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Wednesday, September 16, 2009

Drug product stress testing forced degradation not required when stability test stability indicating

Drug product stress testing (forced degradation) is not necessarily always be conducted for the drug product when determining if a drug product stability test method is stability-indicating . What CGMPs requirements for this ?

Answer given by US FDA for this question is as follows.

(Forced degradation ) Drug product stress testing is not necessary when the routes of degradation & the suitability of the analytical procedures can be established with use of the following:

1. Data from stress testing of drug substance
2. Reference materials for process impurities and degradants
3. Data from accelerated as well as long-term studies on drug substance
4. Data from accelerated as well as long-term studies on drug product

You can provide additional supportive information from literatures , about the specificity of the analytical methods and information about degradation pathways of the drug substance.

In Section 211.165(e) of the CGMP regulations it says that the accuracy, sensitivity, specificity, and reproducibility of test methods should be established and documented.
Further, section 211.166(a)(3) of C GMP guidelines requires that stability test methods should be reliable, meaningful, and specific, that is the content of active ingredient,  products of degradation reaction , and other intermediates ,  associated with a drug product can be accurately measured without interference, these test are called "stability-indicating."

The US FDA answer to this question says, the CGMP regulations don't specify which techniques or tests are to be used to ensure that one's test methods are stability-indicating.

Evaluation of the specificity of the test methods during forced degradation studies (i.e., exposing drug to extremes of pH, temperature, oxygen, etc.) of drug substance and drug product often is necessary to ensure that stability test methods are stability-indicating. But in certain circumstances conducting a forced degradation study of just the drug substance may be sufficient to evaluate the stability-indicating properties of a test method.

To determine is it necessary to conduct forced degradation studies of the drug product, the specificity of the test method should be evaluated for its ability to assay drug substance, degradants, and impurities, in the presence of each other, without interference. The evaluation also should provide assurance that there is not a potential for interaction between drug substance, degradants, impurities, excipients, and container-closure system during the course of the shelf-life of the finished drug product.
The rationale for decisions made concerning the extent of the forced degradation studies conducted as well as the rationale for concluding that a test method is stability-indicating should be fully documented.

What are the References for above answer:

21 CFR 211.137: Expiration dating
21 CFR 211.165(e): Testing and release for distribution
21 CFR 211.166(a)(3): Stability testing
Compliance Policy Guide, Section 480.100 (7132a.04), Requirements for Expiration Dating and Stability Testing

Also see Accelerated stability study
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