0338 21cfr610 11 2007

§ 610.2

21 CFR Ch. I (4–1–05 Edition)

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.

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

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

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

§ 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 § 600.3(s) of this
chapter.
§ 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

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

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Food and Drug Administration, HHS

§ 610.11

the additional standards for specific
products, or variation is approved as a
supplement to the product license
under § 610.9.
(a) Product to be tested. The general
safety test shall be conducted upon a
representative sample of the product in
the final container from every final
filling of each lot of the product. If any
product is processed further after filling, such as by freeze-drying, sterilization, or heat treatment, the test shall
be conducted upon a sample from each
filling of each drying chamber run,
sterilization chamber, or heat treatment bath.
(b) Test animals. Only overtly healthy
guinea pigs weighing less than 400
grams each and mice weighing less
than 22 grams each shall be used. The
animals shall not have been used previously for any test purpose.
(c) Procedure. The duration of the
general safety test shall be 7 days for
both species, except that a longer period may be established for specific
products in accordance with § 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 § 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 in accordance with § 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 in accordance with § 610.9.
Dissolve or grind and suspend the product in the approved diluent. Administer the test product as approved on at
least two mice and at least two guinea
pigs.
(d) Test requirements. A safety test is
satisfactory if all animals meet all of
the following requirements:
(1) They survive the test period.
(2) They do not exhibit any response
which is not specific for or expected
from the product and which may indicate a difference in its quality.
(3) They weigh no less at the end of
the test period than at the time of injection.
(e) Repeat tests—(1) First repeat test. If
a filling fails to meet the requirements
of paragraph (d) of this section in the
initial test, a repeat test may be conducted on the species which failed the
initial test, as prescribed in paragraph
(c) of this section. The filling is satisfactory only if each retest animal
meets the requirements prescribed in
paragraph (d) of this section.
(2) Second repeat test. If a filling fails
to meet the requirements of the first
repeat test, a second repeat test may
be conducted on the species which
failed the test: Provided, That 50 percent of the total number of animals in
that species has survived the initial
and first repeat tests. The second repeat test shall be conducted as prescribed in paragraph (c) of this section,
except that the number of animals
shall be twice that used in the first repeat test. The filling is satisfactory
only if each second repeat test animal
meets the requirements prescribed in
paragraph (d) of this section.
(f) [Reserved]
(g) Exceptions—(1) The test prescribed
in this section need not be performed
for Whole Blood, Red Blood Cells,
Cryoprecipitated AHF, Platelets, Plasma, or Cellular Therapy Products.
(2) For products other than those
identified in paragraph (g)(1) of this
section, a manufacturer may request
from the Director, Center for Biologics

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§ 610.11a

21 CFR Ch. I (4–1–05 Edition)

Evaluation and Research or the Director, Center for Drug Evaluation and
Research (see mailing addresses in
§ 600.2 of this chapter), an exemption
from the general safety test. The manufacturer must submit information as
part of a biologics license application
submission or supplement to an approved biologics license application establishing that because of the mode of
administration, the method of preparation, or the special nature of the product a test of general safety is unnecessary to assure the safety, purity, and
potency of the product or cannot be
performed. The request must include
alternate procedures, if any, to be performed. The Director, Center for Biologics Evaluation and Research or the
Director, Center for Drug Evaluation
and Research, upon finding that the
manufacturer’s request justifies an exemption, may exempt the product from
the general safety test subject to any
condition necessary to assure the safety, purity, and potency of the product.

§ 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 °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 °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

[41 FR 10891, Mar. 15, 1976, as amended at 49
FR 15187, Apr. 18, 1984; 49 FR 23834, June 8,
1984; 50 FR 4133, Jan. 29, 1985; 51 FR 15607,
Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990; 59 FR
49351, Sept. 28, 1994; 63 FR 19403, Apr. 20, 1998;
63 FR 41718, Aug. 5, 1998; 68 FR 10160, Mar. 4,
2003; 70 FR 14984, Mar. 24, 2005]

§ 610.11a Inactivated influenza
cine, general safety test.

vac-

For inactivated influenza vaccine,
the general safety test shall be conducted in the manner indicated in
§ 610.11 of this chapter except that, with
reference to guinea pigs, the test shall
be satisfied if the product provides satisfactory results using either the subcutaneous or intraperitoneal injection
of 5.0 milliliters of inactivated influenza vaccine into each guinea pig. The
requirements for general safety for inactivated influenza vaccine shall not
be considered to be satisfied unless
each lot of influenza vaccine is assayed
for endotoxin in comparison to a reference preparation provided by the
Food and Drug Administration, and
such lot is found to contain no more
endotoxin than the reference preparation.
[39 FR 40016, Nov. 13, 1974]

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