Biologics Evaluation and Research and to enforce, or direct the
enforcement of, discipline and the performance of assigned functions by
employees engaged in the collection, processing, compatibility testing,
storage and distribution of blood and blood components. The designated
director shall have an understanding of the scientific principles and
techniques involved in the manufacture of blood products and shall have
the responsibility for ensuring that employees are adequately trained in
standard operating procedures and that they are aware of the application
of the pertinent provisions of this chapter to their respective
functions.
(b) The personnel responsible for the collection, processing,
compatibility testing, storage or distribution of blood or blood
components shall be adequate in number, educational background, training
and experience, including professional training as necessary, or
combination thereof, to assure competent performance of their assigned
functions, and to ensure that the final product has the safety, purity,
potency, identity and effectiveness it purports or is represented to
possess. All personnel shall have capabilities commensurate with their
assigned functions, a thorough understanding of the procedures or
control operations they perform, the necessary training or experience,
and adequate information concerning the application of pertinent
provisions of this part to their respective functions.
(c) Persons whose presence can adversely affect the safety and
purity of the products shall be excluded from areas where the
collection, processing, compatibility testing, storage or distribution
of blood or blood components is conducted.
[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55
FR 11014, Mar. 26, 1990]
Subpart C--Plant and Facilities
Sec. 606.40 Facilities.
Facilities shall be maintained in a clean and orderly manner, and
shall be of suitable size, construction and location to facilitate
adequate cleaning, maintenance and proper operations. The facilities
shall:
(a) Provide adequate space for the following when applicable:
(1) Private and accurate examinations of individuals to determine
their suitability as blood donors.
(2) The withdrawal of blood from donors with minimal risk of
contamination, or exposure to activities and equipment unrelated to
blood collection.
(3) The storage of blood or blood components pending completion of
tests.
(4) The quarantine storage of blood or blood components in a
designated location pending repetition of those tests that initially
gave questionable serological results.
(5) The storage of finished products prior to distribution.
(6) The quarantine storage, handling and disposition of products and
reagents not suitable for use.
(7) The orderly collection, processing, compatibility testing,
storage and distribution of blood and blood components to prevent
contamination.
(8) The adequate and proper performance of all steps in
plasmapheresis, plateletpheresis and leukapheresis procedures.
(9) The orderly conduction of all packaging, labeling and other
finishing operations.
(b) Provide adequate lighting, ventilation and screening of open
windows and doors.
(c) Provide adequate, clean, and convenient handwashing facilities
for personnel, and adequate, clean, and convenient toilet facilities for
donors and personnel. Drains shall be of adequate size and, where
connected directly to a
[[Page 35]]
sewer, shall be equipped with traps to prevent back-siphonage.
(d) Provide for safe and sanitary disposal for the following:
(1) Trash and items used during the collection, processing and
compatibility testing of blood and blood components.
(2) Blood and blood components not suitable for use or distribution.
Subpart D--Equipment
Sec. 606.60 Equipment.
(a) Equipment used in the collection, processing, compatibility
testing, storage and distribution of blood and blood components shall be
maintained in a clean and orderly manner and located so as to facilitate
cleaning and maintenance. The equipment shall be observed, standardized
and calibrated on a regularly scheduled basis as prescribed in the
Standard Operating Procedures Manual and shall perform in the manner for
which it was designed so as to assure compliance with the official
requirements prescribed in this chapter for blood and blood products.
(b) Equipment that shall be observed, standardized and calibrated
with at least the following frequency, include but are not limited to:
----------------------------------------------------------------------------------------------------------------
Equipment Performance check Frequency Frequency of calibration
----------------------------------------------------------------------------------------------------------------
Temperature recorder.............. Compare against Daily................ As necessary.
thermometer.
Refrigerated centrifuge........... Observe speed and Each day of use...... Do.
temperature.
Hematocrit centrifuge............. .......................... ..................... Standardize before
initial use, after
repairs or adjustments,
and annually. Timer
every 3 mo.
General lab centrifuge............ .......................... ..................... Tachometer every 6 mo.
Automated blood-typing machine.... Observe controls for Each day of use......
correct results.
Hemoglobinometer.................. Standardize against ......do.............
cyanmethemoglobin
standard.
Refractometer..................... Standardize against ......do.............
distilled water.
Blood container scale............. Standardize against ......do............. As necessary.
container of known weight.
Water bath........................ Observe temperature....... ......do............. Do.
Rh view box....................... ......do.................. ......do............. Do.
Autoclave......................... ......do.................. Each time of use..... Do.
Serologic rotators................ Observe controls for Each day of use...... Speed as necessary.
correct results.
Laboratory thermometers........... .......................... ..................... Before initial use.
Electronic thermometers........... .......................... ..................... Monthly.
Vacuum blood agitator............. Observe weight of the Each day of use...... Standardize with
first container of blood container of known mass
filled for correct or volume before initial
results. use, and after repairs
or adjustments.
----------------------------------------------------------------------------------------------------------------
(c) Equipment employed in the sterilization of materials used in
blood collection or for disposition of contaminated products shall be
designed, maintained and utilized to ensure the destruction of
contaminating microorganisms. The effectiveness of the sterilization
procedure shall be no less than that achieved by an attained temperature
of 121.5 deg. C (251 deg. F) maintained for 20 minutes by saturated
steam or by an attained temperature of 170 deg. C (338 deg. F)
maintained for 2 hours with dry heat.
[40 FR 53532, Nov. 18, 1975; 40 FR 55849, Dec. 2, 1975, as amended at 45
FR 9261, Feb. 12, 1980; 57 FR 11263, Apr. 2, 1992; 57 FR 12862, Apr. 13,
1992]
Sec. 606.65 Supplies and reagents.
All supplies and reagents used in the collection, processing,
compatibility testing, storage and distribution of blood and blood
components shall be stored in a safe, sanitary and orderly manner.
(a) All surfaces coming in contact with blood and blood components
intended for transfusion shall be sterile, pyrogen-free, and shall not
interact with the product in such a manner as to have an adverse effect
upon the safety, purity, potency or effectiveness of the product. All
final containers and closures for blood and blood components not
intended for transfusion shall be clean and free of surface solids and
other contaminants.
[[Page 36]]
(b) Each blood collecting container and its satellite container(s),
if any, shall be examined visually for damage or evidence of
contamination prior to its use and immediately after filling. Such
examination shall include inspection for breakage of seals, when
indicated, and abnormal discoloration. Where any defect is observed, the
container shall not be used, or, if detected after filling, shall be
properly discarded.
(c) Representative samples of each lot of the following reagents or
solutions shall be tested on a regularly scheduled basis by methods
described in the Standard Operating Procedures Manual to determine their
capacity to perform as required:
------------------------------------------------------------------------
Reagent or solution Frequency of testing
------------------------------------------------------------------------
Anti-human globulin...................... Each day of use.
Blood grouping reagents.................. Do.
Lectins.................................. Do.
Antibody screening and reverse grouping Do.
cells.
Hepatitis test reagents.................. Each run.
Syphilis serology reagents............... Do.
Enzymes.................................. Each day of use.
------------------------------------------------------------------------
(d) Supplies and reagents that do not bear an expiration date shall
be stored in such a manner that the oldest is used first.
(e) Supplies and reagents shall be used in a manner consistent with
instructions provided by the manufacturer.
(f) Items that are required to be sterile and come into contact with
blood should be disposable whenever possible.
[40 FR 53532, Nov. 18, 1975, as amended at 59 FR 23636, May 6, 1994]
Subpart E--[Reserved]
Subpart F--Production and Process Controls
Sec. 606.100 Standard operating procedures.
(a) In all instances, except clinical investigations, standard
operating procedures shall comply with published additional standards in
part 640 of this chapter for the products being processed; except that,
references in part 640 relating to licenses, licensed establishments and
submission of material or data to or approval by the Director, Center
for Biologics Evaluation and Research, are not applicable to
establishments not subject to licensure under section 351 of the Public
Health Service Act.
(b) Written standard operating procedures shall be maintained and
shall include all steps to be followed in the collection, processing,
compatibility testing, storage and distribution of blood and blood
components for homologous transfusion, autologous transfusion and
further manufacturing purposes. Such procedures shall be available to
the personnel for use in the areas where the procedures are performed,
unless this is impractical. The written standard operating procedures
shall include, but are not limited to, descriptions of the following,
when applicable:
(1) Criteria used to determine donor suitability, including
acceptable medical history criteria.
(2) Methods of performing donor qualifying tests and measurements,
including minimum and maximum values for a test or procedure when a
factor in determining acceptability.
(3) Solutions and methods used to prepare the site of phlebotomy to
give maximum assurance of a sterile container of blood.
(4) Method of accurately relating the product(s) to the donor.
(5) Blood collection procedure, including in-process precautions
taken to measure accurately the quantity of blood removed from the
donor.
(6) Methods of component preparation, including any time
restrictions for specific steps in processing.
(7) All tests and repeat tests performed on blood and blood
components during processing, including testing for hepatitis B surface
antigen as prescribed in Sec. 610.40 of this chapter.
(8) Pretransfusion testing, where applicable, including precautions
to be taken to identify accurately the recipient blood samples and
crossmatched donor units.
(9) Procedures for investigating adverse donor and recipient
reactions.
(10) Storage temperatures and methods of controlling storage
temperatures for all blood products and reagents as prescribed in
Secs. 600.15 and 610.53 of this chapter.
[[Page 37]]
(11) Length of expiration dates, if any, assigned for all final
products as prescribed in Sec. 610.53 of this chapter.
(12) Criteria for determining whether returned blood is suitable for
reissue.
(13) Procedures used for relating a unit of blood or blood component
from the donor to its final disposition.
(14) Quality control procedures for supplies and reagents employed
in blood collection, processing and pretransfusion testing.
(15) Schedules and procedures for equipment maintenance and
calibration.
(16) Labeling procedures, including safeguards to avoid labeling
mixups.
(17) Procedures of plasmapheresis, plateletpheresis, and
leukapheresis, if performed, including precautions to be taken to ensure
reinfusion of a donor's own cells.
(18) Procedure for preparing recovered (salvaged) plasma, if
performed, including details of separation, pooling, labeling, storage
and distribution.
(c) All records pertinent to the lot or unit maintained pursuant to
these regulations shall be reviewed before the release or distribution
of a lot or unit of final product. The review or portions of the review
may be performed at appropriate periods during or after blood
collecting, processing, compatibility testing and storing. A thorough
investigation, including the conclusions and followup, of any
unexplained discrepancy or the failure of a lot or unit to meet any of
its specifications shall be made and recorded.
(d) In addition to the requirements of this subpart and in
conformity with this section, any facility may utilize current standard
operating procedures such as the manuals of the following organizations,
as long as such specific procedures are consistent with, and at least as
stringent as, the requirements contained in this part.
(1) American Association of Blood Banks.
(2) American National Red Cross.
(3) Other organizations or individual blood banks, subject to
approval by the Director, Center for Biologics Evaluation and Research.
[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Sec. 606.110 Plateletpheresis, leukapheresis, and plasmapheresis.
(a) The use of plateletpheresis and leukapheresis procedures to
obtain a product for a specific recipient may be at variance with the
additional standards for specific products prescribed in this part
provided that: (1) A physician has determined that the recipient must be
transfused with the leukocytes or platelets from a specific donor, and
(2) the procedure is performed under the supervision of a qualified
licensed physician who is aware of the health status of the donor, and
the physician has certified in writing that the donor's health permits
plateletpheresis or leukapheresis.
(b) Plasmapheresis of donors who do not meet the donor requirements
of Secs. 640.63, 640.64 and 640.65 of this chapter for the collection of
plasma containing rare antibodies shall be permitted only with the prior
approval of the Director, Center for Biologics Evaluation and Research.
[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Subpart G--Finished Product Control
Sec. 606.120 Labeling, general requirements.
(a) Labeling operations shall be separated physically or spatially
from other operations in a manner adequate to prevent mixups.
(b) The labeling operation shall include the following labeling
controls:
(1) Labels shall be held upon receipt, pending review and proofing
against an approved final copy, to ensure accuracy regarding identity,
content, and conformity with the approved copy.
(2) Each type of label representing different products shall be
stored and maintained in a manner to prevent mixups, and stocks of
obsolete labels shall be destroyed.
(3) All necessary checks in labeling procedures shall be utilized to
prevent errors in translating test results to container labels.
(c) All labeling shall be clear and legible.
[50 FR 35469, Aug. 30, 1985]
[[Page 38]]
Sec. 606.121 Container label.
(a) The container label requirements are designed to facilitate the
use of a uniform container label for blood and blood components (except
Source Plasma) by all blood establishments. Single copies of an FDA
guideline entitled ``Guideline for the Uniform Labeling of Blood and
Blood Components'' are available upon request (under Docket No. 80N-
0120) from the Dockets Management Branch (HFA-305), Food and Drug
Administration, Rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857
(copies of the guideline are available also from the American Blood
Commission, 1901 North Ft. Myer Drive, Suite 300, Arlington, VA 22209).
(b) The label provided by the collecting facility and the initial
processing facility shall not be removed, altered, or obscured, except
that the label may be altered to indicate the proper name and other
information required to identify accurately the contents of a container
after blood components have been prepared.
(c) The container label shall include the following information, as
well as other specialized information as required in this section for
specific products:
(1) The proper name of the product in a prominent position, and
modifier(s), if appropriate.
(2) The name, address, registration number, and, if a licensed
product, the license number of each manufacturer.
(3) The donor, pool, or lot number relating the unit to the donor.
(4) The expiration date, including the day, month, and year, and, if
the dating period for the product is 72 hours or less, the hour of
expiration.
(5) If the product is intended for transfusion, the appropriate
donor classification statement, i.e., ``paid donor'' or ``volunteer
donor'', in no less prominence than the proper name of the product.
(i) A paid donor is a person who receives monetary payment for a
blood donation.
(ii) A volunteer donor is a person who does not receive monetary
payment for a blood donation.
(iii) Benefits, such as time off from work, membership in blood
assurance programs, and cancellation of nonreplacement fees that are not
readily convertible to cash, do not constitute monetary payment within
the meaning of this paragraph.
(6) For Whole Blood, Plasma, Platelets, and partial units of Red
Blood Cells, the volume of the product, accurate to within
10 percent; or optionally for Platelets, the volume range
within reasonable limits.
(7) The recommended storage temperature (in degrees Celsius).
(8) If the product is intended for transfusion, the statements:
(i) ``Caution: Federal law prohibits dispensing without
prescription.''
(ii) ``See circular of information for indications,
contraindications, cautions, and methods of infusion.''
(iii) ``Properly identify intended recipient.''
(9) The statement: ``This product may transmit infectious agents.''
(10) Where applicable, the name and volume of source material.
(11) The statement: ``Caution: For Manufacturing Use Only'', when
applicable.
(12) If the product is intended for transfusion, the ABO and Rh
groups of the donor shall be designated conspicuously. For
Cryoprecipitated AHF, the Rh group may be omitted. The Rh group shall be
designated as follows:
(i) If the test using Anti-D Blood Grouping Reagent is positive, the
product shall be labeled: ``Rh positive.''
(ii) If the test using Anti-D Blood Grouping Reagent is negative but
the test for Du is positive, the product shall be labeled: ``Rh
positive.''
(iii) If the test using Anti-D Blood Grouping Reagent is negative
and the test for Du is negative, the product shall be labeled: ``Rh
negative.''
(13) The container label may bear encoded information in the form of
machine-readable symbols approved for use by the Director, Center for
Biologics Evaluation and Research (HFB-1).
(d) Except for recovered plasma intended for manufacturing use or as
otherwise approved by the Director, Center for Biologics Evaluation and
Research (HFB-1), the paper of the container label shall be white and
print shall be solid black, with the following additional exceptions:
[[Page 39]]
(1) The Rh blood group shall be printed as follows:
(i) Rh positive: Use black print on white background.
(ii) Rh negative: Use white print on black background.
(2) The proper name of the product, any appropriate modifier(s), the
donor classification statement, and the statement ``properly identify
intended recipient'' shall be printed in solid red.
(3) The following color scheme may be used optionally for
differentiating ABO Blood groups:
------------------------------------------------------------------------
Blood group Color of label paper
------------------------------------------------------------------------
O Blue.
A Yellow.
B Pink.
AB White.
------------------------------------------------------------------------
(4) Ink colors used for the optional color coding system described
in paragraph (d)(3) of this section shall be a visual match to specific
color samples designated by the Director, Center for Biologics
Evaluation and Research (HFB-1).
(5) Special labels, such as those described in paragraphs (h) and
(i) of this section, may be color coded using the colors recommended in
the guideline (see paragraph (a) of this section), or colors otherwise
approved for use by the Director, Center for Biologics Evaluation and
Research (HFB-1).
(e) Container label requirements for particular products or groups
of products.
(1) Whole Blood labels shall include:
(i) The volume of anticoagulant.
(ii) The name of the applicable anticoagulant immediately preceding
and of no less prominence than the proper name and expressd as follows:
(a) ACD, (b) CPD, (c) Heparin, (d) CPDA-1, (e) CP2D, or by other
nomenclature approved for use by the Director, Office of Biologics
Research and Review (HFN-800), Center for Drugs and Biologics.
(iii) If tests for unexpected antibodies are positive, blood
intended for transfusion shall be labeled: ``Contains (name of
antibody).''
(2) Except for frozen, deglycerolized, or washed Red Blood Cell
products, red blood cell labels shall include:
(i) The volume and kind of Whole Blood, including the type of
anticoagulant, from which the product was prepared.
(ii) If tests for unexpected antibodies are positive and the product
is intended for transfusion, the statement: ``Contains (name of
antibody).''
(3) Labels for products with a dating period of 72 hours or less,
including any product prepared in a system that may compromise
sterility, shall bear the hour of expiration.
(4) If tests for unexpected antibodies are positive, Plasma intended
for transfusion shall be labeled: ``Contains (name of antibody).''
(5) Recovered plasma labels shall include:
(i) In lieu of an expiration date, the date of collection of the
oldest material in the container.
(ii) The statement: ``Caution: For Manufacturing Use Only''; or
``Caution: For Use in Manufacturing Noninjectable Products Only'', as
applicable.
(iii) For recovered plasma not meeting the requirements for
manufacture into licensable products, the statement: ``Not for Use in
Products Subject to License Under Section 351 of the Public Health
Service Act.''
(f) Blood and blood components determined to be unsuitable for
transfusion shall be prominently labeled: ``NOT FOR TRANSFUSION'', and
the label shall state the reason the unit is considered unsuitable. The
provision does not apply to recovered plasma labeled according to
paragraph (e)(5) of this section.
(g) As required under Sec. 610.40 of this chapter, labels for blood
and blood components that are reactive for Hepatitis B Surface Antigen,
but that are intended for further manufacturing, shall state
conspicuously that the material is reactive when tested for hepatitis B
surface antigen and may transmit viral hepatitis or, as applicable, that
blood was collected from a donor known to be reactive for hepatitis B
surface antigen and is presumed to be infectious, although confirmatory
hepatitis testing has not been done.
(h) The following additional information shall appear on the label
for blood or blood components shipped in an emergency, prior to
completion of
[[Page 40]]
required tests, in accordance with Sec. 640.2(f) of this chapter:
(1) The statement: ``FOR EMERGENCY USE ONLY BY ________.''
(2) Results of any tests prescribed under Secs. 610.40, 610.45, and
640.5 (a), (b), or (c) of this chapter completed before shipment.
(3) Indication of any tests prescribed under Secs. 610.40, 610.45,
and 640.5 (a), (b), or (c) of this chapter and not completed before
shipment.
(i) The following additional information shall appear on the label
for Whole Blood or Red Blood Cells intended for autologous infusion:
(1) Information adequately identifying the patient, e.g., name,
blood group, hospital, and identification number.
(2) Date of donation.
(3) The statement: ``FOR AUTOLOGOUS USE ONLY.''
(4) In place of the blood group label, each container of blood
intended for autologous use and obtained from a donor who fails to meet
any of the donor suitability requirements under Sec. 640.3 of this
chapter or who is reactive in the hepatitis tests prescribed under
Sec. 610.40 of this chapter shall be prominently and permanently
labeled: ``FOR AUTOLOGOUS USE ONLY.''
(5) Units of blood originally intended for autologous use, except
those labeled as prescribed under paragraph (i)(4) of this section, may
be issued for homologous transfusion provided the container label
complies with all applicable provisions of paragraphs (b) through (e) of
this section. In such case, the special label required under paragraph
(i) (1), (2), and (3) of this section shall be removed or otherwise
obscured.
(j) A tie-tag attached to the container may be used for providing
the information required by paragraph (e) (1)(iii), (2)(ii), and (4),
(h), or (i)(1), (2), and (3) of this section.
[50 FR 35469, Aug. 30, 1985, as amended at 53 FR 116, Jan. 5, 1988; 55
FR 11014, Mar. 26, 1990; 57 FR 10814, Mar. 31, 1992; 59 FR 23636, May 6,
1994]
Effective Date Note: The information collection requirements
contained in Sec. 606.121 will not become effective until OMB approval
has been obtained. FDA will publish a notice of OMB approval in the
Federal Register.
Sec. 606.122 Instruction circular.
An instruction circular shall be available for distribution if the
product is intended for transfusion. The instruction circular shall
provide adequate directions for use, including the following
information:
(a) Instructions to mix the product before use.
(b) Instructions to use a filter in the administration equipment.
(c) The statement ``Do Not Add Medications'' or an explanation
concerning allowable additives.
(d) A description of the product, its source, and preparation,
including the name and proportion of the anticoagulant used in
collecting the Whole Blood from each product is prepared.
(e) Statements that the product was prepared from blood that was
negative when tested for antibody to Human Immunodeficiency Virus (HIV)
and nonreactive for hepatitis B surface antigen by FDA required tests
and nonreactive when tested for syphilis by a serologic test for
syphilis (STS).
(f) The statements: ``Warning. The risk of transmitting hepatitis is
present. Careful donor selection and available laboratory tests do not
eliminate the hazard.''
(g) The names of cryoprotective agents and other additives that may
still be present in the product.
(h) The names and results of all tests performed when necessary for
safe and effective use.
(i) The use of the product, indications, contradications, side
effects and hazards, dosage and administration recommendations.
(j) [Reserved]
(k) For Red Blood Cells, the instruction circular shall contain:
(1) Instructions to administer a suitable plasma volume expander if
Red Blood Cells are substituted when Whole Blood is the indicated
product.
(2) A warning not to add Lactated Ringer's Injection U.S.P. solution
to Red Blood Cell products.
(l) For Platelets, the instruction circular shall contain:
[[Page 41]]
(1) The approximate volume of plasma from which a sample unit of
Platelets is prepared.
(2) Instructions to begin administration as soon as possible, but
not more than 4 hours after entering the container.
(m) For Plasma, the instruction circular shall contain:
(1) A warning against further processing of the frozen product if
there is evidence of breakage or thawing.
(2) Instructions to thaw the frozen product at a temperature between
30 and 37 deg.C.
(3) When applicable, instructions to begin administration of the
product within 6 hours after thawing.
(4) Instructions to administer to ABO-group-compatible recipients.
(5) A statement that this product has the same hepatitis risk as
Whole Blood; other plasma volume expanders without this risk are
available for treating hypovolemia.
(n) For Cryoprecipitated AHF, the instruction circular shall
contain:
(1) A statement that the average potency is 80 or more International
Units of antihemophilic factor.
(2) The statement: ``Usually contains at least 150 milligrams of
fibrinogen''; or, alternatively, the average fibrinogen level determined
by assay of representative units.
(3) A warning against further processing of the product if there is
evidence of breakage or thawing.
(4) Instructions to thaw the product for no more than 15 minutes at
a temperature of 37 deg.C.
(5) Instructions to store at room temperature after thawing and to
begin administration as soon as possible but no more than 4 hours after
entering the container or after pooling and within 6 hours after
thawing.
(6) A statement that 0.9 percent Sodium Chloride Injection U.S.P. is
the preferred diluent.
(7) Adequate instructions for pooling to ensure complete removal of
all concentrated material from each container.
(8) The statement: ``Good patient management requires monitoring
treatment responses to Cryoprecipitated AHF transfusions with periodic
plasma factor VIII or fibrinogen assays in hemophilia A and
hypofibrinogenemic recipients, respectively.''
[50 FR 35470, Aug. 30, 1985, as amended at 53 FR 116, Jan. 5, 1988]
Effective Date Note: The information collection requirements
contained in Sec. 606.122 will not become effective until OMB approval
has been obtained. FDA will publish a notice of OMB approval in the
Federal Register.
Subpart H--Laboratory Controls
Sec. 606.140 Laboratory controls.
Laboratory control procedures shall include:
(a) The establishment of scientifically sound and appropriate
specifications, standards and test procedures to assure that blood and
blood components are safe, pure, potent and effective.
(b) Adequate provisions for monitoring the reliability, accuracy,
precision and performance of laboratory test procedures and instruments.
(c) Adequate identification and handling of all test samples so that
they are accurately related to the specific unit of product being
tested, or to its donor, or to the specific recipient, where applicable.
Sec. 606.151 Compatibility testing.
Standard operating procedures for compatibility testing shall
include the following:
(a) A method of collecting and identifying the blood samples of
recipients to ensure positive identification.
(b) The use of fresh recipient serum samples less than 48 hours old
for all pretransfusion testing.
(c) The testing of the donor's cells with the recipient's serum
(major crossmatch) by a method that will demonstrate agglutinating,
coating and hemolytic antibodies, which shall include the antiglobulin
method.
(d) A provision that, if the unit of donor's blood has not been
screened by a method that will demonstrate agglutinating, coating and
hemolytic antibodies, the recipient's cells shall be tested with the
donor's serum (minor crossmatch) by a method that will so demonstrate.
[[Page 42]]
(e) Procedures to expedite transfusions in life-threatening
emergencies. Records of all such incidents shall be maintained,
including complete documentation justifying the emergency action, which
shall be signed by the physician requesting the procedure.
Subpart I--Records and Reports
Sec. 606.160 Records.
(a)(1) Records shall be maintained concurrently with the performance
of each significant step in the collection, processing, compatibility
testing, storage and distribution of each unit of blood and blood
components so that all steps can be clearly traced. All records shall be
legible and indelible, and shall identify the person performing the
work, include dates of the various entries, show test results as well as
the interpretation of the results, show the expiration date assigned to
specific products, and be as detailed as necessary to provide a complete
history of the work performed.
(2) Appropriate records shall be available from which to determine
lot numbers of supplies and reagents used for specific lots or units of
the final product.
(b) Records shall be maintained that include, but are not limited
to, the following when applicable:
(1) Donor records:
(i) Donor selection, including medical interview and examination and
where applicable, informed consent.
(ii) Permanent and temporary deferrals for health reasons including
reason(s) for deferral.
(iii) Donor adverse reaction complaints and reports, including
results of all investigations and followup.
(iv) Therapeutic bleedings, including signed requests from attending
physicians, the donor's disease and disposition of units.
(v) Immunization, including informed consent, identification of the
antigen, dosage and route of administration.
(vi) Blood collection, including identification of the phlebotomist.
(2) Processing records:
(i) Blood processing, including results and interpretation of all
tests and retests.
(ii) Component preparation, including all relevant dates and times.
(iii) Separation and pooling of recovered plasma.
(iv) Centrifugation and pooling of source plasma.
(v) Labeling, including initials of person(s) responsible.
(3) Storage and distribution records:
(i) Distribution and disposition, as appropriate, of blood and blood
products.
(ii) Visual inspection of whole blood and red blood cells during
storage and immediately before distribution.
(iii) Storage temperature, including initialed temperature recorder
charts.
(iv) Reissue, including records of proper temperature maintenance.
(v) Emergency release of blood, including signature of requesting
physician obtained before or after release.
(4) Compatibility test records:
(i) Results of all compatibility tests, including crossmatching,
testing of patient samples, antibody screening and identification.
(ii) Results of confirmatory testing.
(5) Quality control records:
(i) Calibration and standardization of equipment.
(ii) Performance checks of equipment and reagents.
(iii) Periodic check on sterile technique.
(iv) Periodic tests of capacity of shipping containers to maintain
proper temperature in transit.
(v) Proficiency test results.
(6) Transfusion reaction reports and complaints, including records
of investigations and followup.
(7) General records:
(i) Sterilization of supplies and reagents prepared within the
facility, including date, time interval, temperature and mode.
(ii) Responsible personnel.
(iii) Errors and accidents.
(iv) Maintenance records for equipment and general physical plant.
(v) Supplies and reagents, including name of manufacturer or
supplier, lot numbers, expiration date and date of receipt.
(vi) Disposition of rejected supplies and reagents used in the
collection, processing and compatibility testing of blood and blood
components.
[[Page 43]]
(c) A donor number shall be assigned to each accepted donor, which
relates the unit of blood collected to that donor, to his medical
record, to any component or blood product from that donor's unit of
blood, and to all records describing the history and ultimate
disposition of these products.
(d) Records shall be retained for such interval beyond the
expiration date for the blood or blood component as necessary to
facilitate the reporting of any unfavorable clinical reactions. The
retention period shall be no less than 5 years after the records of
processing have been completed or 6 months after the latest expiration
date for the individual product, whichever is a later date. When there
is no expiration date, records shall be retained indefinitely.
(e) A record shall be available from which unsuitable donors may be
identified so that products from such individuals will not be
distributed.
Sec. 606.165 Distribution and receipt; procedures and records.
(a) Distribution and receipt procedures shall include a system by
which the distribution or receipt of each unit can be readily determined
to facilitate its recall, if necessary.
(b) Distribution records shall contain information to readily
facilitate the identification of the name and address of the consignee,
the date and quantity delivered, the lot number of the unit(s), the date
of expiration or the date of collection, whichever is applicable, or for
crossmatched blood and blood components, the name of the recipient.
(c) Receipt records shall contain the name and address of the
collecting facility, date received, donor or lot number assigned by the
collecting facility and the date of expiration or the date of
collection, whichever is applicable.
Sec. 606.170 Adverse reaction file.
(a) Records shall be maintained of any reports of complaints of
adverse reactions regarding each unit of blood or blood product arising
as a result of blood collection or transfusion. A thorough investigation
of each reported adverse reaction shall be made. A written report of the
investigation of adverse reactions, including conclusions and followup,
shall be prepared and maintained as part of the record for that lot or
unit of final product by the collecting or transfusing facility. When it
is determined that the product was at fault in causing a transfusion
reaction, copies of all such written reports shall be forwarded to and
maintained by the manufacturer or collecting facility.
(b) When a complication of blood collection or transfusion is
confirmed to be fatal, the Director, Office of Compliance, Center for
Biologics Evaluation and Research, shall be notified by telephone or
telegraph as soon as possible; a written report of the investigation
shall be submitted to the Director, Office of Compliance, Center for
Biologics Evaluation and Research, within 7 days after the fatality by
the collecting facility in the event of a donor reaction, or by the
facility that performed the compatibility tests in the event of a
transfusion reaction.
(Information collection requirements approved by the Office of
Management and Budget under control number 0910-0116)
[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 50
FR 35471, Aug. 30, 1985; 55 FR 11014, Mar. 26, 1990]
PART 607--ESTABLISHMENT REGISTRATION AND PRODUCT LISTING FOR MANUFACTURERS OF HUMAN BLOOD AND BLOOD PRODUCTS--Table of Contents
Subpart A--General Provisions
Sec.
607.3 Definitions.
607.7 Establishment registration and product listing of blood banks and
other firms manufacturing human blood and blood products.
Subpart B--Procedures for Domestic Blood Product Establishments
607.20 Who must register and submit a blood product list.
607.21 Times for establishment registration and blood product listing.
607.22 How and where to register establishments and list blood
products.
607.25 Information required for establishment registration and blood
product listing.
607.26 Amendments to establishment registration.
607.30 Updating blood product listing information.
[[Page 44]]
607.31 Additional blood product listing information.
607.35 Notification of registrant; blood product establishment
registration number and NDC Labeler Code.
607.37 Inspection of establishment registrations and blood product
listings.
607.39 Misbranding by reference to establishment registration or to
registration number.
Subpart C--Procedures for Foreign Blood Product Establishments
607.40 Blood product listing requirements for foreign blood product
establishments.
Subpart D--Exemptions
607.65 Exemptions for blood product establishments.
Authority: Secs. 201, 301, 501, 502, 505, 510, 701, 704 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 355,
360, 371, 374); secs. 215, 351 of the Public Health Service Act (42
U.S.C. 216, 262).
Source: 40 FR 52788, Nov. 12, 1975, unless otherwise noted.
Subpart A--General Provisions
Sec. 607.3 Definitions.
(a) The term act means the Federal Food, Drug, and Cosmetic Act
approved June 25, 1938 (52 Stat. 1040 et seq., as amended, 21 U.S.C.
301-392).
(b) Blood and blood product means a drug which consists of human
whole blood, plasma, or serum or any product derived from human whole
blood, plasma or serum, hereinafter referred to as ``blood product.''
(c) Establishment means a place of business under one management at
one general physical location. The term includes, among others, human
blood and plasma donor centers, blood banks, transfusion services, other
blood product manufacturers and independent laboratories that engage in
quality control and testing for registered blood product establishments.
(d) Manufacture means the collection, preparation, processing or
compatibility testing by chemical, physical, biological, or other
procedures of any blood product which meets the definition of a drug as
defined in section 201(g) of the act, and including manipulation,
sampling, testing, or control procedures applied to the final product or
to any part of the process. The term includes packaging, labeling,
repackaging or otherwise changing the container, wrapper, or labeling of
any blood product package in furtherance of the distribution of the
blood product from the original place of manufacture to the person who
makes final delivery or sale to the ultimate consumer.
(e) Commercial distribution means any distribution of a blood
product except pursuant to the investigational use provisions of part
312 of this chapter, but does not include internal or interplant
transfer of a bulk product substance between registered domestic
establishments within the same parent, subsidiary, and/or affiliate
company.
(f) Any material change includes but is not limited to any change in
the name of the blood product, in the quantity or identity of the active
ingredient(s) or in the quantity or identity of the inactive
ingredient(s) where quantitative listing of all ingredients is required
pursuant to Sec. 607.31(a)(2) and any significant change in the labeling
of a blood product. Changes that are not significant include changes in
arrangement or printing or changes of an editorial nature.
(g) Bulk product substance means any substance that is represented
for use in a blood product and when used in the manufacturing of a blood
product becomes an active ingredient or a finished dosage form of such
product.
(h) Advertising and labeling include the promotional material
described in Sec. 202.1(l) (1) and (2) of this chapter, respectively.
(i) The definitions and interpretations contained in sections 201
and 510 of the act shall be applicable to such terms when used in this
part 607.
[40 FR 52788, Nov. 12, 1975, as amended at 55 FR 11014, Mar. 26, 1990]
Sec. 607.7 Establishment registration and product listing of blood banks and other firms manufacturing human blood and blood products.
(a) All owners or operators of establishments that engage in the
manufacturing of blood products are required to register, pursuant to
section 510 of the Federal Food, Drug, and Cosmetic Act.
[[Page 45]]
Registration and listing of blood products shall comply with this part.
Registration does not permit any blood bank or similar establishment to
ship blood products in interstate commerce.
(b) Forms for registration of an establishment are obtainable on
request from the Center for Biologics Evaluation and Research (HFB-240),
8800 Rockville Pike, Bethesda, MD 20892 or at any of the Food and Drug
Administration district offices.
(c) The completed form should be mailed to the Center for Biologics
Evaluation and Research (HFB-240), 8800 Rockville Pike, Bethesda, MD
20892.
[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 55
FR 11014, Mar. 26, 1990]
Subpart B--Procedures for Domestic Blood Product Establishments
Sec. 607.20 Who must register and submit a blood product list.
(a) Owners or operators of all establishments, not exempt under
section 510(g) of the act or subpart D of this part 607, that engage in
the manufacture of blood products are required to register and to submit
a list of every blood product in commercial distribution (except that
listing information may be submitted by the parent, subsidiary, and/or
affiliate company for all establishments when operations are conducted
at more than one establishment and there exists joint ownership and
control among all the establishments), whether or not the output of such
blood product establishment or any particular blood product so listed
enters interstate commerce.
(b) Preparatory to engaging in the manufacture of blood products,
owners or operators of establishments who are submitting an
establishment license application to manufacture blood products are
required to register before the establishment license application is
approved.
(c) No registration fee is required. Establishment registration and
blood product listing do not constitute an admission or agreement or
determination that a blood product is a ``drug'' within the meaning of
section 201(g) of the act.
Sec. 607.21 Times for establishment registration and blood product listing.
The owner or operator of an establishment entering into an operation
defined in Sec. 607.3(d) shall register such establishment within 5 days
after the beginning of such operation and submit a list of every blood
product in commercial distribution at the time. If the owner or operator
of the establishment has not previously entered into such operation
(defined in Sec. 607.3(d)) for which a license is required, registration
shall follow within 5 days after the submission of an establishment and
product license application in order to manufacture blood products.
Owners or operators of all establishments so engaged shall register
annually between November 15 and December 31 and shall update their
blood product listing information every June and December.
Sec. 607.22 How and where to register establishments and list blood products.
(a) The first registration of an establishment shall be on Form FD-
2830 (Blood Establishment Registration and Product Listing) obtainable
on request from the Department of Health and Human Services, Food and
Drug Administration, Center for Biologics Evaluation and Research (HFB-
240), 8800 Rockville Pike, Bethesda, MD 20892, or from Food and Drug
Administration district offices. Subsequent annual registration shall
also be accomplished on Form FD-2830 which will be furnished by the Food
and Drug Administration before November 15 of each year to
establishments whose product registration for that year was validated
pursuant to Sec. 607.35. The completed form shall be mailed to the above
address before December 31 of that year.
(b) The first list of blood products and subsequent June and
December updatings shall be on Form FD-2830, obtainable upon request as
described in paragraph (a) of this section. In lieu of Form FD-2830,
tapes for computer input may be submitted if equivalent
[[Page 46]]
in all elements of information as specified in Form FD-2830. All formats
proposed for such use will require initial review and approval by the
Office of Compliance, Center for Biologics Evaluation and Research, Food
and Drug Administration.
[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 55
FR 11014, Mar. 26, 1990]
Sec. 607.25 Information required for establishment registration and blood product listing.
(a) Form FD-2830 (Blood Establishment Registration and Product
Listing) requires furnishing or confirming registration information
required by the act. This information includes the name and street
address of the establishment, including post office ZIP code; all trade
names used by the establishment; the kind of ownership or operation
(that is, individually owned partnership, or corporation); and the name
of the owner or operator of such establishment. The term ``name of the
owner or operator'' shall include in the case of a partnership the name
of each partner, and in the case of a corporation the name and title of
each corporate officer and director and the name of the State of
incorporation. The information required shall be given separately for
each establishment, as defined in Sec. 607.3(c).
(b) Form FD-2830 also requires furnishing blood product listing
information required by the act as follows:
(1) A list of blood products, including bulk product substances as
well as finished dosage forms, by established name as defined in section
502(e) of the act and by proprietary name, which are being manufactured
for commercial distribution and which have not been included in any list
previously submitted on Form FD-2830 (Blood Establishment Registration
and Product Listing) or Form FD-2250 (National Drug Code Directory
Input).
(2) For each blood product so listed which is subject to section 351
of the Public Health Service Act, the license number of the manufacturer
issued by the Center for Biologics Evaluation and Research, Food and
Drug Administration.
(3) For each blood product listed, the registration number of every
blood product establishment within the parent company at which it is
manufactured.
[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Sec. 607.26 Amendments to establishment registration.
Changes in individual ownership, corporate or partnership structure
location or blood-product-handling activity, shall be submitted on Form
FD-2830 (Blood Establishment Registration and Product Listing) as
amendment to registration within 5 days of such changes. Changes in the
names of officers and directors of the corporations do not require such
amendment but must be shown at time of annual registration.
Sec. 607.30 Updating blood product listing information.
(a) After submission of the initial blood product listing
information, every person who is required to list blood products
pursuant to Sec. 607.20 shall submit on Form FD-2830 (Blood
Establishment Registration and Product Listing) during each subsequent
June and December, or at the discretion of the registrant at the time
the change occurs, the following information:
(1) A list of each blood product introduced by the registrant for
commercial distribution which has not been included in any list
previously submitted. All of the information required by Sec. 607.25(b)
shall be provided for each such blood product.
(2) A list of each blood product formerly listed pursuant to
Sec. 607.25(b) for which commercial distribution has been discontinued,
including for each blood product so listed the identity by established
name and proprietary name, and date of discontinuance. It is requested
but not required that the reason for discontinuance of distribution be
included with this information.
(3) A list of each blood product for which a notice of
discontinuance was submitted pursuant to paragraph (a)(2) of this
section and for which commercial distribution has been resumed,
including for each blood product so listed
[[Page 47]]
the identity by established name as defined in section 502(e) of the act
and by any proprietary name, the date of resumption, and any other
information required by Sec. 607.25(b) not previously submitted.
(4) Any material change in any information previously submitted.
(b) When no changes have occurred since the previously submitted
list, no listing information is required.
Sec. 607.31 Additional blood product listing information.
(a) In addition to the information routinely required by
Secs. 607.25 and 607.30, the Commissioner may require submission of the
following information by letter or by Federal Register notice:
(1) For a particular blood product so listed, upon request made by
the Commissioner for good cause, a copy of all advertisements.
(2) For a particular blood product so listed, upon a finding by the
Commissioner that it is necessary to carry out the purposes of the act,
a quantitative listing of all ingredients.
(3) For each registrant, upon a finding by the Commissioner that it
is necessary to carry out the purposes of the act, a list of each listed
blood product containing a particular ingredient.
(b) It is requested but not required that information concerning the
quantity of blood product distributed be submitted in conjunction with
the annual registration in the format prescribed in a section of Form
FD-2831 (Blood Establishment Resource Summary), for each blood product
currently listed.
Sec. 607.35 Notification of registrant; blood product establishment registration number and NDC Labeler Code.
(a) The Commissioner will provide to the registrant a validated copy
of Form FD-2830 (Blood Establishment Registration and Product Listing)
as evidence of registration. This validated copy will be sent only to
the location shown for the registering establishment. A permanent
registration number will be assigned to each blood product establishment
registered in accordance with these regulations.
(b) If a registered blood product establishment has not previously
participated in the National Drug Code system, or in the National Health
Related Items Code system, the National Drug Code (NDC) numbering system
shall be used in assigning the first five numeric characters, otherwise
known as the Labeler Code, of the 10-character NDC Code. The Labeler
Code identifies the manufacturer.
(c) Although establishment registration and blood product listing
are required as described in Sec. 607.20, validation of registration and
the assignment of a NDC Labeler Code do not, in themselves, establish
that the holder of the registration is legally qualified to deal in such
products.
[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984]
Sec. 607.37 Inspection of establishment registrations and blood product listings.
(a) A copy of the Form FD-2830 (Blood Establishment Registration and
Product Listing) filed by the registrant will be available for
inspection pursuant to section 510(f) of the act, at the Department of
Health and Human Services, Food and Drug Administration, Office of
Compliance, Center for Biologics Evaluation and Research (HFB-100), 8800
Rockville Pike, Bethesda, MD 20892. In addition, there will be available
for inspection at each of the Food and Drug Administration district
offices the same information for firms within the geographical area of
such district office. Upon request and receipt of a self-addressed
stamped envelope, verification of registration number, or location of a
registered establishment will be provided. The following information
submitted pursuant to the blood product listing requirements is
illustrative of the type of information that will be available for
public disclosure when it is compiled:
(1) A list of all blood products.
(2) A list of all blood products manufactured by each establishment.
(3) A list of blood products discontinued.
(4) All data or information that has already become a matter of
public knowledge.
[[Page 48]]
(b) Requests for information regarding blood establishment
registrations and blood product listings should be directed to the
Department of Health and Human Services, Food and Drug Administration,
Office of Compliance, Center for Biologics Evaluation and Research (HFB-
100), 8800 Rockville Pike, Bethesda, MD 20892.
[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 55
FR 11014, Mar. 26, 1990]
Sec. 607.39 Misbranding by reference to establishment registration or to registration number.
Registration of an establishment or assignment of a registration
number or assignment of a NDC number does not in any way denote approval
of the firm or its products. Any representation that creates an
impression of official approval because of establishment registration or
possession of registration number or NDC number is misleading and
constitutes misbranding.
Subpart C--Procedures for Foreign Blood Product Establishments
Sec. 607.40 Blood product listing requirements for foreign blood product establishments.
(a) Every foreign establishment shall comply with the blood product
listing requirements contained in Subpart B of this part, unless exempt
under Subpart D of this part, whether or not it is also registered.
(b) No blood product may be imported from a foreign establishment
into the United States except a blood product imported or offered for
import pursuant to the investigational use provisions of part 312 of
this chapter, unless it is first the subject of a blood product listing
as required in Subpart B of this part. The blood product listing
information shall be in the English language.
(c) Foreign establishments shall submit, as part of the blood
product listing, the name and address of the establishment and the name
of the individual responsible for submitting blood product listing
information. Any changes in this information shall be reported to the
Food and Drug Administration at the intervals specified for updating
blood product listing information in Sec. 607.30(a).
[40 FR 52788, Nov. 12, 1975, as amended at 55 FR 11014, Mar. 26, 1990]
Subpart D--Exemptions
Sec. 607.65 Exemptions for blood product establishments.
The following classes of persons are exempt from registration and
blood product listing in accordance with this part 607 under the
provisions of section 510(g) (1), (2), and (3) of the act, or because
the Commissioner has found, under section 510(g)(4), that such
registration is not necessary for the protection of the public health.
(a) Pharmacies that are operating under applicable local laws
regulating dispensing of prescription drugs and that are not
manufacturing blood products for sale other than in the regular course
of the practice of the profession of pharmacy including the business of
dispensing and selling blood products at retail. The supplying by such
pharmacies of blood products to a practitioner licensed to administer
such blood products for his use in the course of his professional
practice or to other pharmacies to meet temporary inventory shortages
are not acts which require such pharmacies to register.
(b) Practitioners who are licensed by law to prescribe or administer
drugs and who manufacture blood products solely for use in the course of
their professional practice.
(c) Persons who manufacture blood products which are not for sale,
rather, are solely for use in research, teaching, or analysis, including
laboratory samples.
(d) Carriers, by reason of their receipt, carriage, holding, or
delivery of blood products in the usual course of business as carriers.
(e) Persons who engage solely in the manufacture of in vitro
diagnostic blood products and reagents not subject to licensing under
section 351 of the Public Health Service Act (42 U.S.C. 262). This
paragraph does not exempt such persons from registration and listing for
medical devices required under part 807 of this chapter.
(f) Transfusion services which are a part of a facility approved for
Medicare
[[Page 49]]
reimbursement and engaged in the compatibility testing and transfusion
of blood and blood components, but which neither routinely collect nor
process blood and blood components. The collection and processing of
blood and blood components in an emergency situation as determined by a
responsible person and documented in writing, therapeutic collection of
blood or plasma, the preparation of recovered human plasma for further
manufacturing use, or preparation of red blood cells for transfusion are
not acts requiring such transfusion services to register.
(g) Clinical laboratories that are approved for Medicare
reimbursement and are engaged in the testing of blood products in
support of other registered blood establishments.
[40 FR 52788, Nov. 12, 1975, as amended at 43 FR 37997, Aug. 25, 1978;
45 FR 85729, Dec. 30, 1980; 49 FR 34449, Aug. 31, 1984]
PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS--Table of Contents
Subpart A--Release Requirements
Sec.
610.1 Tests prior to release required for each lot.
610.2 Requests for samples and protocols; official release.
Subpart B--General Provisions
610.9 Equivalent methods and processes.
610.10 Potency.
610.11 General safety.
610.11a Inactivated influenza vaccine, general safety test.
610.12 Sterility.
610.13 Purity.
610.14 Identity.
610.15 Constituent materials
610.16 Total solids in serums.
610.17 Permissible combinations.
610.18 Cultures.
610.19 Status of specific products; Group A streptococcus.
Subpart C--Standard Preparations and Limits of Potency
610.20 Standard preparations.
610.21 Limits of potency.
Subpart D--Mycoplasma
610.30 Test for Mycoplasma.
Subpart E--Hepatitis Requirements
610.40 Test for hepatitis B surface antigen.
610.41 History of hepatitis B surface antigen.
610.45 Human Immunodeficiency Virus (HIV) requirements.
Subpart F--Dating Period Limitations
610.50 Date of manufacture.
610.53 Dating periods for licensed biological products .
Subpart G--Labeling Standards
610.60 Container label.
610.61 Package label.
610.62 Proper name; package label; legible type.
610.63 Divided manufacturing responsibility to be shown.
610.64 Name of selling agent or distributor.
610.65 Products for export.
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360,
371); secs. 215, 351, 352, 353, 361 of the Public Health Service Act (42
U.S.C. 216, 262, 263, 263a, 264).
Source: 38 FR 32056, Nov. 20, 1973, unless otherwise noted.
Cross References: For U.S. Customs Service regulations relating to
viruses, serums, and toxins, see 19 CFR 12.21--12.23. For U.S. Postal
Service regulations relating to the admissibility to the United States
mails see parts 124 and 125 of the Domestic Mail Manual, that is
incorporated by reference in 39 CFR part 111.
Subpart A--Release Requirements
Sec. 610.1 Tests prior to release required for each lot.
No lot of any licensed product shall be released by the manufacturer
prior to the completion of tests for conformity with standards
applicable to such product. Each applicable test shall be made on each
lot after completion of all processes of manufacture which may affect
compliance with the standard to which the test applies. The results of
all tests performed shall be considered in determining whether or not
the test results meet the test objective, except that a test result may
be disregarded when it is established that the test is invalid due to
causes unrelated to the product.
[[Page 50]]
Sec. 610.2 Requests for samples and protocols; official release.
(a) General. Samples of any lot of any licensed product, except for
radioactive biological products, together with the protocols showing
results of applicable tests, may at any time be required to be sent to
the Director, Center for Biologics Evaluation and Research. Upon
notification by the Director, Center for Biologics Evaluation and
Research, a manufacturer shall not distribute a lot of a product until
the lot is released by the Director, Center for Biologics Evaluation and
Research: Provided, That the Director, Center for Biologics Evaluation
and Research, shall not issue such notification except when deemed
necessary for the safety, purity, or potency of the product.
(b) Radioactive biological products. Samples of any lot of a
radioactive biological product, as defined in Sec. 600.3(ee) of this
chapter, together with the protocols showing results of applicable
tests, may at any time be required to be sent to the Food and Drug
Administration for official release. Upon notification by the Director,
Center for Drug Evaluation and Research, a manufacturer shall not
distribute a lot of a radioactive biological product until the lot is
released by the Director, Center for Drug Evaluation and Research:
Provided, That the Director, Center for Drug Evaluation and Research
shall not issue such notification except when deemed necessary for the
safety, purity, or potency of the product.
(Information collection requirements approved by the Office of
Management and Budget under control number 0910-0206)
[40 FR 31313, July 25, 1975, as amended by 49 FR 23834, June 8, 1984; 50
FR 10941, Mar. 19, 1985; 55 FR 11013 and 11014, Mar. 26, 1990]
Subpart B--General Provisions
Sec. 610.9 Equivalent methods and processes.
Modification of any particular test method or manufacturing process
or the conditions under which it is conducted as required in this part
or in the additional standards for specific biological products in parts
620 through 680 of this chapter shall be permitted only under the
following conditions:
(a) The manufacturer presents evidence, in the form of a product
license supplement, demonstrating that the modification will provide
assurances of the safety, purity, potency, and effectiveness of the
biological product equal to or greater than the assurances provided by
the method or process specified in the general standards or additional
standards for the biological product; and
(b) Approval of the modification is received in writing from the
Director, Center for Biologics Evaluation and Research (HFB-1), 8800
Rockville Pike, Bethesda, MD 20892.
[49 FR 15187, Apr. 18, 1984; 49 FR 21317, May 21, 1984, as amended at 51
FR 15607, Apr. 25, 1986; 55 FR 11014, Mar. 26, 1990; 59 FR 49351, Sept.
28, 1994]
Sec. 610.10 Potency.
Tests for potency shall consist of either in vitro or in vivo tests,
or both, which have been specifically designed for each product so as to
indicate its potency in a manner adequate to satisfy the interpretation
of potency given by the definition in Sec. 600.3(s) of this chapter.
Sec. 610.11 General safety.
A general safety test for the detection of extraneous toxic
contaminants shall be performed on biological products intended for
administration to humans. The general safety test is required in
addition to other specific tests prescribed in the additional standards
for individual products in this subchapter, except that, the test need
not be performed on those products listed in paragraph (g) of this
section. The general safety test shall be performed as specified in this
section, unless: Modification is prescribed in the additional standards
for specific products, or variation is approved as a supplement to the
product license under Sec. 610.9.
(a) Product to be tested. The general safety test shall be conducted
upon a representative sample of the product in the final container from
every final filling of each lot of the product. If any product is
processed further after filling, such as by freeze-drying,
sterilization, or heat treatment, the test shall be conducted upon a
sample from each
[[Page 51]]
filling of each drying chamber run, sterilization chamber, or heat
treatment bath.
(b) Test animals. Only overtly healthy guinea pigs weighing less
than 400 grams each and mice weighing less than 22 grams each shall be
used. The animals shall not have been used previously for any test
purpose.
(c) Procedure. The duration of the general safety test shall be 7
days for both species, except that a longer period may be established
for specific products in accordance with Sec. 610.9. Once the
manufacturer has established a specific duration of the test period for
a specific product, it cannot be varied subsequently, except, in
accordance with Sec. 610.9. Each test animal shall be weighed and the
individual weights recorded immediately prior to injection and on the
last day of the test. Each animal shall be observed every working day.
Any animal response including any which is not specific for or expected
from the product and which may indicate a difference in its quality
shall be recorded on the day such response is observed. The test product
shall be administered as follows:
(1) Liquid product or freeze-dried product which has been
reconstituted as directed on the label. Inject intraperitoneally 0.5
milliliter of the liquid product or the reconstituted product into each
of at least two mice, and 5.0 milliliters of the liquid product or the
reconstituted product into each of at least two guinea pigs.
(2) Freeze-dried product for which the volume of reconstitution is
not indicated on the label. The route of administration, test dose, and
diluent shall be as approved by the Director, Center for Biologics
Evaluation and Research, in accordance with Sec. 610.9. Administer the
test product as approved on at least two mice and at least two guinea
pigs.
(3) Nonliquid products other than freeze-dried product. The route of
administration, test dose, and diluent shall be as approved by the
Director, Center for Biologics Evaluation and Research, in accordance
with Sec. 610.9. Dissolve or grind and suspend the product in the
approved diluent. Administer the test product as approved on at least
two mice and at least two guinea pigs.
(d) Test requirements. A safety test is satisfactory if all animals
meet all of the following requirements:
(1) They survive the test period.
(2) They do not exhibit any response which is not specific for or
expected from the product and which may indicate a difference in its
quality.
(3) They weigh no less at the end of the test period than at the
time of injection.
(e) Repeat tests--(1) First repeat test. If a filling fails to meet
the requirements of paragraph (d) of this section in the initial test, a
repeat test may be conducted on the species which failed the initial
test, as prescribed in paragraph (c) of this section. The filling is
satisfactory only if each retest animal meets the requirements
prescribed in paragraph (d) of this section.
(2) Second repeat test. If a filling fails to meet the requirements
of the first repeat test, a second repeat test may be conducted on the
species which failed the test: Provided, That 50 percent of the total
number of animals in that species has survived the initial and first
repeat tests. The second repeat test shall be conducted as prescribed in
paragraph (c) of this section, except that the number of animals shall
be twice that used in the first repeat test. The filling is satisfactory
only if each second repeat test animal meets the requirements prescribed
in paragraph (d) of this section.
(f) [Reserved]
(g) Exceptions. The test prescribed in this section need not be
performed for Whole Blood, Red Blood Cells, Cryoprecipitated AHF,
Platelets, or Plasma.
[41 FR 10891, Mar. 15, 1976, as amended at 49 FR 15187, Apr. 18, 1984;
49 FR 23834, June 8, 1984; 50 FR 4133, Jan. 29, 1985; 51 FR 15607, Apr.
25, 1986; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994]
Sec. 610.11a Inactivated influenza vaccine, general safety test.
For inactivated influenza vaccine, the general safety test shall be
conducted in the manner indicated in Sec. 610.11 of this chapter except
that, with reference to guinea pigs, the test shall be satisfied if the
product provides satisfactory results using either the subcutaneous or
intraperitoneal injection
[[Page 52]]
of 5.0 milliliters of inactivated influenza vaccine into each guinea
pig. The requirements for general safety for inactivated influenza
vaccine shall not be considered to be satisfied unless each lot of
influenza vaccine is assayed for endotoxin in comparison to a reference
preparation provided by the Food and Drug Administration, and such lot
is found to contain no more endotoxin than the reference preparation.
[39 FR 40016, Nov. 13, 1974]
Sec. 610.12 Sterility.
Except as provided in paragraphs (f) and (g) of this section, the
sterility of each lot of each product shall be demonstrated by the
performance of the tests prescribed in paragraphs (a) and (b) of this
section for both bulk and final container material.
(a) The test. Bulk material shall be tested separately from final
container material and material from each final container shall be
tested in individual test vessels as follows:
(1) Using Fluid Thioglycollate Medium--(i) Bulk and final container
material. The volume of product, as required by paragraph (d) of this
section (hereinafter referred to also as the ``inoculum''), from samples
of both bulk and final container material, shall be inoculated into test
vessels of Fluid Thioglycollate Medium. The inoculum and medium shall be
mixed thoroughly and incubated at a temperature of 30 to 35 deg.C for a
test period of no less than 14 days and examined visually for evidence
of growth on the third, fourth, or fifth day, and on the seventh or
eighth day, and on the last day of the test period. Results of each
examination shall be recorded. If the inoculum renders the medium turbid
so that the absence of growth cannot be determined reliably by visual
examination, portions of this turbid medium in amounts of no less than
1.0 milliliter shall be transferred on the third, fourth, or fifth day
of incubation, from each of the test vessels and inoculated into
additional vessels of the medium. The material in the additional vessels
shall be incubated at a temperature of 30 to 35 deg.C for no less than
14 days. Notwithstanding such transfer of material, examination of the
original vessels shall be continued as prescribed above. The additional
test vessels shall be examined visually for evidence of growth on the
third, fourth, or fifth day of incubation, and on the seventh or eighth
day, and on the last day of the incubation period. If growth appears,
repeat tests may be performed as prescribed in paragraph (b) of this
section and interpreted as specified in paragraph (c) of this section.
(ii) Final container material containing a mercurial preservative.
In addition to the test prescribed in paragraph (a)(1)(i) of this
section, final container material containing a mercurial preservative
shall be tested using Fluid Thioglycollate Medium following the
procedures prescribed in such subparagraph, except that the incubation
shall be at a temperature of 20 deg. to 25 deg. C.
(2) Using Soybean-Casein Digest Medium. Except for products
containing a mercurial preservative, a test shall be made on final
container material, following the procedures prescribed in paragraph
(a)(1)(i) of this section, except that the medium shall be Soybean-
Casein Digest Medium and the incubation shall be at a temperature of
20 deg. to 25 deg. C.
(b) Repeat tests. If growth appears in any of the test media during
testing of either bulk or final container material, the test may be
repeated to rule out faulty test procedures as follows:
(1) Repeat bulk test. Only one repeat bulk test may be conducted.
The volume of inoculum to be used for the repeat bulk test shall be as
prescribed in paragraph (d)(1) of this section. The repeat test shall be
performed using the procedure prescribed in paragraph (a)(1)(i) of this
section.
(2) First repeat final container test. The number of test samples
and the volumes of product used for the first repeat test shall be as
prescribed in paragraph (d)(2) of this section. For products that do not
contain a mercurial preservative, the repeat test shall be performed,
using both Fluid Thioglycollate Medium and Soybean-Casein Digest Medium,
following the procedures prescribed in paragraphs (a)(1)(i) and (a)(2),
respectively, of this section. If the product contains a mercurial
preservative, the repeat test shall be performed using Fluid
[[Page 53]]
Thioglycollate Medium and the procedures prescribed in paragraphs (a)(1)
(i) and (ii) of this section.
(3) Second repeat final container test. If growth appears in any of
the first repeat final container tests, all tests of the first repeat
final container test shall be repeated, provided there was no evidence
of growth in any test of the bulk material. The test samples used for
the second repeat final container test shall be twice the number used
for the first repeat final container test.
(c) Interpretation of test results. The results of all tests
performed on a lot shall be considered in determining whether or not the
lot meets the requirements for sterility, except that tests may be
excluded when demonstrated by adequate controls to be invalid. The lot
meets the test requirements if no growth appears in the tests prescribed
in paragraph (a) of this section. If repeat tests are performed, the lot
meets the test requirements if no growth appears in the tests prescribed
in paragraph (b)(2) or (3) of this section, whichever is applicable.
(d) Test samples and volumes--(1) Bulk. Each sample for the bulk
sterility test shall be representative of the bulk material and the
volume tested shall be no less than 10 ml. (Note exceptions in paragraph
(g) of this section.)
(2) Final containers. The sample used for each test medium or each
incubation temperature of a test medium for the final container and
first repeat final container test shall be no less than 20 final
containers from each filling of each lot, selected to represent all
stages of filling from the bulk vessel. If the amount of material in the
final container is 1.0 milliliter or less, the entire contents shall be
tested. If the amount of material in the final container is more than
1.0 milliliter, the volume tested shall be the largest single dose
recommended by the manufacturer or 1.0 milliliter, whichever is larger,
but no more than 10 milliliters of material or the entire contents from
a single final container need be tested. If more than 2 filling
machines, each with either single or multiple filling stations, are used
for filling one lot, no less than 10 filled containers shall be tested
from each filling machine for each test medium or each incubation
temperature condition, but no more than 100 containers of each lot need
be tested. The items tested shall be representative of each filling
assembly and shall be selected to represent all stages of the filling
operation. (Note exceptions in paragraph (g) of this section.)
(e) Culture medium--(1) Formulae. (i) The formula for Fluid
Thioglycollate Medium is as follows:
Fluid Thioglycollate Medium
1-cystine................................ 0.5 Gm.
Sodium chloride.......................... 2.5 Gm.
Dextrose (C6H12O6H2O).......... 5.5 Gm.
Granular agar (less than 15% moisture by 0.75 Gm.
weight).
Yeast extract (water-soluble)............ 5.0 Gm.
Pancreatic digest of casein.............. 15.0 Gm.
Purified water........................... 1,000.0 ml.
Sodium thioglycollate (or thioglycolic 0.5 Gm.
acid--0.3 ml).
Resazurin (0.10% solution, 1.0 ml.
freshly prepared).
pH after sterilization 7.1plus-minus0.2.
(ii) The formula for Soybean-Casein Digest Medium is as follows:
Soybean-Casein Digest Medium
Pancreatic Digest of Casein.............. 17.0 Gm.
Papaic Digest of Soybean Meal............ 3.0 Gm.
Sodium Chloride.......................... 5.0 Gm.
Dibasic Potassium Phosphate.............. 2.5 Gm.
Dextrose (C6H12O6H2O).......... 2.5 Gm.
Purified water........................... 1,000.0 ml.
pH after sterilization 7.3plus-minus0.2.
(2) Culture media requirements--(i) Definition of a lot of culture
medium and test requirements. A lot of culture medium is that quantity
of uniform material identified as having been thoroughly mixed in a
single vessel, dispensed into a group of vessels of the same composition
and design, sterilized in a single autoclave run, and identified in a
manner to distinguish one lot from another. Each lot of culture medium
shall be tested for its growth-promoting qualities unless it meets the
exception for dehydrated culture medium described in this subpart. The
growth-promoting quality test shall be performed on the smallest sized
vessel used in an autoclave run. When using a single batch of dehydrated
culture medium, a manufacturer need not perform growth-promoting tests
on each lot of prepared liquid medium, provided that a validation
program exists for autoclaves used to sterilize the culture
[[Page 54]]
medium, and the manufacturer has received approval for this practice
from the Director, Center for Biologics Evaluation and Research.
(ii) Test organisms, strains, characteristics, identity, and
verification. Two or more strains of microorganisms that are exacting in
their nutritive and aerobic/anaerobic requirements shall be used to test
the growth-promoting qualities of each lot of test medium. When using
Fluid Thioglycollate medium, both an aerobic and an anaerobic test
microorganism shall be chosen. When using Soybean Casein Digest Medium,
the yeast, Candida albicans, shall be one of the two test microorganisms
chosen. Manufacturers shall choose the strains of microorganisms from
the chart in this paragraph.
------------------------------------------------------------------------
Incubation
Medium Test microorganisms temperature
------------------------------------------------------------------------
Spore-formers
Fluid Thioglycollate........... 1. Bacillus subtilis 30 to 35
(ATCC No. 6633). deg.C.
2. Clostridium Do.
sporogenes (ATCC No.
11437).
Non-spore-formers
3. Candida albicans Do.
(ATCC No. 10231).
4. Micrococcus luteus Do.
(ATCC No. 9341).
5. Bacteroides Do.
vulgatus (ATCC No.
8482).
Spore-formers
Soybean-Casein Digest.......... 1. Bacillus subtilis 20 to 25
(ATCC No. 6633). deg.C.
Non-spore-formers
2. Candida albicans Do.
(ATCC No. 10231).
3. Micrococcus luteus Do.
(ATCC No. 9341).
------------------------------------------------------------------------
ATCC strains of microorganisms described in this section are
available from the American Type Culture Collection, 12301 Parklawn Dr.,
Rockville, MD 20852. Periodic tests shall be performed to verify the
integrity of the test organisms in accordance with Sec. 610.18 (a) and
(b). The results of these periodic tests shall be recorded and retained
in accordance with Sec. 600.12(b) of this chapter.
(iii) Storage and maintenance of cultures of test organisms.
Cultures of the test organisms used to determine the growth-promoting
qualities of the medium shall be stored in a manner that will prevent
cross contamination or loss of identity, at a temperatre and by a method
that will retain the initial characteristics of the organisms and ensure
freedom from contamination and deterioration. If the test organisms are
stored in the freeze-dried state, or frozen, they shall be reconstituted
or thawed, whichever is applicable, and plated periodically to verify
the colony count of the suspension. If the test suspensions are stored
in a state other than freeze-dried or frozen, they shall be plated, and
a colony count shall be performed at the time of each growth-promoting
quality test to assure that not more than 100 organisms are used per
test vessel. The results of tests for verification of the colony count
shall be recorded and retained in accordance with Sec. 600.12(b) of this
chapter.
(iv) Storage and condition of media. A medium shall not be used if
the extent of evaporation affects its fluidity, nor shall it be reused
in a sterility test of the product. Fluid Thioglycollate Medium shall be
stored in the dark at room temperature if the vessels are unsealed.
Sealed vessels shall be stored at the manufacturer's specified storage
temperature.
Fluid Thioglycollate Medium shall not be used if more than the upper
one-third of the medium has acquired a pink color. The medium may be
restored once by heating on a steam bath or in free-flowing steam until
the pink color disappears. The design of the test vessel for Fluid
Thioglycollate Medium shall provide favorable aerobic and anaerobic
conditions for growth of the microorganisms throughout the test period.
Soybean-Casein Digest Medium shall be stored in the dark at 20 to 25
deg.C. Unsealed vessels of either medium may be stored for more than 10
days at the proper temperature, provided they
[[Page 55]]
are tested monthly for growth-promotion and found to be satisfactory.
Sealed vessels of either medium may be stored at the proper temperature
for a period of time not to exceed 1 year, provided they are tested for
growth-promotion every 3 months and found to be satisfactory. The
results of such testing shall be recorded and retained in accordance
with Sec. 600.12(b) of this chapter.
(v) Criteria for a satisfactory growth-promoting quality test. (a)
One hundred or fewer organisms of each strain tested shall be used. The
test is satisfactory if evidence of growth appears within 7 days in all
vessels inoculated. If a lot of medium fails to support the growth of
any test organism, or if the test results show that more than 100
organisms of a strain were used or are necessary to promote growth in
the lot of medium being tested, or if the growth is not a pure culture
of the test organism, a second test may be performed. If it fails the
second test, the lot of medium shall be rejected.
(b) Inoculated Fluid Thioglycollate Medium shall be incubated at 30
to 35 deg.C for 7 days. If the test medium is to be used in determining
the sterility of a product containing a mercurial preservative, a second
test shall be performed in accordance with paragraph (e)(2)(v)(a) of
this section, except that the test shall be incubated at 20 to 25 deg.C
for 7 days. Inoculated Soybean-Casein Digest Medium shall be incubated
at 20 to 25 deg.C for 7 days. The sterility of each lot of medium shall
be confirmed by the incubation of uninoculated control test vessels for
7 days at the temperature(s) for that particular medium. The lot of
medium is satisfactory if no growth is observed in the control test
vessels within the incubation period. The tests for growth-promoting
qualities of culture media may be performed simultaneously with
sterility testing of biological products, provided the sterility test is
considered invalid if the test medium shows no growth response.
(vi) Volume of culture medium. The volume of each culture medium
shall be determined for each bulk and final container sterility test
required for each product. The ratio of the volume of inoculum to the
volume of culture medium shall result in a dilution of the product that
is not bacteriostatic or fungistatic, except for products to be tested
by membrane filtration. The volume of inhibitors or neutralizers of
preservatives added should be considered in determining the proper ratio
of inoculum/medium. Vessels of the product-medium mixture(s) and control
vessels of the medium shall be inoculated with dilutions of cultures of
bacteria or fungi which are viable in the product being tested, and
incubated at the appropriate temperature for no less than 7 days.
(f) Membrane filtration. Bulk and final container material or
products containing oil products in water-insoluble ointments may be
tested for sterility using the membrane filtration procedure set forth
in the United States Pharmacopeia (21st Revision, 1985), section
entitled ``Test Procedures Using Membrane Filtration,'' p. 1159, which
is incorporated by reference (copies are available from the United
States Pharmacopeial Convention Inc., 12601 Twinbrook Parkway,
Rockville, MD 20852, or available for inspection at the Office of the
Federal Register, 800 North Capitol Street, NW., suite 700, Washington,
DC 20408), except that (1) the test samples shall conform with paragraph
(d) of this section; and (2) in addition, for products containing a
mercurial preservative, the product shall be tested in a second test
using Fluid Thioglycollate Medium incubated at 20 to 25 deg.C in lieu
of the test in Soybean-Casein Digest Medium.
(g) Exceptions. Bulk and final container material shall be tested
for sterility as described above in this section, except as follows:
(1) Different sterility tests prescribed. When different sterility
tests are prescribed for a product in this subchapter.
(2) Alternate incubation temperatures. Two tests may be performed as
prescribed in paragraph (a)(1)(i) of this section, one test using an
incubation temperature of 18 to 22 deg.C, the other test using an
incubation temperature of 30 to 37 deg.C, in lieu of performing one
test using an incubation temperature of 30 to 35 deg.C, provided that
growth-promoting quality tests have been performed at these
temperatures.
[[Page 56]]
(3) [Reserved]
(4) Test precluded or not required. (i) The tests prescribed in this
section need not be performed for Whole Blood, Cryoprecipitated AHF,
Platelets, Red Blood Cells, Plasma, Source Plasma, Smallpox Vaccine,
Reagent Red Blood Cells, Anti-Human Globulin, or Blood Grouping Reagent.
(ii) Where a manufacturer submits data which the Director, Center
for Biologics Evaluation and Research, finds adequate to establish that
the mode of administration, the method of preparation, or the special
nature of the product precludes or does not require a sterility test or
that the sterility of the lot is not necessary to assure the safety,
purity, and potency of the product, the Director may exempt a product
from the sterility requirements of this section subject to any
conditions necessary to assure the safety, purity, and potency of the
product.
(5) Number of final containers more than 20, less than 200. If the
number of final containers in the filling is more than 20 or less than
200, the sample shall be no less than 10 percent of the containers.
(6) Number of final containers--20 or less. If the number of final
containers in a filling is 20 or less, the sample shall be two final
containers, or the sample need be no more than one final container,
provided (i) the bulk material met the sterility test requirements and
(ii) after filling, it is demonstrated by testing a simulated sample
that all surfaces to which the product was exposed were free of
contaminating microorganisms. The simulated sample shall be prepared by
rinsing the filling equipment with sterile 1.0 percent peptone solution,
pH 7.1plus-minus0.1, which shall be discharged into a final
container by the same method used for filling the final containers with
the product.
(7) Samples--large volume of product in final containers. For
Albumin (Human) and Plasma Protein Fraction (Human), when the volume of
product in the final container is 50 milliliters or more, the final
containers selected as the test sample may contain less than the full
volume of product in the final containers of the filling from which the
sample is taken: Provided, That the containers and closures of the
sample are identical with those used for the filling to which the test
applies, and the sample represents all stages of that filling.
(8) Diagnostic biological products not intended for injection. For
diagnostic biological products not intended for injection, (i) only the
Fluid Thioglycollate Medium test incubated at 30 to 35 deg.C is
required, (ii) the volume of material for the bulk test shall be no less
than 2.0 milliliters, and (iii) the sample for the final container test
shall be no less than three final containers if the total number filled
is 100 or less, and, if greater, one additional container for each
additional 50 containers or fraction thereof, but the sample need be no
more than 10 containers.
(9) Immune globulin preparations. For immune globulin preparations,
the test samples from the bulk material and from each final container
need be no more than 2.0 ml.
(h) Records. The records related to the testing requirements of this
section shall be prepared and maintained as required by Secs. 211.167
and 211.194 of this chapter.
(Information collection requirements approved by the Office of
Management and Budget under control number 0910-0139)
[38 FR 32056, Nov. 20, 1973, as amended at 41 FR 4015, Jan. 28, 1976; 41
FR 10428, Mar. 11, 1976; 44 FR 11754, Mar. 2, 1979; 49 FR 15187, Apr.
18, 1984; 49 FR 23834, June 8, 1984; 50 FR 4133, Jan. 29, 1985; 51 FR
44906, Dec. 15, 1986; 53 FR 12764, Apr. 19, 1988; 55 FR 11013, Mar. 26,
1990]
Sec. 610.13 Purity.
Products shall be free of extraneous material except that which is
unavoidable in the manufacturing process described in the approved
license. In addition, products shall be tested as provided in paragraphs
(a) and (b) of this section.
(a)(1) Test for residual moisture. Each lot of dried product shall
be tested for residual moisture and shall meet and not exceed
established limits as specified by an approved method on file in the
product license application. The test for residual moisture may be
exempted by the Director, Center for Biologics Evaluation and Research,
when deemed not necessary for the continued
[[Page 57]]
safety, purity, and potency of the product.
(2) Records. Appropriate records for residual moisture under
paragraph (a)(1) of this section shall be prepared and maintained as
required by the applicable provisions of Secs. 211.188 and 211.194 of
this chapter.
(b) Test for pyrogenic substances. Each lot of final containers of
any product intended for use by injection shall be tested for pyrogenic
substances by intravenous injection into rabbits as provided in
paragraphs (b) (1) and (2) of this section: Provided, That
notwithstanding any other provision of Subchapter F of this chapter, the
test for pyrogenic substances is not required for the following
products: Products containing formed blood elements; Cryoprecipitate;
Plasma; Source Plasma; Normal Horse Serum; bacterial, viral, and
rickettsial vaccines and antigens; toxoids; toxins; allergenic extracts;
venoms; diagnostic substances and trivalent organic arsenicals.
(1) Test dose. The test dose for each rabbit shall be at least 3
milliliters per kilogram of body weight of the rabbit and also shall be
at least equivalent proportionately, on a body weight basis, to the
maximum single human dose recommended, but need not exceed 10
milliliters per kilogram of body weight of the rabbit, except that: (i)
Regardless of the human dose recommended, the test dose per kilogram of
body weight of each rabbit shall be at least 1 milliliter for immune
globulins derived from human blood; (ii) for Streptokinase, the test
dose shall be at least equivalent proportionately, on a body weight
basis, to the maximum single human dose recommended.
(2) Test procedure, results, and interpretation; standards to be
met. The test for pyrogenic substances shall be performed according to
the requirements specified in United States Pharmacopeia XX.
(3) Retest. If the lot fails to meet the test requirements
prescribed in paragraph (b)(2) of this section, the test may be repeated
once using five other rabbits. The temperature rises recorded for all
eight rabbits used in testing shall be included in determining whether
the requirements are met. The lot meets the requirements for absence of
pyrogens if not more than three of the eight rabbits show individual
rises in temperature of 0.6 deg. C or more, and if the sum of the eight
individual maximum temperature rises does not exceed 3.7 deg. C.
(Information collection requirements were approved by the Office of
Management and Budget (OMB) and assigned OMB control number 0910-0139)
[38 FR 32056, Nov. 20, 1973, as amended at 40 FR 29710, July 15, 1975;
41 FR 10429, Mar. 11, 1976; 41 FR 41424, Sept. 22, 1976; 44 FR 40289,
July 10, 1979; 46 FR 62845, Dec. 29, 1981; 49 FR 15187, Apr. 18, 1984;
50 FR 4134, Jan. 29, 1985; 55 FR 28381, July 11, 1990]
Sec. 610.14 Identity.
The contents of a final container of each filling of each lot shall
be tested for identity after all labeling operations shall have been
completed. The identity test shall be specific for each product in a
manner that will adequately identify it as the product designated on
final container and package labels and circulars, and distinguish it
from any other product being processed in the same laboratory. Identity
may be established either through the physical or chemical
characteristics of the product, inspection by macroscopic or microscopic
methods, specific cultural tests, or in vitro or in vivo immunological
tests.
Sec. 610.15 Constituent materials.
(a) Ingredients, preservatives, diluents, adjuvants. All ingredients
used in a licensed product, and any diluent provided as an aid in the
administration of the product, shall meet generally accepted standards
of purity and quality. Any preservative used shall be sufficiently
nontoxic so that the amount present in the recommended dose of the
product will not be toxic to the recipient, and in the combination used
it shall not denature the specific substances in the product to result
in a decrease below the minimum acceptable potency within the dating
period when stored at the recommended temperature. Products in multiple-
dose containers shall contain a preservative, except that a preservative
need not be added to Yellow Fever Vaccine; Poliovirus Vaccine Live Oral;
viral vaccines
[[Page 58]]
labeled for use with the jet injector; dried vaccines when the
accompanying diluent contains a preservative; or to an Allergenic
Product in 50 percent or more volume in volume (v/v) glycerin. An
adjuvant shall not be introduced into a product unless there is
satisfactory evidence that it does not affect adversely the safety or
potency of the product. The amount of aluminum in the recommended
individual dose of a biological product shall not exceed:
(1) 0.85 milligrams if determined by assay;
(2) 1.14 milligrams if determined by calculation on the basis of the
amount of aluminum compound added; or
(3) 1.25 milligrams determined by assay provided that data
demonstrating that the amount of aluminum used is safe and necessary to
produce the intended effect are submitted to and approved by the
Director, Center for Biologics Evaluation and Research.
(b) Extraneous protein; cell culture produced vaccines. Extraneous
protein known to be capable of producing allergenic effects in human
subjects shall not be added to a final virus medium of cell culture
produced vaccines intended for injection. If serum is used at any stage,
its calculated concentration in the final medium shall not exceed
1:1,000,000.
(c) Antibiotics. A minimum concentration of antibiotics, other than
penicillin, may be added to the production substrate of viral vaccines.
[38 FR 32056, Nov. 20, 1973, as amended at 46 FR 51903, Oct. 23, 1981;
48 FR 13025, Mar. 29, 1983; 48 FR 37023, Aug. 16, 1983; 49 FR 23834,
June 8, 1984; 50 FR 4134, Jan. 29, 1985; 51 FR 15607, Apr. 25, 1986; 55
FR 11013, Mar. 26, 1990]
Sec. 610.16 Total solids in serums.
Except as otherwise provided by regulation, no liquid serum or
antitoxin shall contain more than 20 percent total solids.
Sec. 610.17 Permissible combinations.
Licensed products may not be combined with other licensed products
either therapeutic, prophylactic or diagnostic, except as a license is
obtained for the combined product. Licensed products may not be combined
with nonlicensable therapeutic, prophylactic, or diagnostic substances
except as a license is obtained for such combination.
Sec. 610.18 Cultures.
(a) Storage and maintenance. Cultures used in the manufacture of
products shall be stored in a secure and orderly manner, at a
temperature and by a method that will retain the initial characteristics
of the organisms and insure freedom from contamination and
deterioration.
(b) Identity and verification. Each culture shall be clearly
identified as to source strain. A complete identification of the strain
shall be made for each new stock culture preparation. Primary and
subsequent seed lots shall be identified by lot number and date of
preparation. Periodic tests shall be performed as often as necessary to
verify the integrity of the strain characteristics and freedom from
extraneous organisms. Results of all periodic tests for verification of
cultures and determination of freedom from extraneous organisms shall be
recorded and retained.
(c) Cell lines used for manufacturing biological products--(1)
General requirements. Cell lines used for manufacturing biological
products shall be:
(i) Identified by history;
(ii) Described with respect to cytogenetic characteristics and
tumorigenicity;
(iii) Characterized with respect to in vitro growth characteristics
and life potential; and
(iv) Tested for the presence of detectable microbial agents.
(2) Tests. Tests that are necessary to assure the safety, purity,
and potency of a product may be required by the Director, Center for
Biologics Evaluation and Research.
(3) Applicability. This paragraph applies to diploid and nondiploid
cell lines. Primary cell cultures that are not subcultivated and primary
cell cultures that are subsequently subcultivated for only a very
limited number of population doublings are not subject to the provisions
of this paragraph (c).
(d) Records. The records appropriate for cultures under this section
shall be prepared and maintained as required by
[[Page 59]]
the applicable provisions of Secs. 211.188 and 211.194 of this chapter.
(Approved by the Office of Management and Budget under control number
0910-0139)
[38 FR 32056, Nov. 20, 1973, as amended at 51 FR 44453, Dec. 10, 1986;
55 FR 11013, Mar. 26, 1990]
Sec. 610.19 Status of specific products; Group A streptococcus.
The presence of Group A streptococcus organisms and derivatives of
Group A streptococcus in Bacterial Vaccines and Bacterial Antigens with
``No U.S. Standard of Potency'' may induce dangerous tissue reactions in
humans. Available data demonstrate that they are unsafe as ingredients
in products for human use. Group A streptococcus organisms and
derivatives of Group A streptococcus are prohibited from Bacterial
Vaccines and Bacterial Antigens with ``No U.S. Standard of Potency.''
Any Bacterial Vaccine or Bacterial Antigen with ``No U.S. Standard of
Potency'' containing Group A streptococcus organisms or derivatives of
Group A streptococcus in interstate commerce is in violation of section
351 of the Public Health Service Act (42 U.S.C. 262).
[44 FR 1549, Jan. 5, 1979]
Subpart C--Standard Preparations and Limits of Potency
Sec. 610.20 Standard preparations.
Standard preparations made available by the Center for Biologics
Evaluation and Research shall be applied in testing, as follows:
(a) Potency standards. Potency standards shall be applied in testing
for potency all forms of the following:
Antibodies
Botulism Antitoxin, Type A.
Botulism Antitoxin, Type B.
Botulism Antitoxin, Type E.
Diphtheria Antitoxin.
Histolyticus Antitoxin.
Oedematiens Antitoxin.
Perfringens Antitoxin.
Antipertussis Serum.
Antirabies Serum.
Sordellii Antitoxin.
Staphylococcus Antitoxin.
Tetanus Antitoxin.
Vibrion Septique Antitoxin.
Antigens
Cholera Vaccine, Inaba serotype.
Cholera Vaccine, Ogawa serotype.
Diphtheria Toxin for Schick Test.
Pertussis Vaccine.
Tuberculin, Old.
Tuberculin, Purified Protein Derivative.
Typhoid Vaccine.
Blood Derivative
Thrombin.
(b) Opacity standard. The U.S. Opacity Standard shall be applied in
estimating the bacterial concentration of all bacterial vaccines. The
assigned value of the standard when observed visually is 10 units. The
assigned value of the standard when observed with a photometer is (1) 10
units when the wavelength of the filter is 530 millimicrons, (2) 10.6
units when the wavelength of the filter is 650 millimicrons, and (3) 9
units when the wavelength of the filter is 420 millimicrons.
[38 FR 32056, Nov. 20, 1973, as amended at 41 FR 10429, Mar. 11, 1976;
41 FR 18295, May 3, 1976; 49 FR 23834, June 8, 1984; 55 FR 11013, Mar.
26, 1990]
Sec. 610.21 Limits of potency.
The potency of the following products shall be not less than that
set forth below and products dispensed in the dried state shall
represent liquid products having the stated limitations.
Antibodies
Diphtheria Antitoxin, 500 units per milliliter.
Tetanus Antitoxin, 400 units per milliliter.
Tetanus Immune Globulin (Human), 50 units of tetanus antitoxin per
milliliter.
Antigens
Cholera Vaccine, 8 units each of Inaba and Ogawa serotype antigens per
milliliter.
Pertussis Vaccine, 12 units per total human immunizing dose.
Typhoid Vaccine, 8 units per milliliter.
[41 FR 10429, Mar. 11, 1976, as amended at 41 FR 18295, May 3, 1976]
[[Page 60]]
Subpart D--Mycoplasma
Sec. 610.30 Test for Mycoplasma.
Except as provided otherwise in this subchapter, prior to
clarification or filtration in the case of live virus vaccines produced
from in vitro living cell cultures, and prior to inactivation in the
case of inactivated virus vaccines produced from such living cell
cultures, each virus harvest pool and control fluid pool shall be tested
for the presence of Mycoplasma, as follows:
Samples of the virus for this test shall be stored either (1)
between 2 deg. and 8 deg. C. for no longer than 24 hours, or (2) at
-20 deg. C. or lower if stored for longer than 24 hours. The test shall
be performed on samples of the viral harvest pool and on control fluid
pool obtained at the time of viral harvest, as follows: No less than 2.0
ml. of each sample shall be inoculated in evenly distributed amounts
over the surface of no less than 10 plates of at least two agar media.
No less than 1.0 ml. of sample shall be inoculated into each of four
tubes containing 10 ml. of a semisolid broth medium. The media shall be
such as have been shown to be capable of detecting known Mycoplasma and
each test shall include control cultures of at least two known strains
of Mycoplasma, one of which must be M. pneumoniae. One half of the
plates and two tubes of broth shall be incubated aerobically at 36 deg.
C. plus-minus1 deg. C. and the remaining plates and tubes shall be
incubated anaerobically at 36 deg. C. plus-minus1 deg. C. in an
environment of 5-10 percent CO2 in N2. Aerobic incubation
shall be for a period of no less than 14 days and the broth in the two
tubes shall be tested after 3 days and 14 days, at which times 0.5 ml.
of broth from each of the two tubes shall be combined and subinoculated
on to no less than 4 additional plates and incubated aerobically.
Anaerobic incubation shall be for no less than 14 days and the broth in
the two tubes shall be tested after 3 days and 14 days, at which times
0.5 ml. of broth from each of the two tubes shall be combined and
subinoculated onto no less than four additional plates and incubated
anaerobically. All inoculated plates shall be incubated for no less than
14 days, at which time observation for growth of Mycoplasma shall be
made at a magnification of no less than 300 x . If the Dienes Methylene
Blue-Azure dye or an equivalent staining procedure is used, no less than
a one square cm. plug of the agar shall be excised from the inoculated
area and examined for the presence of Mycoplasma. The presence of the
Mycoplasma shall be determined by comparison of the growth obtained from
the test samples with that of the control cultures, with respect to
typical colonial and microscopic morphology. The virus pool is
satisfactory for vaccine manufacture if none of the tests on the samples
show evidence of the presence of Mycoplasma.
Subpart E--Hepatitis Requirements
Sec. 610.40 Test for hepatitis B surface antigen.
(a) Test sensitivity. Each donation of blood, plasma, or serum to be
used in preparing a biological product shall be tested for the presence
of hepatitis B surface antigen by a method of sufficient sensitivity to
detect all sera labeled A, (A), B, (B), and C in the Reference Hepatitis
B Surface Antigen Panel distributed by the Center for Biologics
Evaluation and Research; except that, in emergency situations, a test
method of sufficient sensitivity to detect all sera labeled A, (A), and
B in the Reference Hepatitis B Surface Antigen Panel may be used and, in
dire emergency situations, blood and blood products may be issued
without any HB8Ag testing, provided that a test otherwise required
by this paragraph is performed as soon as possible after issuance of the
blood and blood product.
(b) Procedures. Only Antibody to Hepatitis B Surface Antigen
licensed under this subchapter shall be used in performing the test and
the test method(s) used shall be that for which the antibody product is
specifically designed to be effective as recommended by the manufacturer
in the package insert. The sample of blood, plasma, or serum to be
tested shall have been taken from the donor at the time of donation of
that unit. The test need not be performed on the day of the withdrawal
of the sample. If the radioimmunoassay method is used, it must be
performed in one of the following ways:
(1) The complete test is performed at the collection facility.
(2) The test is performed at the collection facility up to the point
of counting the radioactivity of the samples, which counting,
thereafter, is performed at another facility by personnel from the
collection facility or by personnel from the counting facility.
(3) The complete test is performed by the personnel at an
establishment licensed to manufacture blood or blood derivatives under
section 351(a) of the
[[Page 61]]
Public Health Service Act (42 U.S.C. 262(a)), or by a clinical
laboratory which meets the standards of the Clinical Laboratories
Improvement Act of 1967 (CLIA) (42 U.S.C. 263a), provided the
establishment or the clinical laboratory is qualified to perform
radioimmunoassay testing for the presence of hepatitis B surface
antigen.
(4) Except as provided in this paragraph (b)(4), a collection
facility shall not ship any blood product as a biological product or
ship such a blood product where it is intended for use in manufacturing
a biological product until the test for hepatitis B surface antigen is
completed and the written test results are received by the collection
facility. Notwithstanding the provisions of Sec. 610.1 of this chapter,
in the case of an emergency, or as otherwise approved in writing by the
Director, Center for Biologics Evaluation and Research, a collection
facility may ship a blood product before the test for hepatitis B
surface antigen is completed. To obtain approval for such shipments, the
collection facility shall submit a description of the control procedures
to be used by both the collection facility and the manufacturing
facility to the Director, Center for Biologics Evaluation and Research
(HFB-1), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD
20892. The control procedures to be used by the collection facility and
the manufacturing facility shall include, but may not be limited to, a
system of communicating the test results to the manufacturing facility,
use of specific labeling warnings for the product to ensure that persons
handling the shipment know that it may be infectious, procedures for
quarantine of the untested or incompletely tested product both at the
collection facility and at the manufacturing facility, and a procedure
at the manufacturing facility to identify, preclude use of, and dispose
of any blood product that is received and later found to be reactive for
hepatitis B surface antigen.
(c) Materials in storage. All blood, plasma, or serum in storage
which has not been tested for the presence of the hepatitis B surface
antigen shall be tested as required in paragraphs (a) and (b) of this
section before use as a biological product, or before use in the
manufacture of a biological product. All blood, plasma, or serum in
storage which has been tested for the presence of the hepatitis B
surface antigen by a method of second generation sensitivity may be used
as a biological product or in manufacture of a biological product,
provided it is used on or before March 15, 1976.
(d) Restrictions on use. Blood, plasma, or serum that is reactive
when tested for hepatitis B surface antigen or that was collected from a
donor known to be reactive for hepatitis B surface antigen shall not be
used in manufacturing biological products except as provided in
paragraphs (d) (1) and (2) of this section.
(1) Injectable biological products and licensed in vitro diagnostic
biological products. Blood, plasma, or serum that is reactive when
tested for hepatitis B surface antigen or that was collected from a
donor known to be reactive for hepatitis B surface antigen may be used
in manufacturing hepatitis B vaccine and licensed in vitro diagnostic
biological products if all of the following conditions are met:
(i) The final product cannot be prepared from blood, plasma, or
serum that is nonreactive when tested for hepatitis B surface antigen,
due either to the nature or to the scarcity of the final product.
(ii) The label of the source blood, plasma, or serum conspicuously
states either that it is reactive when tested for hepatitis B surface
antigen and it may transmit viral hepatitis; or that the source blood,
plasma, or serum was collected from a donor known to be reactive for
hepatitis B surface antigen and it may transmit viral hepatitis,
although confirmatory hepatitis testing has not been done.
(iii) The package label of the licensed in vitro diagnostic
biological product prepared from such blood, plasma, or serum states
conspicuously that either the product was prepared from source material
that was reactive when tested for hepatitis B surface antigen and it may
transmit viral hepatitis; or that the source material was collected from
a donor known to be reactive for hepatitis B surface antigen and it may
[[Page 62]]
transmit viral hepatitis, although confirmatory hepatitis testing has
not been done.
(iv) The package label of the licensed injectable biological product
prepared from such blood, plasma, or serum states that the product has
been inactivated.
(v) The Director, Center for Biologics Evaluation and Research (HFB-
1), Food and Drug Administration, 8800 Rockville Pike, Bethesda MD
20892, is notified in writing at the time of the shipment, or in the
case of repetitive shipments, or April 1 and October 1 of each year, of
each shipment of source blood, plasma, or serum for manufacture into
hepatitis B vaccine or into a licensed in vitro diagnostic biological
product. Such shipments shall not be subject to the requirements of
paragraph (b)(3) of this section. Each notification shall identify the
kind and amount of source material shipped, the name and address of the
consignee, the date of shipment, and the manner in which the source
material is labeled.
(2) Unlicensed in vitro diagnostic biological products. Blood,
plasma, or serum that is reactive when tested for hepatitis B surface
antigen or that was collected from a donor known to be reactive for
hepatitis B surface antigen may be used in manufacturing unlicensed in
vitro diagnostic biological products including clinical chemistry
control reagents if all of the following conditions are met:
(i) The final product cannot be prepared from blood, plasma, or
serum that is nonreactive when tested for hepatitis B surface antigen,
due either to the nature or to the scarcity of the final product.
(ii) The label of the source blood, plasma, or serum states
conspicuously that either it is reactive when tested for hepatitis B
surface antigen and it may transmit viral hepatitis; or that the source
blood, plasma, or serum was collected from a donor known to be reactive
for hepatitis B surface antigen and it may transmit viral hepatitis,
although confirmatory hepatitis testing has not been done.
(iii) The manufacturer of the source blood, plasma, or serum obtains
written assurance from the manufacturer(s) of the final unlicensed
product that package labels of all unlicensed products will
conspicuously state, as required by Sec. 809.10(a)(4) of this chapter,
that the product was prepared from blood, plasma, or serum that was
reactive when tested for hepatitis B surface antigen and it may transmit
viral hepatitis; or that the source material was collected from a donor
known to be reactive for hepatitis B surface antigen and it may transmit
viral hepatitis, although confirmatory hepatitis testing has not been
done.
(iv) At the time of shipment, the Director, Center for Biologics
Evaluation and Research (HFB-1), Food and Drug Administration, 8800
Rockville Pike, Bethesda, MD 20892, is notified in writing of each
shipment of source blood, plasma, or serum signifying the kind and the
amount of source material shipped, the name and address of the
consignee, the date of shipment, and the manner in which such source
material was labeled. Such shipments shall not be subject to the
requirements of paragraph (b)(3) of this section.
(e) Manufacturing responsibility. When the radioimmunoassay method
for hepatitis B surface antigen testing is performed by personnel other
than those of the facility collecting the blood, plasma, or serum, as
provided in paragraph (b) of this section, it shall not be considered as
divided manufacturing as described in Sec. 610.63, provided the
following conditions are met:
(1) The collecting facility has obtained a written agreement that
the testing laboratory will permit authorized representatives of the
Food and Drug Administration to inspect its testing procedures and
facilities during reasonable business hours.
(2) The testing laboratory will participate in any proficiency
testing programs undertaken by the Center for Biologics Evaluation and
Research, Food and Drug Administration.
(f) The information collection requirements in paragraph (d) of this
section were approved by the Office of Management and Budget and
assigned OMB control number 0910-0136.
(Information collection requirements contained in paragraph (b)(4) were
approved by the Office of
[[Page 63]]
Management and Budget under control number 0910-0168)
[40 FR 29710, July 15, 1975, as amended at 48 FR 23181, May 24, 1983; 49
FR 23834, June 8, 1984; 49 FR 26718, June 29, 1984; 51 FR 15607, Apr.
25, 1986; 55 FR 11013 and 11014, Mar. 26, 1990]
Sec. 610.41 History of hepatitis B surface antigen.
A person known to have previously tested positive for hepatitis B
surface antigen, testing positive, or both, may not serve as a donor of
human blood, plasma, or serum, except that under Sec. 640.120 of this
chapter, such a donor may serve as a source of hepatitis B surface
antigen for the manufacture of hepatitis B vaccine or the preparation of
a diagnostic product for laboratory tests, or a person known to have
previously tested positive for hepatitis B surface antigen may serve as
a source of antibody to hepatitis B surface antigen for the preparation
of a biological product or a diagnostic product for laboratory tests.
[48 FR 23182, May 24, 1983, as amended at 57 FR 10814, Mar. 31, 1992]
Sec. 610.45 Human Immunodeficiency Virus (HIV) requirements.
(a) Testing requirements. (1) Each donation of human blood or blood
components intended for use in preparing a product shall be tested for
antibody to HIV by a test approved for such use by FDA, except as
otherwise approved in writing by FDA. When the test for antibody to HIV
is required, blood and blood products may be issued before the results
of the test for antibody to HIV are available only in dire emergency
situations or as otherwise approved in writing by FDA and, provided the
test required by this paragraph is performed as soon as possible after
issuance of the blood or blood product.
(2) Tests approved by FDA for the screening of blood and blood
components for evidence of HIV may only be used in place of a test for
antibody to HIV to satisfy the requirements of this section and related
sections if so specified by FDA.
(b) Testing responsibility. The test for antibody to HIV shall be
performed by the collection facility, by personnel of an establishment
licensed to manufacture blood or blood derivatives under section 351(a)
of the Public Health Service Act (42 U.S.C. 262(a)), or by a clinical
laboratory which meets the standards of the Clinical Laboratory
Improvement Act of 1967 (CLIA) (42 U.S.C. 263a), provided the
establishment or clinical laboratory is qualified to perform the test.
(c) Restrictions on use. (1) Blood, plasma, or other blood
components that are repeatably reactive to a test for antibody to HIV or
that were collected from a donor whose blood is known to be repeatably
reactive to a test for antibody to HIV, shall not be shipped or used to
prepare any product, including products not subject to licensure; except
that such blood and blood components shall be shipped or used only for
purposes and under conditions specifically approved in writing by FDA.
(2) The restrictions on use contained in this paragraph shall not
apply in the following cases:
(i) Blood and blood components testing repeatably reactive or from a
donor whose blood is known to be repeatably reactive that are shown to
be negative for evidence of HIV infection by a method or process
approved for such use by FDA;
(ii) The distribution of blood, plasma, or serum samples, except
when intended for use in the manufacture of a product;
(iii) The in-house use of blood and blood components for research
purposes; or
(iv) The distribution of blood and blood components for research
purposes, if not distributed by sale, barter, or exchange.
[53 FR 116, Jan. 5, 1988]
Subpart F--Dating Period Limitations
Sec. 610.50 Date of manufacture.
The date of manufacture shall be determined as follows:
[[Page 64]]
(a) For products for which an official standard of potency is
prescribed in either Sec. 610.20 or Sec. 610.21, or which are subject to
official potency tests, the date of initiation by the manufacturer of
the last valid potency test.
(b) For products that are not subject to official potency tests, (1)
the date of removal from animals, (2) the date of extraction, (3) the
date of solution, (4) the date of cessation of growth, or (5) the date
of final sterile filtration of a bulk solution, whichever is applicable.
[38 FR 32056, Nov. 20, 1973, as amended at 42 FR 27582, May 31, 1977]
Sec. 610.53 Dating periods for licensed biological products.
(a) General. The minimum dating periods in paragraph (c) of this
section are based on data relating to usage, clinical experience, or
laboratory tests that establish the reasonable period beyond which the
product cannot be expected to yield its specific results and retain its
safety, purity, and potency, provided the product is maintained at the
recommended temperatures. The standards prescribed by the regulations in
this subchapter are designed to ensure the continued safety, purity, and
potency of the products and are based on the dating periods set forth in
paragraph (c) of this section. Package labels for each product shall
recommend storage at the stated temperatures.
(b) When the dating period begins. The dating period for a product
shall begin on the date of manufacture, as prescribed in Sec. 610.50.
The dating period for a combination of two or more products shall be no
longer than the dating period of the component with the shortest dating
period.
(c) Table of dating periods. In using the table in this paragraph, a
product in column A may be stored by the manufacturer at the prescribed
temperature and length of time in either column B or C, plus the length
of time in column D. The dating period in column D shall be applied from
the day the product leaves the manufacturer's storage, provided the
product has not exceeded its maximum storage period, as prescribed in
column B or C. If a product is held in the manufacturer's storage beyond
the period prescribed, the dating period for the product being
distributed shall be reduced by a corresponding period.
Dating period after
Manufacturer's storage Manufacturer's storage leaving manufacturer's
Product period 1 to 5 C (unless period 0 C or colder storage when stored at 2
otherwise stated) (unless otherwise to 8 C (unless otherwise
stated) stated)
A B...................... C..................... D
----------------------------------------------------------------------------------------------------------------
Adenovirus Vaccine Live Oral....... 6 months............... Not applicable........ 6 months.
Albumin (Human).................... 3 years................ ......do.............. (a) 5 years.
......do............... ......do.............. (b) 3 years, provided
labeling recommends
storage at room
temperature, no warmer
than 37 C.
Not applicable......... ......do.............. (c) 10 years, if in a
hermetically sealed metal
container and provided
labeling recommends
storage between 2 and 8
C.
Allergenic Extracts labeled ``No
U.S. Standard of Potency'':
1. With 50 percent or more 3 years................ ......do.............. 3 years.
glycerin.
2. With less than 50 percent 18 months.............. ......do.............. 18 months.
glycerin.
3. Products for which cold Not applicable......... ......do.............. 18 months (from date of
storage conditions are manufacture), provided
inappropriate. labeling recommends
storage at 30 C or
colder.
4. Powders and tablets......... ......do............... ......do.............. 5 years (from date of
manufacture), provided
labeling recommends
storage at 30 C or
colder.
5. Freeze-dried products:
a. Unreconstituted........... ......do............... ......do.............. 4 years (from date of
manufacture).
b. Reconstituted............. ......do............... ......do.............. 18 months (cannot exceed 4-
year unreconstituted
dating period plus an
additional 12 months).
Allergenic Extracts, Alum 18 months.............. ......do.............. 18 months.
Precipitated labeled ``No U.S.
Standard of Potency''.
Anthrax Vaccine Adsorbed........... 2 years................ ......do.............. 1 year.
[[Page 65]]
Antibody to Hepatitis B Surface
Antigen:
1. Antibody to Hepatitis B 6 months............... ......do.............. 6 months.
Surface Antigen.
2. Lyophilized coated red blood ......do............... ......do.............. Do.
cells.
3. Enzyme conjugated products.. ......do............... ......do.............. Do.
Iodinated (\125\l) products........ Not applicable......... ......do.............. 45 days (from date of
manufacture).
Antihemophilic Factor (Human)...... ......do............... ......do.............. 1 year (from date of
manufacture).
Anti-Human Globulin Liquid......... ......do............... ......do.............. 2 years.
Anti-Inhibitor Coagulant Complex... ......do............... ......do.............. Do.
Antirabies Serum................... 1 year................. ......do.............. Do.
Antivenin (Crotalidae) Polyvalent.. ......do............... ......do.............. 5 years with an initial 10
percent excess of
potency, provided
labeling recommends
storage at 37 C or
colder.
Antivenin (Latrodectus Mactans).... ......do............... ......do.............. 5 years with an initial 10
percent excess of
potency.
Antivenin (Micurus fulvius)........ ......do............... ......do.............. Do.
Asparaginase....................... Not applicable......... ......do.............. 18 months from the date of
the last valid potency
test.
BCG Vaccine........................ 1 year................. Not applicable........ 6 months.
Blood Grouping Reagents
1. Liquid...................... Not applicable......... Not applicable........ 2 years.
2. Dried....................... 1 year................. 2 years............... 5 years.
Blood Group Substance AB........... ......do............... ......do.............. 2 years.
Blood Group Substance A............ ......do............... ......do.............. Do.
Blood Group Substance B............ ......do............... ......do.............. Do.
Botulism Antitoxin................. ......do............... Not applicable........ 5 years with an initial 20
percent excess of
potency.
Cholera Vaccine.................... ......do............... ......do.............. 18 months.
Coccidioidin....................... ......do............... ......do.............. 3 years.
Collagenase........................ Not applicable......... ......do.............. 4 years (from date of
manufacture), provided
labeling recommends
storage at 37 C or
colder.
Cryoprecipitated AFH............... ......do............... ......do.............. 12 months from the date of
collection of source
blood, provided labeling
recommends storage at -18
C or colder.
Diphtheria Antitoxin:
1. Liquid...................... 1 year................. ......do.............. 5 years with an initial 20
percent excess of
potency.
2. Dried....................... ......do............... 2 years............... 5 years with an initial 10
percent excess of
potency.
Diphtheria and Tetanus Toxoids and ......do............... Not applicable........ 18 months.
Pertussis Vaccine Adsorbed.
Diphtheria and Tetanus Toxoids, ......do............... ......do.............. 2 years.
Adsorbed.
Diphtheria Toxin for Schick Test... ......do............... ......do.............. 1 year.
Diphtheria Toxoid.................. ......do............... ......do.............. 2 years.
Diphtheria Toxoid Adsorbed......... ......do............... 2 years............... Do.
Diphtheria Toxoid-Schick Test Not applicable......... Not applicable........ 1 year.
Control.
Factor IX Complex.................. ......do............... ......do.............. 1 year (from date of
manufacture).
Fibrinolysin (Human)............... 1 year................. 2 years............... 2 years.
Fibrinolysin and Desoxyribonuclease ......do............... ......do.............. 3 years, provided labeling
Combined (Bovine). recommends storage at 30
C or colder.
Fibrinolysin and Desoxyribonuclease ......do............... ......do.............. Do.
Combined (Bovine) with
Chloramphenicol.
Hepatitis B Surface Antigen:
1. Unlyophilized coated red Not applicable......... ......do.............. 14 days (from date of
blood cells. manufacture).
2. Iodinated (\125\ l) product. ......do............... ......do.............. 45 days (from date of
manufacture).
3. Enzyme conjugated product... 6 months............... ......do.............. 6 months.
Histoplasmin....................... 1 year................. Not applicable........ 2 years.
Immunoglobulins:
1. Hepatitis B Immune Globulin Not applicable......... ......do.............. 1 year.
(Human).
2. Immune Globulin (Human)..... 3 years................ ......do.............. 3 years.
3. Immune Globulin Intravenous Not applicable......... ......do.............. 1 year.
(Human).
4. Lymphocyte Immune Globulin, ......do............... Not applicable........ 2 years.
Anti-Thymocyte Globulin
(Equine).
5. Pertussis Immune Globulin 3 years................ ......do.............. 3 years from date the
(Human). dried or frozen bulk
product is placed in
final solution.
[[Page 66]]
6. Rabies Immune Globulin 1 year................. ......do.............. 1 year.
(Human).
7. Rho(D) Immune Globulin 6 months............... ......do.............. 6 months.
(Human).
8. Tetanus Immune Globulin 1 year................. ......do.............. 3 years with an initial 10
(Human). percent excess of
potency.
9. Vaccinia Immune Globulin 3 years................ ......do.............. 3 years.
(Human).
10. Varicella-Zoster Immune Not applicable......... ......do.............. 1 year.
Globulin (Human).
Hepatitis B Vaccine................ 2 years at 2 to 8 C.... Not applicable........ 3 years.
Influenza Virus Vaccine............ 1 year................. ......do.............. 18 months.
Limulus Amebocyte Lysate........... Not applicable......... Not applicable........ 18 months (from date of
manufacture).
Measles, Mumps, and Rubella Virus ......do............... 1 year (-20 C or 1 year.
Vaccine Live. colder).
Measles and Mumps Virus Vaccine ......do............... ......do.............. 1 year.
Live.
Measles and Rubella Virus Vaccine ......do............... ......do.............. Do.
Live.
Measles Live and Smallpox Vaccine.. Not applicable......... ......do.............. 1 year (from date of
manufacture).
Measles Virus Vaccine Live......... ......do............... ......do.............. 1 year.
Meningococcal Polysaccharide
Vaccine Group A:
1. Final bulk powder........... ......do............... 2 years (-20 C or Not applicable.
colder).
2. Final container............. Not applicable......... 3 years (-20 C or 2 years.
colder).
Meningococcal Polysaccharide
Vaccine Group C:
1. Final bulk powder........... ......do............... 2 years (-20 C or Not applicable.
colder).
2. Final container............. ......do............... 3 years (-20 C or 2 years.
colder).
Meningococcal Polysaccharide
Vaccine Groups A and C combined:
1. Final bulk powder........... ......do............... 2 years (-20 C or Not applicable.
colder).
2. Final container............. ......do............... 3 years (-20 C or 2 years.
colder).
Meningococcal Polysaccharide
Vaccine Groups A, C, Y, and W135
combined:
1. Final bulk power............ ......do............... 2 years (-20 C or Not applicable.
colder).
2. Final container............. ......do............... 3 years (-20 C or 2 years.
colder).
Mumps Skin Test Antigen............ 6 months............... Not applicable........ 18 months.
Mumps Virus Vaccine Live........... Not applicable......... 1 year (-20 C or 1 year.
colder).
Normal Horse Serum................. 1 year................. 2 years............... 5 years.
Pertussis Vaccine.................. ......do............... Not applicable........ 18 months.
Pertussis Vaccine Adsorbed......... ......do............... ......do.............. Do.
Plague Vaccine..................... ......do............... ......do.............. Do.
Plasma products:
1. Fresh Frozen Plasma......... Not applicable......... ......do.............. 1 year from date of
collection of source
blood (-18 C or colder).
2. Liquid Plasma............... ......do............... ......do.............. (a) 26 days from date of
collection of source
blood (between 1 and 6
C).
(b) 40 days from date of
collection of source
blood only when CPDA-1
solution is used as the
anticoagulant (between 1
and 6 C).
3. Plasma...................... ......do............... ......do.............. 5 years from date of
collection of source
blood (-18 C or colder).
4. Platelet Rich Plasma........ ......do............... ......do.............. 72 hours from time of
collection of source
blood, provided labeling
recommends storage (20 to
24 C or between 1 and 6
C). 5 days if certain
approved containers are
used (20 to 24 C).
5. Source Leukocytes........... ......do............... ......do.............. In lieu of expiration
date, the collection date
shall appear on the
label.
6. Source Plasma............... ......do............... ......do.............. 10 years (at the
recommended storage
temperature stated on the
label).
[[Page 67]]
7. Therapeutic Exchange Plasma. ......do............... ......do.............. 10 years.
Plasma Protein Fraction (Human).... 1 year................. ......do.............. (a) 5 years.
(b) 3 years provided
labeling recommends
storage at room
temperature, no warmer
than 30 C).
Platelets.......................... Not applicable......... ......do.............. 72 hours from time of
collection of source
blood, provided labeling
recommends storage at 20
to 24 C or between 1 and
6 C. 5 days if certain
approved containers are
used (20 to 24 C).
Pneumococcal Vaccine Polyvalent:
1. Final bulk powder........... ......do............... 24 months after Not applicable.
potency assay (-20 C
or colder).
2. Final container............. ......do............... Not applicable........ 2 years (from date of
manufacture).
Poliovirus Vaccine Inactivated..... 1 year................. ......do.............. 1 year.
Poliovirus Vaccine Live Oral
Trivalent:
1. Frozen...................... Not applicable......... 1 year (-10 C or 1 year, provided labeling
colder). recommends storage at a
temperature which will
maintain ice continuously
in a solid state.
2. Liquid...................... ......do............... Not applicable........ 30 days, provided labeling
recommends storage
between 2 and 8 C and
container has been
unopened.
Poliovirus Vaccine Live Oral Type
I:
1. Frozen...................... ......do............... 1 year (-10 C or 1 year, provided labeling
colder). recommends storage at a
temperature which will
maintain ice continuously
in a solid state.
2. Liquid...................... ......do............... Not applicable........ 30 days, provided labeling
recommends storage
between 2 and 8 C and
container has been
unopened.
Poliovirus Vaccine Live Oral Type
II:
1. Frozen...................... ......do............... 1 year (-10 C or 1 year, provided labeling
colder). recommends storage at a
temperature which will
maintain ice continuously
in a solid state.
2. Liquid...................... ......do............... Not applicable........ 30 days, provided labeling
recommends storage
between 2 and 8 C and
container has been
unopened.
Poliovirus Vaccine Live Oral Type
III:
1. Frozen...................... ......do............... 1 year (-10 C or 1 year, provided labeling
colder). recommends storage at a
temperature which will
maintain ice continuously
in a solid state.
2. Liquid...................... ......do............... Not applicable........ 30 days, provided labeling
recommends storage
between 2 and 8 C and
container has been
unopened.
Polyvalent bacterial antigens with 1 year................. ......do.............. 18 months.
``No U.S. Standard of Potency''
liquid.
Polyvalent bacterial vaccines with ......do............... ......do.............. Do.
``No U.S. Standard of Potency''
liquid.
Rabies Vaccine:
1. Dried....................... ......do............... 2 years............... Do.
2. Liquid...................... 3 months............... Not applicable........ 6 months.
Reagent red blood cells............ Not applicable......... Not applicable........ Thirty-five days from
earliest date of
collection if kept in
liquid form (indefinite
storage of reagent red
blood cell source
material at -65 C or
colder).
[[Page 68]]
ACD Red Blood Cells................ ......do............... ......do.............. (a) 21 days from date of
collection of source
blood, provided labeling
recommends storage
between 1 and 6 C and the
hermetic seal is not
broken during processing.
(b) 24 hours after plasma
removal, provided
labeling recommends
storage between 1 and 6 C
and the hermetic seal is
broken during processing.
CPD Red Blood Cells................ ......do............... ......do.............. (a) 21 days from date of
collection of source
blood, provided labeling
recommends storage
between 1 and 6 C and the
hermetic seal is not
broken during processing.
(b) 24 hours after plasma
removal, provided
labeling recommends
storage between 1 and 6 C
and the hermetic seal is
broken during processing.
CPDA-1 Red Blood Cells............. ......do............... ......do.............. (a) 35 days from date of
collection of source
blood, provided labeling
recommends storage
between 1 and 6 C and the
hermetic seal is not
broken during processing.
(b) 24 hours after plasma
removal, provided
labeling recommends
storage between 1 and 6 C
and the hermetic seal is
broken during processing.
Red Blood Cells Deglycerolized..... ......do............... ......do.............. 24 hours after removal
from storage at -65 C or
colder, provided labeling
recommends storage
between 1 and 6 C.
Red Blood Cells Frozen............. ......do............... ......do.............. 3 years from date of
collection of source
blood, provided labeling
recommends storage at -65
C or colder.
Rubella and Mumps Virus Vaccine ......do............... 1 year (-20 C or 1 year.
Live. colder).
Rubella Virus Vaccine Live......... ......do............... C..................... Do.
Skin Test Antigens for Cellular 6 months............... Not applicable........ Do.
Hypersensitivity.
Smallpox Vaccine:
1. Liquid...................... Not applicable......... 9 months (-10 C or 3 months, provided
colder, if product is labeling recommends
maintained as storage at 0 C or colder.
glycerinated or
equivalent vaccine in
bulk or final
containers).
2. Dried....................... 6 months............... Not applicable........ 18 months.
Streptokinase...................... Not applicable......... ......do.............. Do.
Tetanus and Diphtheria Toxoids 1 year................. ......do.............. 2 years.
Adsorbed for Adult Use.
Tetanus Antitoxin:
1. Liquid...................... ......do............... ......do.............. 5 years with an initial 20
percent excess or
potency.
2. Dried....................... ......do............... 2 years............... 5 years with an initial 10
percent excess or
potency.
Tetanus Toxoid..................... ......do............... Not applicable........ 2 years.
Tetanus Toxoid Adsorbed............ ......do............... ......do.............. Do.
Thrombin........................... ......do............... 2 year................ 3 years.
Thrombin Impregnated Pad........... Not applicable......... Not applicable........ 1 year, or 6 months at 20
to 24 C.
Tuberculin:
1. Purified Protein Derivative, 6 months............... ......do.............. 1 year.
diluted.
2. Old or Purified Protein 1 year (not to exceed ......do.............. 2 years, provided labeling
Derivative dried on multiple 30 C; do not recommends storage at a
puncture device. refrigerate). temperature not to exceed
30 C. Do not refrigerate.
3. Old on multiple puncture ......do............... ......do.............. Do.
device.
Typhoid Vaccine.................... 1 year................. ......do.............. 18 months.
[[Page 69]]
ACD Whole Blood.................... Not applicable......... ......do.............. 21 days from date of
collection, provided
labeling recommends
storage between 1 and 6
C.
CPD Whole Blood.................... ......do............... ......do.............. Do.
CPDA-1 Whole Blood................. ......do............... ......do.............. 35 days from date of
collection, provided
labeling recommends
storage between 1 and 6
C.
Heparin Whole Blood................ ......do............... ......do.............. 48 hours from date of
collection, provided
labeling recommends
storage between 1 and 6
C.
Yellow Fever Vaccine............... ......do............... 1 year (-20 C or 1 year, provided labeling
colder). recommends storage at 5 C
or colder.
(d) Exemptions. Exemptions or modifications shall be made only upon
written approval, in the form of a supplement of the product license,
issued by the Director, Center for Biologics Evaluation and Research
(HFB-1).
[50 FR 4134, Jan. 29, 1985, as amended at 51 FR 15607, Apr. 25, 1986; 51
FR 19750, June 2, 1986; 52 FR 37450, Oct. 7, 1987; 53 FR 12764, Apr. 19,
1988; 55 FR 11014, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994]
Subpart G--Labeling Standards
Sec. 610.60 Container label.
(a) Full label. The following items shall appear on the label
affixed to each container of a product capable of bearing a full label:
(1) The proper name of the product;
(2) The name, address, and license number of manufacturer;
(3) The lot number or other lot identification;
(4) The expiration date;
(5) The recommended individual dose, for multiple dose containers.
(6) The statement: ``Caution: Federal law prohibits dispensing
without prescription,'' for prescription biologicals.
(b) Package label information. If the container is not enclosed in a
package, all the items required for a package label shall appear on the
container label.
(c) Partial label. If the container is capable of bearing only a
partial label, the container shall show as a minimum the name (expressed
either as the proper or common name), the lot number or other lot
identification and the name of the manufacturer; in addition, for
multiple dose containers, the recommended individual dose. Containers
bearing partial labels shall be placed in a package which bears all the
items required for a package label.
(d) No container label. If the container is incapable of bearing any
label, the items required for a container label may be omitted, provided
the container is placed in a package which bears all the items required
for a package label.
(e) Visual inspection. When the label has been affixed to the
container a sufficient area of the container shall remain uncovered for
its full length or circumference to permit inspection of the contents.
[38 FR 32056, Nov. 20, 1973, as amended at 47 FR 22518, May 25, 1982]
Sec. 610.61 Package label.
The following items shall appear on the label affixed to each
package containing a product:
(a) The proper name of the product;
(b) The name, address, and license number of manufacturer;
(c) The lot number or other lot identification;
(d) The expiration date;
(e) The preservative used and its concentration, or if no
preservative is used and the absence of a preservative is a safety
factor, the words ``no preservative'';
(f) The number of containers, if more than one;
(g) The amount of product in the container expressed as (1) the
number of doses, (2) volume, (3) units of potency,
[[Page 70]]
(4) weight, (5) equivalent volume (for dried product to be
reconstituted), or (6) such combination of the foregoing as needed for
an accurate description of the contents, whichever is applicable;
(h) The recommended storage temperature;
(i) The words ``Shake Well'', ``Do not Freeze'' or the equivalent,
as well as other instructions, when indicated by the character of the
product;
(j) The recommended individual dose if the enclosed container(s) is
a multiple-dose container;
(k) The route of administration recommended, or reference to such
directions in an enclosed circular;
(l) Known sensitizing substances, or reference to an enclosed
circular containing appropriate information;
(m) The type and calculated amount of antibiotics added during
manufacture;
(n) The inactive ingredients when a safety factor, or reference to
an enclosed circular containing appropriate information;
(o) The adjuvant, if present;
(p) The source of the product when a factor in safe administration;
(q) The identity of each microorganism used in manufacture, and,
where applicable, the production medium and the method of inactivation,
or reference to an enclosed circular containing appropriate information;
(r) Minimum potency of product expressed in terms of official
standard of potency or, if potency is a factor and no U.S. standard of
potency has been prescribed, the words ``No U.S. standard of potency.''
(s) The statement: ``Caution: Federal law prohibits dispensing
without prescription,'' for prescription biologicals.
[38 FR 32056, Nov. 20, 1973, as amended at 47 FR 22518, May 25, 1982; 55
FR 10423, Mar. 21, 1990]
Sec. 610.62 Proper name; package label; legible type.
(a) Position. The proper name of the product on the package label
shall be placed above any trademark or trade name identifying the
product and symmetrically arranged with respect to other printing on the
label.
(b) Prominence. The point size and typeface of the proper name shall
be at least as prominent as the point size and typeface used in
designating the trademark and trade name. The contrast in color value
between the proper name and the background shall be at least as great as
the color value between the trademark and trade name and the background.
Typography, layout, contrast, and other printing features shall not be
used in a manner that will affect adversely the prominence of the proper
name.
(c) Legible type. All items required to be on the container label
and package label shall be in legible type. ``Legible type'' is type of
a size and character which can be read with ease when held in a good
light and with normal vision.
Sec. 610.63 Divided manufacturing responsibility to be shown.
If two or more establishments participate in the manufacture of a
product, the name, address, and license number of each must appear on
the package label, and on the label of the container if capable of
bearing a full label.
Sec. 610.64 Name of selling agent or distributor.
The name and address of the selling agent or distributor of a
product may appear on the label under the designation of ``selling
agent'' or ``distributor'' provided that the name and address of the
manufacturer is given precedence in prominence.
Sec. 610.65 Products for export.
Labels on packages or containers of products for export may be
adapted to meet specific requirements of the regulations of the country
to which the product is to be exported provided that in all such cases
the minimum label requirements prescribed in Sec. 610.60 are observed.
PART 620--ADDITIONAL STANDARDS FOR BACTERIAL PRODUCTS--Table of Contents
Subpart A--Pertussis Vaccine
Sec.
620.1 Pertussis Vaccine.
620.2 Production.
620.3 U.S. Standard preparations.
620.4 Potency test.
620.5 Mouse toxicity test.
[[Page 71]]
620.6 General requirements.
Subpart B--Typhoid Vaccine
620.10 Typhoid Vaccine.
620.11 Production.
620.12 U.S. Standard preparations.
620.13 Potency test.
620.14 General requirements.
Subpart C--Anthrax Vaccine Adsorbed
620.20 Anthrax Vaccine Adsorbed.
620.21 Production.
620.22 U.S. Reference preparation.
620.23 Potency test.
620.24 General requirements.
Subpart D--Cholera Vaccine
620.30 Cholera Vaccine.
620.31 Production.
620.32 U.S. Standard preparations.
620.33 Potency tests.
620.34 Mouse toxicity test.
620.35 General requirements.
Subpart E--Bacillus of Calmette and Guerin (BCG) Vaccine
620.40 BCG Vaccine.
620.41 Establishment and personnel requirements.
620.42 Production.
620.43 Reference BCG Vaccine.
620.44 Potency tests.
620.45 Test for freedom from virulent mycobacteria.
620.46 General requirements.
620.47 Labeling.
620.48 Samples; protocols; official release.
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360,
371); secs. 215, 351, 352, 353, 361 of the Public Health Service Act (42
U.S.C. 216, 262, 263, 263a, 264).
Source: 38 FR 32064, Nov. 20, 1973, unless otherwise noted.
Cross References: For U.S. Customs Service regulations relating to
viruses, serums, and toxins, see 19 CFR 12.21--12.23. For U.S. Postal
Service regulations relating to the admissibility to the United States
mails see parts 124 and 125 of the Domestic Mail Manual, that is
incorporated by reference in 39 CFR part 111.
Subpart A--Pertussis Vaccine
Sec. 620.1 Pertussis Vaccine.
The proper name of this product shall be ``Pertussis Vaccine'',
which shall be an aqueous preparation of killed whole Bordetella
pertussis bacteria. The vaccine may be precipitated or adsorbed and may
be combined with other antigens.
[56 FR 63410, Dec. 4, 1991]
Sec. 620.2 Production.
(a) Propagation of bacteria. Human blood shall not be used in
culture medium for propagating bacteria either for seed or for vaccine.
The culture medium for propagating bacteria for vaccine shall not
contain ingredients known to be capable of producing allergenic effects
in human subjects, except blood or blood products from lower animals
other than the horse. When blood or a blood product is used, it shall be
removed by washing the harvested bacteria. The bacterial concentrate
shall be free of extraneous bacteria, fungi, and yeasts, as demonstrated
by microscopic examination and cultural methods.
(b) Bacterial content. (1) The opacity of the bacterial concentrate
shall be determined in terms of the U.S. Opacity Standard not later than
2 weeks after the harvest of the bacteria and before any treatment
capable of altering the opacity of the bacterial concentrate.
(2) The total immunizing dose of a vaccine prepared with whole
bacteria shall contain (i) in the case of nonadsorbed vaccine no more
bacteria than the equivalent of 60 opacity units and (ii) in the case of
adsorbed vaccine no more than the equivalent of 48 opacity units.
(c) Detoxification. After removing a sample for purity testing, the
bacteria shall be killed and detoxified either (1) by heating, (2) by
addition of a chemical agent and appropriate aging, or (3) by any
combination of the stated procedures. The procedure used shall be one
that has been shown to have no adverse effect on required safety,
purity, and potency.
(d) Preservative. The vaccine shall contain a preservative.
Sec. 620.3 U.S. Standard preparations.
(a) The U.S. Standard Pertussis Vaccine shall be used for
determining the potency of Pertussis Vaccine.
(b) The U.S. Opacity Standard shall be used in estimating the
bacterial content of the vaccine and of the challenge culture.
[[Page 72]]
Sec. 620.4 Potency test.
The number of protective units of the total human immunizing dose
shall be estimated for each lot of vaccine from the results of
simultaneous intracerebral mouse protection tests of the vaccine under
test and the U.S. Standard Pertussis Vaccine. The potency test shall be
performed as follows:
(a) Mice. Healthy mice shall be used, all from a single strain and
of the same sex, or an equal number of each sex in each group, with
individual weight varying no more than 4 grams in a single test. In no
event shall any of the mice weigh less than 10 grams or more than 20
grams. A system of randomization shall be used to distribute the mice
into the groups, with respect to shelf position and to determine the
order of challenge. There shall be at least 3 groups consisting of no
less than 16 mice each, for each vaccine. In addition, there shall be at
least 4 groups consisting of no less than 10 mice each, for control
purposes: one group for the challenge dose and 3 groups for titrating
the virulence of the challenge dose.
(b) Vaccination. (1) Five-fold serial dilutions of the vaccine to be
tested and of the standard vaccine shall be made in 0.85 percent sodium
chloride solution. The dilutions of the vaccine under test shall have
the same protective unitage, based on an estimate of 12 units per total
human immunizing dose, as the unitage of the corresponding dilution of
the standard vaccine. Each mouse in each group for vaccination shall be
injected intraperitoneally with 0.5 ml. of the appropriate dilution.
(2) The interval between vaccination and challenge shall be 14 to 17
days. At least 87.5 percent of the mice in each group shall survive the
period between vaccination and challenge and each mouse challenged shall
appear healthy.
(c) The challenge. (1) The challenge culture of Bordetella pertussis
for each test shall be taken from a batch of cultures which have been
maintained by a method, such as freeze-drying, that retains constancy of
virulence.
(2) The challenge and virulence titration doses shall be prepared as
follows: The bacteria shall be harvested from a 20 to 24 hour culture
grown on Bordet-Gengou medium seeded from a rapidly growing culture less
than 48 hours old and uniformly suspended in a solution containing 1.0
percent casein peptone and about 0.6 percent sodium chloride at pH
7.1plus-minus0.1. The suspension, freed from agar particles and
clumps of bacteria, and adjusted to an opacity of 10 units, shall be
diluted in the solution used for suspending the bacteria, to provide in
a volume of 0.03 ml. (i) a challenge dose of 0.0001 opacity units
(1:3000) and (ii) virulence titration doses of \1/50\, \1/250\ and \1/
1250\ respectively of the challenge dose.
(3) Each vaccinated mouse shall be injected intracerebrally with the
challenge dose. The four groups of control mice shall be injected
intracerebrally with the challenge dose and its three dilutions,
respectively. The challenge-dose control mice shall be injected last.
The interval between the removal of the bacteria from the culture medium
and the injection of the last mouse shall not exceed 2\1/2\ hours.
(d) Recording the results. The mice shall be observed for 14 days.
Mice dying within 72 hours after challenge shall be excluded from the
test. Records shall be maintained of the number of mice that die after
72 hours and of the number of mice showing both paralysis and
enlargement of the head at the end of 14 days. All mice that show both
paralysis and enlargement of the head shall be considered as deaths for
the purposes of determining the ED50.
(e) Validity of the test. The test shall be valid provided (1) the
ED50 of the vaccine under test and the standard vaccine is between
the largest and smallest vaccinating doses; (2) the limits of one
standard deviation of each ED50 fall within the range of 64 percent
to 156 percent; (3) the protective response is graded in relation to the
vaccinating doses; (4) the dose-response curves of the vaccine under
test and the standard vaccine are parallel; (5) the challenge dose
contains approximately 200 LD50; (6) the LD50 contains no more
than 300 colony forming units; and (7) the \1/1250\ dilution of the
challenge dose contains no less than 10 and no more than 50 colony
forming units.
(f) Estimate of the potency. The ED50 of each vaccine shall be
calculated by a
[[Page 73]]
method that provides an estimate of the standard deviation. The
protective unit value per total human immunizing dose of the vaccine
under test shall be calculated in terms of the unit value of the
standard vaccine.
(g) Potency requirements. The vaccine shall have a potency of 12
units per total human immunizing dose based upon either a single test
estimate of no less than 8 units or a two-, three- or four-test
geometric mean estimate of no less than 9.6, 10.8, or 12 units,
respectively, except that for the vaccine in a multiple antigen product
containing Poliovirus Vaccine Inactivated, the estimate shall be no less
than 14 units. In no event shall the estimate be more than 36 units.
(h) Test design variation. Variations in the design of the potency
test may be permitted providing the results are demonstrated to be of
equal or greater precision.
[38 FR 32064, Nov. 20, 1973, as amended at 50 FR 4137, Jan. 29, 1985]
Sec. 620.5 Mouse toxicity test.
The final vaccine shall be demonstrated to be free from toxicity by
the following test:
A group of no less than 10 mice, each mouse weighing 14 to 16 grams,
shall have free access to food and water for no less than 2 hours before
injection. The group weight of the mice shall be determined immediately
prior to injection. Each mouse shall be injected intraperitoneally with
a test dose of one-half of the largest recommended single human dose of
the final vaccine in a volume of no less than 0.5 ml. nor more than 0.75
ml. The group weight of the mice shall be determined at the end of 72
hours and at the end of 7 days after injection. At the end of 72 hours
the average weight per mouse may be no less than the average weight per
mouse immediately preceding the injection; at the end of 7 days the
average weight gain per mouse may be no less than 3.0 grams; and at the
end of 7 days there may be vaccine-related deaths of no more than 5
percent of the total number of mice in all the toxicity tests performed.
Sec. 620.6 General requirements.
(a) Safety. Each lot of product containing Pertussis Vaccine shall
be tested for safety by the procedures prescribed in Sec. 610.11 of this
chapter except that the test shall consist of the intraperitoneal
injection of no less than one-half of the recommended largest individual
human dose into each of the mice, and either the intraperitoneal
injection of no less than three times the recommended largest individual
human dose, or the subcutaneous injection of 5.0 milliliters into each
of the guinea pigs.
(b) Dose. These additional standards are based on a single injection
of 0.5 ml., 1.0 ml., or 1.5 ml., and a total human immunizing dose of
three single injections of a nonadsorbed vaccine, and two or three
single injections of an adsorbed vaccine.
(c) Product characteristics. Recommendations shall be made through
appropriate labeling that the product after issue should not be frozen
and should be well shaken immediately prior to use.
(d) Labeling. In addition to the items required by other applicable
labeling provisions of this part, the package label shall give the
following information:
(1) For a vaccine containing a precipitant or an adsorbent, the word
``Adsorbed'' shall follow the proper name in the same style of type and
prominence as the proper name.
(2) The total immunizing dose contains 12 units of pertussis
vaccine.
(e) Multiple antigen products. The Pertussis Vaccine components of
multiple antigen products shall be manufactured pursuant to these
additional standards, except that the mouse toxicity test (Sec. 620.5)
and the potency test (Sec. 620.4) shall be performed on the multiple
antigen product.
(f) Adsorbed vaccines. Only aluminum compound reagents shall be
introduced into the product to cause precipitation or adsorption of
either Pertussis Vaccine or other antigens incorporated with Pertussis
Vaccine.
(g) Freezing prohibition. Pertussis Vaccine and multiple antigen
products of which Pertussis Vaccine is a component shall not be frozen
at any time during storage.
[[Page 74]]
(h) Samples and protocols. For each lot of vaccine, the following
material shall be submitted to the Director, Center for Biologics
Evaluation and Research, Food and Drug Administration, 8800 Rockville
Pike, Bethesda, MD 20892.
(1) A sample of no less than 20 milliliters of the final product for
pertussis vaccine testing.
(2) Protocols showing summaries of the manufacturing processes and
the results of all mouse toxicity (Sec. 620.5) and potency (Sec. 620.4)
tests performed.
[38 FR 32064, Nov. 20, 1973, as amended at 41 FR 35480, Aug. 23, 1976;
48 FR 13025, Mar. 29, 1983; 49 FR 23834, June 8, 1984; 51 FR 15610, Apr.
25, 1986; 55 FR 11013, Mar. 26, 1990]
Subpart B--Typhoid Vaccine
Sec. 620.10 Typhoid Vaccine.
The proper name of this product shall be Typhoid Vaccine which shall
be an aqueous or dried preparation of killed Salmonella typhi bacteria.
[48 FR 7167, Feb. 18, 1983]
Sec. 620.11 Production.
(a) Strain of bacteria. (1) Strain Ty 2 of Salmonella typhi shall be
used in the manufacture of Typhoid Vaccine.
(2) The antigenic integrity of the Ty 2 strain shall be verified by
an appropriate serological procedure.
(b) Propagation of bacteria. The culture medium for propagation of
S. typhi shall not contain ingredients known to be capable of producing
allergenic effects in human subjects. The harvested bacteria shall be
free of extraneous bacteria, fungi, and yeasts, as demonstrated by
microscopic examination and cultural methods.
(c) Bacterial content. (1) The number of bacteria in the concentrate
of harvested bacteria shall be estimated not later than 2 weeks after
harvest and before any treatment capable of altering the accuracy of the
estimate.
(2) The number of S. typhi bacteria in the vaccine shall not exceed
10\9\ per milliliter.
(d) Nitrogen content. The total nitrogen content of the vaccine
shall not exceed 0.035 mg./ml. for nonextracted bacteria preparations
and shall not exceed 0.023 mg./ml. for acetone-extracted bacteria
preparations.
(e) Preservative. Aqueous vaccine and the solution for
reconstitution supplied with dried vaccine shall contain a preservative.
Dried vaccine shall not contain a preservative.
[38 FR 32064, Nov. 20, 1973, as amended at 48 FR 7167, Feb. 18, 1983]
Sec. 620.12 U.S. Standard preparations.
The following U.S. Standard preparations shall be obtained from the
Center for Biologics Evaluation and Research (HFB-210), Food and Drug
Administration, 8800 Rockville Pike, Bethesda, MD 20892, for use as
prescribed in this part:
(a) Vaccine standard. The U.S. Standard Typhoid Vaccine for
determining the potency of Typhoid Vaccine.
(b) Opacity standard. The U.S. Opacity Standard for adjusting the
opacity of the suspension from which the challenge culture is prepared.
[48 FR 7167, Feb. 18, 1983, as amended at 49 FR 23834, June 8, 1984; 51
FR 15610, Apr. 25, 1986; 55 FR 11015, Mar. 26, 1990]
Sec. 620.13 Potency test.
The number of potency units per milliliter shall be estimated for
each lot of vaccine from the results of simultaneous mouse protection
tests of the vaccine under test and of the U.S. Standard Typhoid
Vaccine. At least four dilutions of each lot of vaccine shall be tested.
The test shall be performed as follows:
(a) Mice. Healthy mice shall be used, all from a single strain and
of the same sex, or an equal number of each sex in each group, with
individual weights between 13 and 16 grams. A system of randomization
shall be used to distribute the mice into the groups, with respect to
shelf position and to determine the order of challenge. A group of at
least 16 mice shall be used for each dilution of each vaccine. There
shall be at least 4 groups consisting of no less than 10 mice each for
control testing purposes, as required under paragraph (c) of this
section.
(b) Inoculation of vaccine. (1) Serial dilutions, no greater than
fivefold, of the vaccine to be tested and of the standard vaccine shall
be made in saline (0.85 percent sodium chloride solution or phosphate-
buffered saline). The mean
[[Page 75]]
effective dose (ED50) value shall be bracketed by the dilutions
used. Each mouse in each group for inoculation shall be injected
intraperitoneally with 0.5 milliliter of the appropriate dilution.
(2) The interval between inoculation of the vaccine and challenge
shall be no less than 7 days nor more than 14 days. At least 87.5
percent of the mice in each group shall survive the period between
vaccine inoculation and challenge and each mouse challenged shall appear
healthy.
(c) The challenge. (1) The challenge culture of Strain Ty 2 of S.
typhi for each test shall be taken from a batch of cultures maintained
by a method, such as freeze-drying, that retains constancy of virulence.
(2) The challenge and virulence titration doses shall be prepared as
follows: The bacteria shall be harvested from a 5- to 6-hour culture
grown at 36 deg.1 deg. C on a suitable agar medium that
shall have been seeded from a 16- to 20-hour culture grown at
36 deg.1 deg. C on a suitable agar medium, and the harvested
bacteria then shall be uniformly suspended in saline or phosphate-
buffered saline. The suspension, freed from agar particles and clumps of
bacteria and adjusted to an opacity of 10 units, shall be diluted in
saline or phosphate-buffered saline by tenfold increments. The
suspensions for the challenge and virulence titration doses shall be put
into a sterile gastric mucin preparation or other suitable virulence-
enhancing preparation. The challenge suspension shall be prepared from
whichever bacteria dilution provides about 1,000 colony forming units
for a 0.5 milliliter challenge dose. The virulence titration suspensions
shall be 101, 102, 103 dilutions, respectively, of the
challenge suspension.
(3) Each mouse inoculated with vaccine shall be injected
intraperitoneally with an 0.5 ml. dose of the challenge suspension. Each
mouse in the four groups of control mice shall be injected
intraperitoneally with an 0.5 ml. dose of the challenge suspension and
its three dilutions, respectively. The challenge dose control mice shall
be injected last. The interval between removal of the bacteria from the
culture medium and the injection of the last mouse shall not exceed 2\1/
2\ hours.
(d) Recording the results. The mice shall be observed daily for 3
days. A record shall be maintained of the number of mice that die. A
record of the number of mice that survive shall be made at the end of
the observation period.
(e) Validity of the test. The test is deemed valid if: (1) The
ED50 of the vaccine under test and the standard vaccine is between
the largest and smallest doses inoculated into the mice;
(2) The homogeneity of the dose response lines for both the vaccine
under test and the standard vaccine is acceptable;
(3) A graded protective response is obtained in relation to the
vaccine dilutions;
(4) The slopes of the dose response curves for the vaccine under
test and the standard vaccine are shown to be parallel by an appropriate
statistical method;
(5) The results of all dilutions are used to calculate the ED50
value of both the standard and test vaccine by a parallel line bioassay
method or a statistically equivalent method;
(6) The challenge dose contains approximately 1,000 colony forming
units; and
(7) The LD50 of the challenge dose contains no more than 20
colony forming units.
(f) Repeat tests. If the test does not meet the criteria prescribed
in paragraph (e) of this section, repeat tests may be performed. The
results of all tests shall be combined by geometric mean. Any test
result established as invalid under Sec. 610.1 of this chapter may be
disregarded. The determination that the vaccine meets the potency
requirements shall be made from the results of not more than four valid
tests.
(g) Estimate of the potency. The ED50 of each vaccine shall be
calculated. The protective unit value per milliliter of the vaccine
under test shall be calculated in terms of the unit value of the
standard vaccine.
(h) Potency requirements. The results of at least two separate tests
shall be included on the release protocol, required under
Sec. 620.14(c)(2), that is submitted to the Center for Biologics
[[Page 76]]
Evaluation and Research, Food and Drug Administration. The vaccine shall
have a potency of 8.0 units per milliliter. This requirement shall be
met only if the geometric mean potency for two tests is not less than
3.9 units per milliliter; or for three tests, not less than 4.4 units
per milliliter; or for four tests, not less than 4.8 units per
milliliter.
[38 FR 32064, Nov. 20, 1973, as amended at 48 FR 7167, Feb. 18, 1983; 49
FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]
Sec. 620.14 General requirements.
(a) Dose. These standards are based on a human adult dose of 0.5 ml.
for a single injection and a total immunizing dose of two injections of
0.5 ml. given at appropriate intervals.
(b) Labeling. In addition to the items required by other applicable
labeling provisions of this subchapter, the package label shall state
that the vaccine contains 8 units per milliliter.
(c) Samples; protocols; official release. For each lot of vaccine,
the following material shall be submitted to the Director, Center for
Biologics Evaluation and Research (HFB-1), 8800 Rockville Pike, Bethesda
MD 20892.
(1) A sample of no less than 40 ml. of the product distributed in no
less than four containers.
(2) A protocol that consists of a summary of the history of
manufacture of each lot including all results of each test for which
test results are requested by the Director, Center for Biologics
Evaluation and Research.
(3) The product shall not be issued by the manufacturer until
written notification of official release of each filling lot of dried
vaccine and of each bulk lot of aqueous vaccine is received from the
Director, Center for Biologics Evaluation and Research.
[38 FR 32064, Nov. 20, 1973, as amended at 42 FR 27582, May 31, 1977; 48
FR 7168, Feb. 18, 1983; 48 FR 11430, Mar. 18, 1983; 49 FR 23834, June 8,
1984; 51 FR 15610, Apr. 25, 1986; 55 FR 11013 and 11015, Mar. 26, 1990]
Subpart C--Anthrax Vaccine Adsorbed
Sec. 620.20 Anthrax Vaccine Adsorbed.
The proper name of this product shall be Anthrax Vaccine Adsorbed,
which shall consist of an aqueous preparation of a fraction of Bacillus
anthracis which contains the protective antigen adsorbed on aluminum
hydroxide.
[38 FR 32064, Nov. 20, 1973, as amended at 50 FR 4137, Jan. 29, 1985]
Sec. 620.21 Production.
(a) Strain of bacteria. A nonencapsulated, nonproteolytic, avirulent
strain of Bacillus anthracis shall be used in the manufacture of anthrax
vaccine.
(b) Medium. A chemically defined medium shall be used for the
propagation of Bacillus anthracis which has protective-antigen promoting
properties that are no less effective than the protective-antigen
promoting properties of the Puziss and Wright 1095 medium as set forth
in U.S. Patent No. 3,208,909, issued September 28, 1965, which patent is
hereby incorporated by reference and deemed published herein. U.S.
Patent No. 3,208,909 has been assigned to the Federal Government and
copies will be provided to persons affected by the provisions of this
subchapter upon request to the Director, Center for Biologics Evaluation
and Research, or to the appropriate Information Center Officer listed in
45 CFR, part 5. Copies also may be obtained upon request from the U.S.
Patent Office, Washington, DC. The medium shall not contain ingredients
known to be capable of producing allergenic effects in human subjects.
(c) Propagation of bacteria. The medium shall be inoculated with a
24-hour old vegetative culture seeded from a stock suspension of spores.
The propagation culture, flushed with nitrogen, shall be incubated at
37 deg. C.plus-minus1.0 deg. C., agitated for approximately 27
hours, cooled to about 20 deg. C., the pH adjusted to
8.0plus-minus0.1 and then filtered through a sterilizing filter(s)
using nitrogen gas under pressure.
[[Page 77]]
(d) Adsorption of the protective antigen. The sterile filtrate shall
be adsorbed on sterile aluminum hydroxide gel and the recovered
precipitate shall be resuspended and diluted in sterile 0.85 percent
sodium chloride solution.
[38 FR 32064, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Sec. 620.22 U.S. Reference preparation.
The U.S. Reference Anthrax Vaccine distributed by the Center for
Biologics Evaluation and Research shall be used for determining the
potency of anthrax vaccine.
[38 FR 32064, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Sec. 620.23 Potency test.
The potency of each lot of vaccine shall be estimated from the
results of simultaneous tests of the vaccine under test and the U.S.
Reference Anthrax Vaccine. The test shall be performed as follows:
(a) Guinea pigs. Healthy guinea pigs shall be used, all from a
single strain and of the same sex, or an equal number of each sex in
each group, with individual weights between 325 and 350 grams. The diet
of the guinea pigs shall be supplemented with vitamin C throughout the
test period. At least three groups of no less than eight guinea pigs
shall be used for each vaccine and at least one group of four guinea
pigs shall be used for the challenge control.
(b) Vaccination. Serial dilutions, not greater than three-fold, of
each vaccine shall be made in 0.85 percent sodium chloride solution. The
mid-dilution of the vaccine under test shall contain that amount of
vaccine which will afford protection to approximately 50 percent of the
guinea pigs in the group vaccinated with that dilution. Each guinea pig
in the test and reference vaccine groups shall be injected
subcutaneously with 0.5 ml. of the appropriate dilution on the left side
of the abdomen and about 2 cm. from the midline. The interval between
vaccination and challenge shall be 14 days.
(c) The challenge. Each vaccinated and control guinea pig shall be
injected intracutaneously on the right side of the abdomen with 0.1 ml.
of a spore suspension of the virulent Vollum strain of Bacillus
anthracis diluted in sterile distilled water to contain 10,000 spores
per milliliter.
(d) Recording the results. The guinea pigs shall be observed daily
for 10 days and the deaths recorded. The number of survivors shall be
recorded at the end of the observation period.
(e) Validity of the test. The test shall be valid provided (1) the
protective response to each vaccine is graded in relation to the amount
of vaccine in the respective dilutions and (2) all control animals die
within 10 days.
(f) Potency requirement. The potency of the product is satisfactory
if the vaccine is no less potent than the reference. The potency of the
product is considered to be equal to the reference when (1) the average
time of death of the product-vaccinated guinea pigs is no less than the
average time of death of the reference-vaccinated guinea pigs and the
number of survivors of the product-vaccinated guinea pigs is no less
than the number of survivors of the reference-vaccinated guinea pigs, or
(2) the use of another statistical procedure, shown to be adequate for
evaluating the potency of anthrax vaccine, demonstrates that the product
is no less potent than the reference.
Sec. 620.24 General requirements.
(a) Dose. These standards are based on a single human dose of 0.5
ml. and a total primary immunizing doses of three single doses, each
given at appropriate intervals.
(b) Product characteristics. Recommendation shall be made through
appropriate labeling that the product after issue should not be frozen.
(c) Samples; protocols; official release. For each lot of vaccine,
the following material shall be submitted to the Director, Center for
Biologics Evaluation and Research, Food and Drug Administration, 8800
Rockville Pike, Bethesda, MD 20892:
(1) A protocol which consists of a summary of the manufacture of
each lot including all results of all tests for which test results are
requested by the Director, Center for Biologics Evaluation and Research.
[[Page 78]]
(2) A sample of no less than 40 milliliters of the final product
distributed in approximately equal amounts into four final containers.
(3) The product shall not be issued by the manufacturer until
written notification of official release of the lot is received from the
Director, Center for Biologics Evaluation and Research.
[38 FR 32064, Nov. 20, 1973, as amended at 42 FR 27582, May 31, 1977; 48
FR 13025, Mar. 29, 1983; 49 FR 23834, June 8, 1984; 51 FR 15610, Apr.
25, 1986; 55 FR 11013, Mar. 26, 1990]
Subpart D--Cholera Vaccine
Sec. 620.30 Cholera Vaccine.
The proper name of this product shall be Cholera Vaccine, which
shall consist of an aqueous preparation of equal parts of Ogawa and
Inaba serotypes of killed Vibrio cholerae bacteria.
[41 FR 18295, May 3, 1976]
Sec. 620.31 Production.
(a) Strains of bacteria. (1) A strain of Ogawa and a strain of Inaba
serotypes of V. cholerae shall be used in the manufacture of the
vaccine. Each serotype strain shall have been shown in controlled field
studies to yield a vaccine no less potent than vaccines prepared from
Ogawa strain 41 and Inaba strain 35A3 obtained from the Center for
Biologics Evaluation and Research.
(2) Antigenic integrity of the strains shall be verified by (i) the
agglutination of living bacteria of each serotype by cholera O Group I
antiserum; (ii) the agglutination of the Ogawa strain in monospecific
Ogawa antiserum and of the Inaba strain in monospecific Inaba antiserum;
and (iii) the absence of spontaneous agglutination of living bacteria of
either strain in 0.85 percent sodium chloride solution during incubation
for at least 5 hours at 37 deg. C.
(b) Propagation of bacteria. The culture medium for the propagation
strains shall not contain ingredients known to be capable of producing
allergenic effects in human subjects. The harvested bacteria shall be
free of extraneous bacteria, fungi, and yeasts as demonstrated by
microscopic examination and cultural methods. Bacteria of the two
serotypes shall be grown separately.
(c) Bacterial content. (1) The number of bacteria in each separate
bacterial harvest shall be determined by use of the U.S. Opacity
Standard not later than 2 hours after harvest and before treatment with
a preservative or other agent capable of altering opacity of the
bacterial suspension.
(2) The vaccine shall contain equal numbers of bacteria of the Ogawa
and Inaba serotypes, and the total number shall not exceed 8 x
109 bacteria per milliliter.
(d) Nitrogen content. The total nitrogen content of the vaccine
shall not exceed 0.3 milligram per milliliter for bacteria grown on
solid medium or 1.0 milligram per milliliter if grown in liquid medium.
In no instance shall the vaccine contain more than 0.07 milligram per
milliliter of nitrogen precipitable by the addition of an equal volume
of 10 percent trichloracetic acid.
(e) Preservative. The vaccine shall contain a preservative.
[41 FR 18295, May 3, 1976, as amended at 49 FR 23834, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Sec. 620.32 U.S. Standard preparations.
The following U.S. Standard preparations shall be obtained from the
Center for Biologics Evaluation and Research, Food and Drug
Administration, for use as prescribed in this subpart:
(a) Vaccine standard. The U.S. Standard Cholera Vaccine, Ogawa
serotype, and U.S. Standard Cholera Vaccine, Inaba serotype, shall be
reconstituted as directed for determining the potency of Cholera
Vaccine.
(b) Opacity standard. The U.S. Opacity Standard for use in
estimating the bacterial content of the vaccine and of the challenge
culture.
(c) Seed culture. Seed cultures of V. cholerae, Inaba serotype,
strain 35A3 and Ogawa serotype, strain 41, for preparation of vaccine
challenge cultures for use in the vaccine potency test.
[41 FR 18295, May 3, 1976, as amended at 49 FR 23834, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Sec. 620.33 Potency tests.
Each lot of vaccine shall be subjected to two potency tests. One
test shall determine the potency of the vaccine in comparison with the
U.S. Standard
[[Page 79]]
Cholera Vaccine, Ogawa serotype, and the other test shall determine the
potency of the vaccine in comparison with the U.S. Standard Cholera
Vaccine, Inaba serotype. At least four dilutions of each vaccine shall
be tested. Each test shall be performed as follows:
(a) Mice. Healthy mice shall be used, all from a single strain and
of the same sex, or an equal number of each sex in each group, with
individual weights between 10 and 14 grams. A group of at least 16 mice
shall be used for each dilution of each vaccine. In addition, there
shall be at least 4 groups consisting of no less than 10 mice each for
each potency test as a control for virulence titration of the challenge
suspension.
(b) Injections of vaccine. Serial dilutions, no greater than
fivefold, of the vaccine to be tested and of the appropriate serotype
standard vaccine shall be made in 0.85 percent sodium chloride solution.
The median effective dose (ED50), which is the dose of vaccine that
is expected to protect 50 percent of the animals that received the
vaccine, shall be bracketed by the dilutions used. Each mouse in each
dilution group shall receive intraperitoneally 0.5 milliliter of the
appropriate vaccine dilution. At least 87.5 percent of the mice in each
dilution group shall survive, and all surviving mice shall appear
healthy at the time of challenge.
(c) The challenge. The challenge shall be administered 12 to 16 days
after injection of the vaccine.
(1) The strains of V. cholerae for challenge shall be Ogawa 41 and
Inaba 35A3, except that V. cholerae, Inaba serotype, strain V86 may be
used instead of Inaba serotype, strain 35A3, for preparation of vaccine
challenge culture: Provided, That the source of the challenge culture
shall be identified and verified by the manufacturer as equal to that
distributed by the World Health Organization. For each test, the
challenge culture shall be taken from a batch of cultures maintained by
a method such as freeze-drying that retains constancy of virulence.
(2) The challenge and virulence titration doses shall be prepared as
follows: The bacteria for each challenge shall be harvested from a 6- to
18-hour culture grown at 36 deg.plus-minus1 deg. C, on a suitable
agar medium adjusted to pH 7.4. The harvested bacteria shall be
uniformly suspended in a diluent consisting of M/15 phosphate buffered
saline adjusted to pH 7.4 and shall contain 0.1 to 0.2 percent gelatin.
The suspension shall be free from agar particles and clumps of bacteria.
The suspension shall be adjusted to an opacity of 10 units, and diluted
in tenfold increments using the same diluent. The suspensions for the
challenge and virulence titrations shall be suspended in a 5 to 10
percent sterile gastric mucin preparation adjusted to pH 7.4. The
challenge suspension shall be prepared from whichever bacterial dilution
provides the required median lethal dose (LD50) for a 0.5
milliliter challenge dose. The LD50 is the dose of the challenge
suspension that is expected to kill 50 percent of the animals that
received the challenge. The virulence titration suspensions shall
consist of the challenge suspension and at least three dilutions of the
challenge suspension calculated to bracket the LD50 value.
(3) At least 16 surviving mice, randomly selected from each dilution
group that received vaccine, shall be inoculated intraperitoneally with
a 0.5-milliliter dose of the challenge suspension. Mice in each of the
four groups of control mice used for the virulence titration of the
challenge suspension shall be inoculated intraperitoneally with a 0.5-
milliliter dose of the challenge suspension and its respective
dilutions. The challenge dose control mice shall be inoculated last. The
interval between removal of the bacteria from the culture medium and the
inoculation of the last mouse shall not exceed 2\1/2\ hours.
(d) Recording the results. The mice shall be observed daily for 2
days following challenge. A daily record shall be maintained of the
number of mice that die. A record of the number of mice that survive
shall be made at the end of the observation period.
(e) Validity of the test. The test is valid provided: (1) The
ED50 value of the vaccine under test and the standard vaccine is
between the largest and smallest doses inoculated into the mice;
[[Page 80]]
(2) The homogeneity of the dose response lines for both the vaccine
under test and the standard vaccine is acceptable;
(3) The log-dose response lines for the vaccine under test and the
standard vaccine are shown to be parallel by an appropriate statistical
method;
(4) The results of all dilutions shall be used to calculate the
ED50 value of both the standard and test vaccine by a parallel line
bioassay method or a method statistically equivalent;
(5) The challenge dose contains between 100 and 10,000 LD50
doses; and
(6) The LD50 value of the challenge suspension contains no more
than 10,000 colony-forming units determined by plate count.
(f) Repeat tests. Repeat tests need be performed only on the
serotype which failed to meet the potency requirements prescribed in
paragraph (h) of this section. The results of each test on each serotype
meeting the criteria in paragraph (e) of this section shall be combined
by means of a geometric mean. The determination that the vaccine meets
the potency requirements shall be made from the results of not more than
three valid tests on each serotype.
(g) Estimate of the potency. The ED50 value of each vaccine
shall be calculated. The protective unit value of each serotype per
milliliter of the vaccine under test shall be calculated in terms of the
unit value of the corresponding standard vaccine.
(h) Potency requirements. The vaccine shall have a potency of not
less than 8 units per serotype per milliliter. This requirement shall be
met only if the potency for a single test is not less than 4.4 units per
serotype per milliliter, or for two tests not less than 5.3 units, or
for three tests not less than 5.7 units.
[41 FR 18295, May 3, 1976, as amended at 41 FR 46587, Oct. 22, 1976]
Sec. 620.34 Mouse toxicity test.
The final vaccine shall be demonstrated to be free from toxicity by
the following test: A group of no less than 10 and no more than 40 mice,
each mouse weighing 14 to 16 grams, shall have free access to food and
water at least 2 hours before injection and throughout the test period.
The group weight of the mice shall be determined immediately before
injection. Each mouse shall be injected intraperitoneally with a test
dose of 0.5 milliliter of undiluted vaccine. The group weight of the
mice shall be determined again at the end of 72 hours. The 72-hour
average weight per mouse shall be no less than the average weight per
mouse immediately preceding the injection. No more than 5 percent of the
total number of mice used may die during the test period; however,
neither death nor significant toxic signs attributable to the vaccine
shall result.
[41 FR 18295, May 3, 1976]
Sec. 620.35 General requirements.
(a) Freezing prohibition. Cholera Vaccine shall not be frozen at any
time.
(b) Dose. These standards are based on a total immunizing dose of
two injections of 0.5 milliliter and 1.0 milliliter, respectively, given
at intervals specified in the manufacturer's labeling.
(c) Date of manufacture. The date of manufacture shall be the date
of initiation of the last valid potency test for the Ogawa serotype or
the Inaba serotype, whichever date is earlier.
(d) Labeling. In addition to the applicable labeling provisions of
this chapter, the package label shall bear the following: (1) A
statement that the vaccine contains 8 units of each serotype antigen per
milliliter.
(2) The statement, ``DO NOT FREEZE''.
(3) The statement, ``SHAKE WELL''.
(e) Samples; protocols; official release. For each lot of vaccine,
the following material shall be submitted to the Director, Center for
Biologics Evaluation and Research, Food and Drug Administration, 8800
Rockville Pike, Bethesda, MD 20892.
(1) A sample consisting of no less than 40 milliliters of the
product. The sample may be in the final container or from the vaccine
bulk lot.
(2) A protocol which consists of a summary of the history of
manufacture of each lot including all results of each test for which
test results are requested by the Director, Center for Biologics
Evaluation and Research,
[[Page 81]]
Food and Drug Administration. The raw data and results from each potency
test performed shall be included.
(3) The product shall not be issued by the manufacturer until
written notification of official release of the lot is received from the
Director, Center for Biologics Evaluation and Research.
[41 FR 18295, May 3, 1976, as amended at 42 FR 27582, May 31, 1977; 49
FR 23834, June 8, 1984; 51 FR 15610, Apr. 25, 1986; 55 FR 11013, Mar.
26, 1990]
Subpart E--Bacillus of Calmette and Guerin (BCG) Vaccine
Source: 44 FR 14545, Mar. 13, 1979, unless otherwise noted.
Sec. 620.40 BCG Vaccine.
(a) Proper name and definition. The proper name of this product is
BCG Vaccine. The product is defined as a freeze-dried preparation
containing viable bacteria of the Bacillus of Calmette and Guerin, which
is an attenuated strain of Mycobacterium bovis.
(b) Criteria for an acceptable strain. The source of the BCG strain
used in the manufacture of any lot of the final product must be
identified by complete historical records.
(1) Seed lot system. The BCG strain must be maintained in the form
of a primary seed lot that is to be the basic material from which all
secondary seed lots are prepared. Production of BCG Vaccine may be from
either primary or secondary seed lots. Each seed lot must be stored in
either a freeze-dried state at -20 deg. C or colder, or in a frozen
state at -70 deg. C or colder.
(2) Freedom from virulence. The BCG strain is demonstrated to be
incapable of producing progressive tuberculosis in guinea pigs tested as
prescribed in Sec. 620.45, except that no fewer than 48 guinea pigs must
be used to test the primary seed lot and no fewer than 12 guinea pigs
must be used to test each secondary seed lot. At least two-thirds of the
animals must survive the observation period of no less than 6 months.
(3) Induction of tuberculin sensitivity in guinea pigs. Each of at
least 10 guinea pigs is to be injected with 1 human dose of BCG Vaccine
and, within 4 to 6 weeks after vaccination, skin tested with tuberculin.
At least 80 percent of the guinea pigs tested must develop tuberculin
sensitivity, as prescribed in Sec. 620.44(b)(3)(ii).
(4) Clinical information. Clinical data must establish that the BCG
strain is safe and induces tuberculin sensitivity. After having passed
all laboratory tests prescribed for BCG Vaccine, each primary and
secondary seed lot of vaccine must be tested for its ability to induce
sensitivity in tuberculin-negative persons. Only those persons tested by
injection of 5 U.S. Tuberculin Units, Purified Protein Derivative, by
the Mantoux technique and found negative in this test are to be selected
for clinical trials. At least 100 tuberculin-negative persons must be
included in the test of the primary seed lot, and at least 20
tuberculin-negative persons must be included in the test of each
secondary seed lot. Within 6 to 8 weeks after BCG vaccination, the
vaccinees must be tested for tuberculin reactivity by injecting not more
than 10 U.S. Tuberculin Units, Purified Protein Derivative, by the
Mantoux technique. The test is considered satisfactory if a least 90
percent of those persons from each group develop tuberculin reactivity
as indicated by an induration reaction of at least 5 millimeters in
diameter.
Sec. 620.41 Establishment and personnel requirements.
In addition to the applicable requirements of Secs. 600.10 and
600.11 of this chapter, the following practices and procedures are
required:
(a) Isolation of BCG unit. (1) A BCG unit is defined as the space
used for storage of primary and secondary seed cultures and for vaccine
preparation, including culture maintenance, media inoculation for
propagation, harvesting, filling into final containers, sealing of final
containers, media production, and cleaning and sterilization of
glassware. For purposes of these additional standards, the space used
for incubation of bulk and final container sterility tests, tests to
determine the numbers of colony-forming units, animal tests, and
necropsies are not part of the BCG unit.
(2) The BCG unit must be completely isolated from other production
and surrounding areas and must be situated
[[Page 82]]
and designed to prevent contamination of the product. It must have a
separate facility for ventilation, designed to prevent contamination of
the product. The facilities for water supply and sewage and trash
disposal must be designed to prevent microbial contamination of the BCG
unit. The equipment used in BCG Vaccine production must remain in the
BCG unit at all times.
(3) Microbial controlled areas must be available for handling the
BCG cultures. No cultures of microorganisms other than the BCG
production strain are permitted in the BCG unit. No animals are
permitted in the BCG unit. All tests necessary for the control of the
vaccine, in which contaminating microorganisms may be cultured, or in
which animals are used, must be conducted in space physically separated
from the BCG unit.
(b) Restrictions on personnel. (1) A staff specially trained in
maintaining the seed cultures, propagating the cultures, preparing the
vaccine, and filling the vaccine into final containers shall be employed
in the production of the BCG Vaccine. Such personnel shall not work with
other infectious agents in any laboratory at any time and shall not be
exposed to a known risk of tuberculosis. Within 30 days before
employment in the BCG unit, each person working in the unit shall have
had a medical examination, including a tuberculin skin test with 5 U.S.
Tuberculin Units, Purified Protein Derivative, by the Mantoux procedure,
and a chest X-ray. No person who has had a history of tuberculosis or
mycobacterial disease is permitted in the BCG unit. There must be
periodic medical examinations of BCG unit personnel, including X-ray
examinations, of sufficient frequency to detect the appearance of early
active tuberculosis. Repeated tuberculin skin testing of staff who are
negative to tuberculin may be used as an additional diagnostic aid in
isolating any potential source of tuberculosis exposure. If a person
working in the BCG unit develops active tuberculosis, (i) the entire
staff shall be examined for possible tuberculosis infection, (ii) all
current vaccine preparations and all cultures with which the person may
have come into contact since his or her last satisfactory medical
examination, except cultures sealed before that examination, must be
discarded, and (iii) the BCG unit and all equipment with which the
person may have come in contact must be decontaminated.
(2) Personnel shall wear protective clothing and use protective
devices to the extent necessary to protect the product from
contamination.
(3) Any person not assigned to the BCG unit shall not be allowed
into the BCG unit at any time unless a medical examination shows the
person to be free from mycobacterial disease.
Sec. 620.42 Production.
(a) BCG inoculum. The inoculum of BCG used for seed lot or
production of final lot in seed buildup must have been removed from the
preceding seed lot in accordance with the following passage and time
schedule:
(1) No more than 3 passages from primary to secondary seed lot
within a 2-month period.
(2) If no secondary seed lot is used, no more than 9 passages from
primary seed lot to final lot within a 6-month period.
(3) No more than 9 passages from secondary seed lot to final lot
within a 6-month period.
(b) Propagation of bacteria. The culture medium for propagation of
BCG Vaccine must not contain ingredients known to be capable of
producing allergenic effects in humans or of causing the bacteria to
become virulent for guinea pigs. The growth in each container must be
examined visually, and only those cultures that have the typical growth
pattern characteristic of BCG are to be used in a vaccine.
(c) Colony-forming units (CFU) before and after freeze-drying. Each
lot of BCG Vaccine must be tested to determine the number of CFU per
individual final container both before and after freeze-drying, by the
method prescribed in Sec. 620.44(a). The upper and lower limits of the
viable count are to be established by the manufacturer of the vaccine
for the particular route of administration recommended and must be
specified in the license application. The loss in viability after drying
must not exceed 90 percent.
[[Page 83]]
Sec. 620.43 Reference BCG Vaccine.
A reference BCG Vaccine, for use in determining the validity of the
test for colony-forming units, is to be obtained from the Director,
Center for Biologics Evaluation and Research, Food and Drug
Administration, 8800 Rockville Pike, Bethesda, MD 20892.
[44 FR 14545, Mar. 13, 1979, as amended at 49 FR 23834, June 8, 1984; 51
FR 15610, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990]
Sec. 620.44 Potency tests.
(a) Colony-forming units (CFU). The number of CFU must be determined
on the contents of each of at least 10 individual final containers of
each lot of BCG Vaccine. Of the 10 or more individual final containers,
the contents of at least 5 before, and an equal number after, freeze-
drying must be tested. Final containers of the freeze-dried vaccine are
to be reconstituted as for human use with the diluent recommended by the
manufacturer. The number of CFU to be reported for each lot of BCG
Vaccine must be determined only from test tubes containing between 10
and 50 CFU. Dilutions must be made as follows:
(1) Dilutions are made from an appropriate volume of the liquid
vaccine before freeze-drying or the reconstituted vaccine after freeze-
drying. Appropriate dilutions are made with modified Youman's medium
specified in paragraph (a)(4) of this section, up to a point where
subsequent serial half-log dilutions will result in at least 1 tube
containing between 10 and 50 CFU.
(2) Serial half-log dilutions are made in 16 x 125 millimeter screw-
capped test tubes into which 4.5 milliliter aliquots of the diluent
prescribed in paragraph (a)(4) of this section have been dispensed. Two
milliliters of thoroughly mixed vaccine are added to the first tube of
the half-log series, mixed thoroughly, and 2.0 milliliters from this
tube are transferred to the next tube in the series. The process of
mixing and serially transferring 2.0 milliliters is repeated through
each consecutive tube and 2.0 milliliters are discarded from the last
tube.
(3) After the serial half-log dilutions are completed, 0.5
milliliter of 1.5 percent agar solution that has been cooled to 42 deg.
C is quickly added, where necessary, to make a final concentration of
0.15 percent agar, and the contents of the tubes are thoroughly mixed.
After mixing, all tubes are incubated at 35 deg. to 37 deg. C for 3 to 4
weeks.
(4) The composition of modified Youman's medium with bovine albumin
is as follows:
Asparagine................................ 5.0 grams.
Monopotassium phosphate (KH2PO4).......... Do.
Potassium sulfate (K2SO4)................. 0.5 grams.
Magnesium citrate......................... 1.5 grams.
Monosodium glutamate...................... 19.0 grams.
Glycerine................................. 20.0 milliliters.
Distillled water q.s. to.................. 900.0 milliliters.
One hundred milliliters of 5-percent aqueous solution of bovine
albumin that has been sterilized by filtration are added to the Youman's
medium to produce a final concentration of 0.5 percent of bovine
albumin. The pH is adjusted to 7.0 with 5N sodium hydroxide.
(b) Intradermal guinea pig test. Two or more guinea pigs, each
weighing no less than 250 grams, must be injected intradermally in 4
different sites with the following amounts and dilutions of each lot of
BCG Vaccine:
(1) Vaccine intended for intradermal injection is reconstituted as
for human use with the diluent recommended by the manufacturer. One-
tenth milliliter of reconstituted vaccine and 0.1 milliliter each of
three ten-fold dilutions (1:10, 1:100, and 1:1000) of the reconstituted
vaccine are injected into the guinea pigs. The diluent for the ten-fold
dilutions is isotonic solution for injection.
(2) Vaccine intended for percutaneous injection into humans is
reconstituted with the diluent recommended by the manufacturer so that
at least one human dose (estimated to be within a range of from 1 to
33 x 105 CFU) is contained in 0.1 milliliter. A narrower range of
CFU is determined for each specific vaccine by the manufacturer and
specified in the license application. One-tenth milliliter of the
selected dose of vaccine and 0.1 milliliter each of three ten-fold
dilutions (1:10, 1:100, and 1:1000) are injected into the guinea pigs.
The diluent for the ten-fold dilutions is an isotonic solution for
injection.
(3) The lot of vaccine is satisfactory if:
[[Page 84]]
(i) At the end of 2 to 4 weeks after BCG vaccination, nodules have
developed that are graded in relation to the amount of the test dose,
with the largest dose inducing a nodule of from 4 to 10 millimeters in
diameter and the smallest dose inducing essentially no nodule, and all
observations are read on the same day;
(ii) By the end of 4 to 6 weeks after BCG vaccination, each guinea
pig shows a degree of sensitivity such that an intradermal injection of
no greater than 25 U.S. Tuberculin Units, Purified Protein Derivative,
in 0.1 milliliter will induce an erythematous reaction at least 10
millimeters in diameter within 18 to 24 hours; and
(iii) At the end of the test period, each guinea pig is weighed and
each shows a weight increase.
(c) Induction of tuberculin sensitivity in tuberculin-negative
humans. At least once annually, no less than one lot of BCG Vaccine that
has satisfied all requirements and has been released by the Center for
Biologics Evaluation and Research must be tested for its ability to
induce sensitivity in 20 persons negative to Tuberculin, Purified
Protein Derivative, as prescribed in Sec. 620.40(b)(4). The results of
these tests must be sent to the Director, Center for Biologics
Evaluation and Research, as they are completed.
[44 FR 14545, Mar. 13, 1979, as amended at 49 FR 23834, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Sec. 620.45 Test for freedom from virulent mycobacteria.
(a) Each lot of BCG Vaccine must be tested to determine that it does
not contain virulent mycobacteria. The test must be performed using at
least 6 guinea pigs, each weighing between 250 and 300 grams. Vaccine
intended for intradermal injection in humans must be tested by injecting
into guinea pigs the number of bacteria contained in at least 50 human
doses. Vaccine intended for percutaneous use in humans must be tested by
injecting into guinea pigs 50 times the number of bacteria estimated to
be introduced parenterally into humans by the recommended procedure. The
vaccine for all tests must be inoculated subcutaneously or
intramuscularly into the guinea pigs. All animals that die during the
observation period must be examined postmortem. All animals that survive
the observation period must be sacrificed and examined post mortem. The
lot passes the test if at least two-thirds of the animals on test
survive an observation period of not less than 6 weeks, and if the post-
mortem examination reveals no evidence of tuberculosis in any of the
test animals.
(b) If any virulent mycobacteria are found in any lot of BCG
Vaccine, whether or not the manufacturer intends to submit samples and
protocols of this lot to the Center for Biologics Evaluation and
Research for release, the following actions must be taken:
(1) In addition to the requirements of Secs. 600.12 and 600.14 of
this chapter, the manufacturer shall immediately report by telephone,
telegraph, or cable the finding of virulent mycobacteria to the
Director, Center for Biologics Evaluation and Research.
(2) All production and distribution of lots of BCG Vaccine produced
from the same secondary seed lot as the contaminated lot of BCG Vaccine
must be discontinued. If no secondary seed lot is used the same
requirements apply to the primary seed lot.
(3) The manufacturer shall conduct a thorough and prompt
investigation concerning the failure of the lot to meet the required
safety and purity specifications, including retesting the suspect lot
and the source secondary seed lot (or primary seed lot, if no secondary
seed lot is used) and shall undertake a thorough review of all
manufacturing records and procedures to determine the probable cause of
the failure.
(4) A written record of the investigation, including the retest
results, must be submitted to the Director, Center for Biologics
Evaluation and Research.
(5) Neither production nor distribution of BCG Vaccine may be
resumed until the manufacturer is notified in writing by the Director,
Center for Biologics Evaluation and Research, that such activity may be
resumed.
[44 FR 14545, Mar. 13, 1979, as amended at 49 FR 23834, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
[[Page 85]]
Sec. 620.46 General requirements.
(a) Dose. These standards are based on (1) vaccine intended for
intradermal injection in a single human immunizing dose of 0.1
milliliter and (2) vaccine intended for percutaneous injection in a
single skin application through which inoculation is made by a multiple
puncture device.
(b) Date of manufacture. The date of manufacture is the date of
initiation of the last valid determination for CFU after freeze-drying.
Sec. 620.47 Labeling.
In addition to conforming to the applicable requirements of
Secs. 610.60, 610.61, and 610.62 of this chapter, the package label must
bear the following information:
(a) Specification of the route of administration.
(b) A statement that the vaccine contains live bacteria and should
be protected against exposure to light.
(c) A statement that the vaccine must be administered within 8 hours
after reconstitution, and that reconstituted vaccine not used within 8
hours must be discarded.
Sec. 620.48 Samples; protocols; official release.
(a) For each lot of vaccine, the following materials must be
submitted to the Director, Center for Biologics Evaluation and Research,
Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892.
(1) Samples and diluent that will provide at least 20 milliliters
when the samples are reconstituted as recommended in the package insert
by the manufacturer of the vaccine.
(2) A protocol that consists of a complete summary of the
manufacture of each lot, including all results of each test required by
all applicable regulations. If the protocol is not included in the
shipment of the samples, it must be sent promptly to the Director,
Center for Biologics Evaluation and Research, Food and Drug
Administration, 8800 Rockville Pike, Bethesda, MD 20892.
(b) The BCG Vaccine must not be issued by the manufacturer until
written notification of official release is received from the Director,
Center for Biologics Evaluation and Research, Food and Drug
Administration.
[44 FR 14545, Mar. 13, 1979, as amended at 49 FR 23834, June 8, 1984; 51
FR 15610, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990]
PART 630--ADDITIONAL STANDARDS FOR VIRAL VACCINES--Table of Contents
Subpart A--Poliovirus Vaccine Inactivated
Sec.
630.1 Poliovirus Vaccine Inactivated.
630.2 Poliovirus Vaccine Inactivated.
630.3 Potency test.
630.4 Tests for safety.
630.5 General requirements.
Subpart B--Poliovirus Vaccine Live Oral Trivalent
630.10 Poliovirus Vaccine Live Oral Trivalent.
630.11 Clinical trails to qualify for license.
630.12 Animal source and quarantine; personnel.
630.13 Manufacture of Poliovirus Vaccine Live Oral Trivalent.
630.14 Reference virus preparations.
630.15 Potency test.
630.16 Test for neurovirulence.
630.17 Alternative test for neurovirulence.
630.18 Additional tests for safety.
630.19 General requirements.
Subpart C--[Reserved]
Subpart D--Measles Virus Vaccine Live
630.30 Measles Virus Vaccine Live.
630.31 Clinical trials to qualify for license.
630.32 Manufacture of live, attenuated Measles Virus Vaccine.
630.33 Reference virus.
630.34 Potency test.
630.35 Test for safety.
630.36 General requirements.
Subpart E--[Reserved]
Subpart F--Mumps Virus Vaccine Live
630.50 Mumps Virus Vaccine Live.
630.51 Clinical trials to qualify for license.
630.52 Manufacture of Mumps Virus Vaccine Live.
630.53 Reference virus.
630.54 Potency test.
630.55 Test for safety.
630.56 General requirements.
Subpart G--Rubella Virus Vaccine Live
630.60 Rubella Virus Vaccine Live.
630.61 Clinical trials to qualify for license.
630.62 Production.
[[Page 86]]
630.63 Reference virus.
630.64 Potency test.
630.65 Test for safety.
630.66 General requirements.
Subpart H--Smallpox Vaccine
630.70 Smallpox Vaccine.
630.71 Production.
630.72 Reference vaccine.
630.73 Potency test.
630.74 Tests for safety.
630.75 General requirements.
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360,
371); secs. 215, 351, 352, 353, 361 of the Public Health Service Act (42
U.S.C. 216, 262, 263, 263a, 264).
Source: 38 FR 32068, Nov. 20, 1973, unless otherwise noted.
Cross References: For U.S. Customs Service regulations relating to
viruses, serums, and toxins, see 19 CFR 12.21--12.23. For U.S. Postal
Service regulations relating to the admissibility to the United States
mails see parts 124 and 125 of the Domestic Mail Manual, that is
incorporated by reference in 39 CFR part 111.
Subpart A--Poliovirus Vaccine Inactivated
Sec. 630.1 Poliovirus Vaccine Inactivated.
(a) Proper name and definition. The proper name of this product
shall be ``Poliovirus Vaccine Inactivated'' which shall consist of an
aqueous preparation of poliovirus types 1, 2, and 3, grown in monkey
kidney tissue cultures, inactivated by a suitable method.
(b) Strains of virus. Strains of poliovirus used in the manufacture
of vaccine shall be identified by historical records, infectivity tests
and immunological methods. Any strain of virus may be used that produces
a vaccine meeting the requirements of Secs. 630.2, 630.3, and 630.4, but
the Director, Center for Biologics Evaluation and Research may from time
to time prohibit the use of any specific strain whenever he finds that
it is practicable to use another strain of the same type that is
potentially less pathogenic to man and that will produce a vaccine of at
least equivalent safety and potency.
(c) Monkeys; species permissible as source of kidney tissue. Only
Macaca or Cercopithecus monkeys, or a species found by the Director,
Center for Biologics Evaluation and Research, to be equally suitable,
which have met all requirements of Secs. 600.11(f)(2) and 600.11(f)(8)
of this chapter shall be used as a source of kidney tissue for the
manufacture of Poliovirus Vaccine Inactivated.
[38 FR 32068, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50
FR 4137, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990]
Sec. 630.2 Poliovirus Vaccine Inactivated.
(a) Cultivation of virus. Virus for manufacturing vaccine shall be
grown with aseptic techniques in monkey kidney cell cultures. Suitable
antibiotics in the minimum concentration required may be used
(Sec. 610.15(c) of this chapter).
(b) Filtration. Within 72 hours preceding the beginning of
inactivation, the virus suspensions shall be filtered or clarified by a
method having an efficiency equivalent to that of filtration through an
S1 Seitz type filter pad.
(c) Virus titer. The 50 percent endpoint (TCID50) of the virus
fluids after filtration shall be 106.5 or greater as confirmed by
comparison in a simultaneous test (using groups of 10 tubes at 1 log
steps or groups of 5 tubes at 0.5 log steps) with a reference virus
distributed by the Center for Biologics Evaluation and Research.
Acceptable titrations of the reference virus shall not vary more than
plus-minus0.5 log10 from its labeled titer using 0.5
milliliter inoculum in tissue culture.
(d) Inactivation of virus. The virus shall be inactivated, as
evidenced by the tests described in Sec. 630.4, through the use of an
agent or method which has been demonstrated to be consistently effective
in the hands of the manufacturer in inactivating a series of lots of
poliovirus. If formaldehyde is used for inactivation, it shall be added
to the virus suspension to a final concentration of U.S.P. solution of
formaldehyde of 1:4000, and the inactivation conducted under controlled
conditions of pH and time, at a temperature of 36 deg. to 38 deg. C.
Three or more virus titers, suitably spaced to indicate rate of
inactivation, shall be determined during the inactivation process.
Filtration equivalent to that described in paragraph (b) of this section
shall be performed after the estimated baseline time (time at which the
50 percent end-
[[Page 87]]
point reaches one tissue culture infective dose per milliliter), but
prior to sampling for the first single strain tissue culture test
required in Sec. 630.4(b), except that this filtration may be omitted
for strains of a virulence for monkeys equal to or less than that of the
MEF-1 Type 2 strain of poliovirus.
(e) Additional processing. Single strain or trivalent pools that
have failed to pass safety tests prescribed in Sec. 630.4 (b), (c), or
(e) may be treated as follows:
(1) Filtration or clarification by a method having an efficiency
equivalent to that of filtration through an S1 Seitz type filter pad.
(2) Negative tests performed as described in Sec. 630.4 (b) and (c)
must be obtained on each of two successive samples taken so as to be
separated by an interval of at least 3 days while the material is being
subjected to treatment with 1:4000 U.S.P. formaldehyde solution and heat
at 36 deg. to 38 deg. C. The first sample may be taken before incubation
is begun and the second sample shall be taken after the incubation of at
least 3 days is completed. For both single strain and trivalent pools
the volume tested for each tissue culture safety test shall be
equivalent to at least 1,500 human doses.
(3) Pools which are positive following such additional processing
shall not be used for the manufacture of Poliovirus Vaccine Inactivated
(f) Supplemental inactivation. Supplemental inactivation employing a
method capable of reducing the titer of a similarly produced virus
suspension by a factor of 10-6 may be applied at any point after
the filtration step described in paragraph (d) or (e)(1) of this
section.
[38 FR 32068, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50
FR 4137, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990]
Sec. 630.3 Potency test.
Each lot of vaccine shall be subjected to a potency test which
permits an estimation of the antigenic capacity of the vaccine. This is
done by means of a simultaneous comparison of the serum antibody levels
produced in monkeys by the vaccine under test with the antibody level of
the reference serum distributed by the Center for Biologics Evaluation
and Research. The potency test shall be performed on samples taken after
all final processing of the product has been completed, including
addition of preservative, except that when the final product contains
material having an adjuvant effect an additional test shall be performed
with a sample taken before the addition of the adjuvant material. The
volume of the test sample for the additional test shall be adjusted to
the equivalent volume of Poliovirus Vaccine Inactivated in the final
product. The test shall be conducted as follows:
(a) Inoculation of monkeys. A group of 12 or more Macaca monkeys, or
a species found by the Director, Center for Biologics Evaluation and
Research, to be equally suitable for the purpose, shall be used. Animals
shall weigh between 4 and 8 pounds and shall be in overt good health.
Animals that become ill and remain ill during the course of immunization
shall be excluded from the group. The test shall not be valid unless at
least 10 animals survive the test period and their preinoculation serum
antibody levels are as prescribed in paragraph (d) of this section. The
test vaccine shall be given intramuscularly to each monkey in 3 doses at
7-day intervals, each dose to be the recommended individual human dose.
Only undiluted vaccine shall be used.
(b) Serum samples. A blood sample shall be taken from each monkey
prior to vaccination and then again 7 days after the last injection.
Serum shall be separated aseptically, and stored under refrigeration.
(c) Serum-virus neutralization test. The titers of individual monkey
serums shall be determined in comparison with the reference serum in
tests designed to include controls for all the variables of significance
including the following:
(1) Serum toxicity control;
(2) Cell control and cell titration;
(3) Virus titration control (at least 4 tubes for each dilution at
0.5 log steps); and
(4) Serum controls using type-specific serums to identify the type
of virus used in the neutralization test.
(d) Interpretation of the test. Animals showing preinoculation
titers of 1:4 or over when tested against not more
[[Page 88]]
than 1,000 TCID50 of virus, shall be excluded from the test. The
geometric mean titer of antibody induced in the monkeys surviving the
course of immunization and bleeding, shall be calculated. A comparison
of the value so obtained shall be made with the value for the reference
serum that was tested simultaneously and expressed as the ratio between
the geometric mean titer value of the serums under test and the mean
titer value of the reference serum.
(e) Potency requirements. A lot of vaccine tested against the
reference serum shall be satisfactory if the geometric mean value of the
group of individual monkey serums representing the lot of vaccine tested
is at least 1.29 times the mean value of the reference serum for Type 1,
at least 1.13 times for Type 2, and at least 0.72 times for Type 3.
[38 FR 32068, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50
FR 4137, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990]
Sec. 630.4 Tests for safety.
In the manufacture of the product, the following tests relating to
safety shall be conducted by the manufacturer.
(a) The virus pool--tests prior to inactivation--(1) B virus and
Mycobacterium tuberculosis. Prior to inactivation, each individual virus
harvest or virus pool shall be tested for the presence of B virus and
Mycobacterium tuberculosis.
(2) SV-40. Prior to inactivation, the material shall be tested for
the presence of SV-40 as follows (or by any other test producing equally
reliable results): A sample of at least 5 ml. from the virus harvest or
virus pool shall be neutralized by high titer specific antiserum of
other than primate origin. A similar sample from the pool of tissue
culture fluids from control vessels representing the tissue from which
the virus was prepared may be tested in place of the virus sample. The
sample shall be tested in primary cercopithecus tissue cultures or in a
cell line demonstrated as at least equally susceptible to SV-40. Each
tissue culture system shall be observed for at least 14 days and at the
end of the observation period at least one subculture of fluid shall be
made in the same tissue culture system and the subculture shall be
observed for at least 14 days.
(3) Test results. The virus harvest or virus pool is satisfactory
for poliovirus vaccine only if the tests produce no evidence of the
presence of B virus, Mycobacterium tuberculosis or SV-40.
(b) Single strain pool tissue culture tests for poliovirus. (1)
Before pooling to make the final poliovirus vaccine, during inactivation
at 36 deg. to 38 deg. C., two samples of each monovalent bulk strain
pool shall be tested for the presence of virus by tissue culture
methods, the second sample to be taken at least 3 days after taking the
first sample.
(2) Each sample shall be no smaller than the equivalent of 1,500
human doses and shall be subjected to the complete testing process and
each test shall be performed on a different monkey kidney tissue culture
cell preparation. The test sample for one of these tests may be used
also for the test prescribed in paragraph (f) of this section provided
the cell cultures used have been demonstrated as fully susceptible to
SV-40 and poliovirus. Each sample shall be inoculated into five or more
tissue culture bottles of a suitable capacity, the ratio of the vaccine
to the nutrient fluid being approximately 1:1 to 1:3, and the area of
the surface growth of cells being at least 3 square centimeters per
milliliter of sample. The tissue culture bottles shall be observed for
at least 14 days.
(3) A first subculture shall be made at the end of 7 days from date
of inoculation by planting at least 2 percent of the volume from each
original bottle into suitable tissue culture vessels, followed by
refeeding.
(4) A second subculture shall be made from each original bottle in
the same manner at the end of 14 days from date of inoculation.
(5) Each of the first and second subcultures shall be observed for
at least 7 days.
(6) If cytopathogenic effects occur either in the original bottles
of the two tests or in the subcultures from them, or if cellular
degeneration appears in the original bottles or in the subcultures
before degeneration occurs in uninoculated cultures, the pool shall be
[[Page 89]]
held until the matter is resolved. If active poliovirus is indicated,
the strain pool shall not be used for inclusion in a final vaccine
unless effectively reprocessed as described in Sec. 630.2(e). If other
viruses are present, the pool shall not be used unless it can be
demonstrated that such viruses have originated from other than the
strain pool being tested.
(c) Trivalent vaccine pool tissue culture test. No less than 1,500
human doses of the trivalent vaccine pool, without final preservative,
prepared by pooling the three type pools, each of which has passed all
tests prescribed in paragraph (b) of this section, shall be subjected to
the complete tissue culture test prescribed in such paragraph (b) in at
least two approximately equal tests in separate monkey kidney tissue
culture preparations. This test sample may be used also for the test
prescribed in paragraph (f) of this section provided the cell cultures
used have been demonstrated as fully susceptible to SV-40 and
poliovirus.
(d) Trivalent vaccine pool lymphocytic choriomeningitis test. The
final vaccine shall be shown to be free of lymphocytic choriomeningitis
virus by intracerebral inoculation of the maximum volume tolerated into
10 or more mice which shall be observed daily for at least 21 days and a
negative test shall not be valid unless at least eight mice survive for
this period.
(e) Test in monkeys for active virus. (1) Vaccine from final
containers selected at random from each filling of each lot shall be
pooled to provide a test sample of at least 400 milliliters representing
the various fillings. An equal volume of bulk vaccine may be substituted
for test samples from each filling lot provided the procedure has been
approved by the Director, Center for Biologics Evaluation and Research.
(2) A total of not less than 20 monkeys shall be inoculated with the
test sample. A preinjection serum sample from each monkey must not
contain neutralizing antibody against the three poliovirus types
detectable in a dilution of 1:4 when tested against not more than 1,000
TCID50 of virus. At least 80 percent of the test animals
representing each filling or each bulk sample must survive the test
period without significant weight loss, except that if at least 60
percent of the test animals survive the first 48 hours after injection,
those animals which do not survive this 48-hour test period may be
replaced by an equal number of test animals. At least 80 percent of the
animals used in the test must show microscopic evidence of inoculation
trauma in the lumbar region of the spinal cord, and gross or microscopic
evidence of inoculation trauma in the thalamic area. If less than 60
percent of the test animals survive the first 48 hours, or if less than
80 percent of the animals fail to meet the other criteria prescribed in
this section, the test must be repeated.
(3) Vaccines shall be injected by combined intracerebral,
intraspinal, and intramuscular routes into Macaca or Cercopithecus
monkeys or a species found by the Director, Center for Biologics
Evaluation and Research, to be equally suitable for the purpose. The
animals shall be in overt good health and injected under deep
barbiturate anesthesia. The intracerebral injection shall consist of 0.5
milliliter of test sample into the thalamic region of each hemisphere.
The intraspinal injection shall consist of 0.5 milliliter of
concentrated test sample into the lumbar spinal cord enlargement, the
test sample to be concentrated 100 fold in the ultracentrifuge by a
method demonstrated to recover at least 90 percent of the virus
particles in the sediment after it has been resuspended in the same lot
of unconcentrated test sample. The intramuscular injection shall consist
of 1.0 milliliter of test sample into the right leg muscles. At the same
time, 200 milligrams of cortisone acetate shall be injected into the
left leg muscles, and 1.0 milliliter of procaine penicillin (300,000
units) into the right arm muscles. The monkeys shall be observed for 17
to 19 days and signs suggestive of poliomyelitis shall be recorded.
(4) At the end of the observation period, samples of cerebral cortex
and of cervical and lumbar spinal cord enlargements shall be taken for
virus recovery and identification. Histological sections shall be
prepared from both spinal cord enlargements and examined.
[[Page 90]]
(5) Doubtful histopathological findings necessitate (i) examination
of a sample of sections from several regions of the brain in question,
and (ii) attempts at virus recovery from the nervous tissues previously
removed from the animal. The test results must be negative. Test results
are negative if the histological and other studies leave no doubt that
poliovirus infection did not occur.
(f) Tissue culture safety test for SV-40. At least 500 human doses
of each monovalent or trivalent pool of vaccine shall be tested for the
presence of SV-40 using primary cercopithecus monkey tissue cultures or
using a cell line demonstrated as at least equally susceptible to SV-40.
The test shall be conducted as described in paragraph (b) of this
section, except for the volume of test sample and except that one
subculture of at least 2 percent of the volume of the fluids shall be
made no less than 14 days from the date of inoculation and examined for
at least 14 days from the date of subinoculation. The vaccine is
satisfactory only if there is no evidence of the presence of SV-40 in
any of the cultures or subcultures.
[38 FR 32068, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50
FR 4137, Jan. 29, 1985; 50 FR 16229, Apr. 25, 1985; 55 FR 11013, Mar.
26, 1990; 57 FR 10814, Mar. 31, 1992]
Sec. 630.5 General requirements.
(a) Consistency of manufacture. No lot of final vaccine shall be
released unless it is one of a series of five consecutive lots produced
by the same manufacturing process, all of which have shown negative
results with respect to all tests for the presence of live poliovirus,
and unless each of the monovalent pools of which a polyvalent final
vaccine is composed similarly is one of a series of five consecutive
monovalent pools of the same type of inactivated poliovirus, all of
which have shown negative results in all tests for the presence of live
poliovirus.
(b) Dose. These additional standards are based on a human dose of
1.0 milliliter for a single injection and a total human immunizing dose
of three injections of 1.0 milliliter given at appropriate intervals.
(c) Samples and protocols. For each lot of vaccine, the following
material shall be submitted to the Director, Center for Biologics
Evaluation and Research, Food and Drug Administration, 8800 Rockville
Pike, Bethesda, MD 20892:
(1) A 2,500 milliliter sample, neutralized, not dialyzed, and
without final preservative, taken at the latest possible stage of
manufacturing before the addition of such preservative.
(2) A 200 milliliter bulk sample of the final vaccine containing
final preservative.
(3) A total of not less than a 200 milliliter sample of the final
vaccine in final labeled containers.
(4) A protocol which consists of a summary of the history of
manufacture of each lot including all results of each test for which
test results are requested by the Director, Center for Biologics
Evaluation and Research.
[38 FR 32068, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 51
FR 18580, May 21, 1986; 55 FR 11013, Mar. 26, 1990]
Subpart B--Poliovirus Vaccine Live Oral Trivalent
Source: 56 FR 21432, May 8, 1991, unless otherwise noted.
Sec. 630.10 Poliovirus Vaccine Live Oral Trivalent.
(a) Proper name and definition. The proper name of this product
shall be Poliovirus Vaccine Live Oral Trivalent. The vaccine shall be a
preparation containing the three types of live, attenuated polioviruses
grown in monkey kidney cell cultures, or in a cell line found by the
Director, Center for Biologics Evaluation and Research, to meet the
requirements of Sec. 610.18(c) of this chapter. The vaccine shall be
prepared in a form suitable for oral administration.
(b) Criteria for acceptable strains. (1) The Sabin strains of
attenuated poliovirus, Type 1 (LS-c, 2ab/KP