Stability-indicating method pathway

Forced degradation samples are used in the process of developing stability-indicating methods early in development prior to initiating formal stability studies. The samples are analyzed for API peak purity (coeluting impurities), specificity, and mass balance. Efforts are also focused on determination degradation pathways/mechanisms for API and DP. 

The stress studies should demonstrate that impurities and degradants from the active ingredient do not interfere with the quantitation of the API [12]. Stress testing of the API, in addition to validating the stability-indicating power of the analytical method, can also help establish the degradation pathways and the intrinsic stability of the molecule [7]. 

Many potential degradation products are not observed in protein pharmaceuticals, primarily because much care is taken in the choice of formulations, lyophilization, and storage conditions in order to maintain protein stability. Thus, degradation is minimized and usable shelf lives are on the order of years. In order to study the degradation pathways of a biopharmaceutical protein, and to evaluate the stability-indicating ability of the analytical methods, it is sometimes necessary to perform forced degradation studies, where the biopharmaceutical protein is subjected to a variety of stress conditions, such as varying pH, elevated temperature, or the addition of oxidants. 

Currently, there are no reliable methods for the quantitative prediction of metabolic stability. However, over the years researchers have accumulated significant knowledge of which chemical groups might be metabolically labile and which are the resulting metabolites. Two software packages based on knowledge bases are available — MetabolExpert and META. ° Both provide alerts about potential metabolic pathways but do not indicate how probable those pathways are. 

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