Forced degradation studies pathway

Forced degradation/stress studies elucidate the inherent stability characteristics of the molecule under study and determine its degradative pathways. Forced degradation studies are needed to support method validation, determine product protection requirements, and guide formulation development. 

Forced degradation studies on the drug product are carried out on a single batch of the formulation to be marketed to determine if there are any additional degradation pathways and degradants formed due to interactions between or among the API and the excipients. 

Forced degradation studies may provide information in regard to degradation pathways and degradation products that could form during storage of the... 

It is however more difficult to define what constitutes good mass balance and what level of mass balance deficit should be of concern. ICH QIA attempted to define mass balance but this definition was removed in the 2002 revision. For simple degradation pathways with no significant change in UV response, a mass balance of 95% can be expected but for complex degradation profiles, it may be more useful to focus on assay specificity than on reconciling mass balance. A review published in 2005 provides a more detailed discussion of mass balance in forced degradation studies [52]. This topic is also addressed in a review by Bashki etal., from 2002 [30],... 

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. 

Forced degradation These testing studies are undertaken to degrade the sample deliberately. These studies, which may be undertaken in the development phase normally on the drug substances, are used to evaluate the overall photosensitivity of the material for method development purposes and/or degradation pathway elucidation. 

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. 

Summary of primary and supportive data including forced degradation and stress studies. Potential and observed degradation pathway(s) and product(s). 

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