PART 610.12— CBER GENERAL BIOLOGICAL PRODUCTS STANDARDS PROPOSED
COMMENT
Enclosed is the summary of the proposed requirements for the revised CBER 610.12 Sterility Test. Comments are due by September 19, 2011. For additional information, please see below for a summary or visit the enclosed web site for the full release http://www.gpo.gov/fdsys/pkg/FR-2011-06-21/pdf/2011-15346.pdf
3. The authority citation for 21 CFR part 610 continues to read as follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 360d, 360h, 360i, 371,
372, 374, 381; 42 U.S.C. 216, 262, 263, 263a, 264.
4. Section 610.12 is revised to read as follows:
§ 610.12 Sterility.
(a) The test. Except as provided in paragraph (h) of this section,
manufacturers of biological products must perform sterility testing of each lot
of each biological product’s final container material or other material, as
appropriate and as approved in the biologics license application or
supplement for that product.
(b) Test requirements.
(1) The sterility test must be appropriate to the material
being tested such that the material does not interfere with or otherwise hinder
the test.
(2) The sterility test must be validated to demonstrate that the test is capable of
reliably and consistently detecting the presence of viable contaminating
microorganisms.
(3) The sterility test and test components must be verified to
demonstrate that the test method can consistently detect the presence of
viable contaminating microorganisms.
(c) Written procedures. Manufacturers must establish, implement, and follow
written procedures for sterility testing that describe, at a minimum, the
following:
(1) The sterility test method to be used;
(i) If culture-based test methods are
used, include, at a minimum:
(A) Composition of the culture media;
(B) Growth-promotion test requirements; and
(C) Incubation conditions (time and temperature).
(ii) If non-culture-based test methods are used, include, at a minimum:
(A) Composition of test components;
(B) Test parameters, including acceptance criteria; and
(C) Controls used to verify the method’s ability to detect the presence
of viable contaminating microorganisms.
(2) The method of sampling, including the number, volume, and size
of articles to be tested;
(3) Written specifications for the acceptance or rejection of each lot; and
(4) A statement of any other function critical to the particular sterility test
method to ensure consistent and accurate results.
(d) The sample. The sample must be appropriate to the material being tested,
considering, at a minimum:
(1) The size and volume of the final product lot;
(2) The duration of manufacturing of the drug product;
(3) The final container configuration and size;
(4) The quantity or concentration of inhibitors, neutralizers, and
preservatives, if present, in the tested material;
(5) For a culture-based test method, the volume of test material that results
in a dilution of the product that is not bacteriostatic or fungistatic; and
(6) For a non-culture-based test method, the volume of test material that
results in a dilution of the product that does not inhibit or otherwise hinder the
detection of viable contaminating microorganisms.
(e) Verification. (1) For culture-based test methods, studies must be conducted
to demonstrate that the performance of the test organisms and culture media are
suitable to consistently detect the presence of viable contaminating
microorganisms, including tests for each lot of culture media to verify its growthpromoting
properties over the shelf-life of the media.
(2) For non-culture-based test methods, within the test itself,
appropriate controls must be used to demonstrate the ability of the test
method to continue to consistently detect the presence of viable
contaminating microorganisms.
(f) Repeat Test Procedures. (1) If the initial test indicates the presence of
microorganisms, the product does not comply with the sterility test
requirements unless a thorough investigation by the quality control unit
can ascribe definitively the microbial presence to a laboratory error or faulty
materials used in conducting the sterility testing.
(2) If the investigation described in paragraph (f)(1) of this section finds that
the initial test indicated the presence of microorganisms due to laboratory error
or the use of faulty materials, a sterility test may be repeated one time. If no
evidence of microorganisms is found in the repeat test, the product examined
complies with the sterility test requirements. If evidence of
microorganisms is found in the repeat test, the product examined does not
comply with the sterility test requirements.
(3) If a repeat test is conducted, the same test method must be used for both
the initial and repeat tests, and the repeat test must be conducted with
comparable product that is reflective of the initial sample in terms of sample
location and the stage in the manufacturing process from which it
was obtained.
(g) Records. The records related to the test requirements of this section must be
prepared and maintained as required by 21 CFR 211.167 and 211.194 of this
chapter.
(h) Exceptions. Sterility testing must be performed on final container material
or other appropriate material as defined in the approved biologics license
application or supplement and as described in this section, except as
follows:
(1) Sterility testing is not required for Whole Blood, Cryoprecipitated
Antihemophilic Factor, Platelets, Red Blood Cells, Plasma, Source Plasma,
Smallpox Vaccine, Reagent Red Blood Cells, Anti-Human Globulin, and Blood
Grouping Reagents.
(2) A manufacturer is not required to comply with the sterility test
requirements if the Director of the Center for Biologics Evaluation and
Research or the Director of the Center for Devices and Radiological Health, as
appropriate, determines that data submitted in the biologics license
application or supplement adequately establish that the route of
administration, the method of preparation, or any other aspect of the
product precludes or does not necessitate a sterility test to assure the
safety, purity, and potency of the product
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