USP In-Process Revision Chapter <1223>, Validation of Alternative Microbiological Methods

The USP Expert Committee in Microbiology recently published a draft in-process revision of chapter <1223>, Validation of Alternative Microbiological Methods in the USP Pharmacopeial Forum (PF). Highlights include more detailed discussion and methods for validation parameters such as methods for demonstrating Limit of Detection, and multiple options and statistical calculations for demonstrating Equivalence of the alternate microbiological method against official compendial methods (e.g. USP <71>, EP 2.6.1).

The table below from USP 1223 shows the validation parameters for Qualitative and Quantitative tests. The most applicable test for cell therapy products is the qualitative presence / absence (i.e. pass / fail) Sterility Test.

Validation Parameter Qualitative Tests (Sterility) Quantitative Tests
Accuracy No Yes
Precision No Yes
Specificity Yes Yes
Limit of detection Yes Yes
Limit of quantification No Yes
Linearity No Yes
Operational (dynamic) range No Yes
Robustness Yes Yes
Repeatability Yes Yes
Ruggedness Yes Yes
Equivalency Yes Yes

Although Equivalence is a required parameter for drug products when validating an alternative method or technology intended to replace a compendial test, it is not necessarily a requirement for cell therapy products regulated as biologics under the recently updated 21 CFR 610.12. According the revised biologics sterility chapter, “The sterility test must be validated to demonstrate that the test is capable of reliably and consistently detecting the presence of viable contaminating microorganisms“. Sterility test method validation parameters were published as Final Rule by the agency in the Federal Register 77, June 2012, “Amendments to Sterility Test Requirements for Biological Products”.

These parameters were: Limit of Detection, Specificity, Ruggedness, and Robustness. Concerning Equivalence, the final rule regarding comparison with a “referee” test (e.g. USP 71) the rule states that “We believe methods validation is a well recognized activity and can be performed without comparison to a “referee” test method.”

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