No. Drug product stress testing (forced degradation) may not be necessary when the routes of degradation and the suitability of the analytical procedures can be determined through use of the following:
- Data stress testing of the drug substance
- Reference materials for process impurities and degradants
- Data accelerated and long-term studies on the drug substance
- Data accelerated and long-term studies on the drug product
Additional supportive information on the specificity of the analytical methods and on degradation pathways of the drug substance may be available literature sources. Section 211.165(e) of the CGMP regulations states that the accuracy, sensitivity, specificity, and reproducibility of test methods shall be established and documented (21 CFR 211.165(e)). Further, 21 CFR 211.166(a)(3) requires that stability test methods be reliable, meaningful, and specific, which means that the content of the active ingredient, degradation products, and other components of interest in a drug product can be accurately measured without interference, often called stability indicating. The CGMP regulations do not specify what techniques or tests are to be used to ensure that one’s test methods are stability indicating. However, evaluating the specificity of the test methods during forced degradation studies (i.e., exposing the drug to extremes of pH, temperature, oxygen, etc.) of the 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. Generally, in determining whether it is 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 the drug substance, degradants, impurities, excipients, and container-closure system during the course of the shelf life of the finished drug product. Last, the rationale for any decision 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.
