(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 growth-promoting properties over the shelf-life of the media.
(2) For non-culture-based test methods, within the test itself, appropriate controls must be used to demonstrate the ability of the test method to continue to consistently detect the presence of viable contaminating microorganisms.
(f) Repeat test procedures. (1) If the initial test indicates the presence of microorganisms, the product does not comply with the sterility test requirements unless a thorough investigation by the quality control unit can ascribe definitively the microbial presence to a laboratory error or faulty materials used in conducting the sterility testing.
(2) If the investigation described in paragraph (f)(1) of this section finds that the initial test indicated the presence of microorganisms due to laboratory error or the use of faulty materials, a sterility test may be repeated one time. If no evidence of microorganisms is found in the repeat test, the product examined complies with the sterility test requirements. If evidence of microorganisms is found in the repeat test, the product examined does not comply with the sterility test requirements.
(3) If a repeat test is conducted, the same test method must be used for both the initial and repeat tests, and 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 §§ 211.167 and 211.194 of this chapter.
(h) Exceptions. Sterility testing must be performed on final container material or other appropriate material as defined in the approved biologics license application or supplement and as described in this section, except as follows:
(1) This section does not require sterility testing for Whole Blood, Cryoprecipitated Antihemophilic Factor, Platelets, Red Blood Cells, Plasma, Source Plasma, Smallpox Vaccine, Reagent Red Blood Cells, Anti-Human Globulin, and Blood Grouping Reagents.
(2) A manufacturer is not required to comply with the sterility test requirements if the Director of the Center for Biologics Evaluation and Research or the Director of the Center for Drug Evaluation and Research, as appropriate, determines that data submitted in the biologics license application or supplement adequately establish that the route of administration, the method of preparation, or any other aspect of the product precludes or does not necessitate a sterility test to assure the safety, purity, and potency of the product.
