An Update for Pharmaceutical Stress Testing Enabled by Modern Informatics Technologies

Stress testing or forced degradation is well recognized as a fundamental part of the drug development process, specifically related to purity through control of stability. Control strategies for stability require “stability-indicating” analytical methods, The development and validation of such methods is built on the foundation of well-designed and conducted stress testing studies. The complete regulatory definition of stress testing is found in Q1A(R2).¹ An excerpt of this definition is: “stress testing…can help identify the likely degradation products, which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used.” Conditions for stressing include elevated heat and humidity, susceptibility to hydrolysis across a wide pH range, susceptibility to oxidative and photolytic degradation, and in the case of biologics, freeze-thaw cycles and shear (when appropriate).³ The primary goal is to induce pharmaceutically-relevant degradation pathways in a comprehensive manner, at levels that facilitate stability-indicating analytical method development and validation, such that all realistic degradation products (i.e., those formed during manufacturing, handling, and normal storage and distribution conditions) are formed and can be analytically detected. A more comprehensive list of the objectives of stress testing studies can be found elsewhere.^4-7 The results of stress testing studies are to “…form an integral part of the information provided to regulatory authorities.”⁶ More recently, there are additional implications for the control of mutagenic degradation products, as outlined by ICH M7.⁸

In the last 20 years much has been written on this topic^4-7,^9-15 including two editions of a book devoted to the topic,⁶,¹⁶ providing helpful guidance on choice of conditions, reasonable endpoints, interpretation of results, and insights into carrying out the studies. This is especially important since the regulatory guidelines are general and do not contain a lot of detail;¹⁷ an exception to this is the legislation  and accompanying guidelines¹⁹,²⁰ from ANVISA, where many of the requirements²¹ are unique to Brazil. 

It is helpful to consider that stress testing is predictive in nature, as opposed to definitive. Stress testing is a research tool that is designed to discover potential stability issues with a drug molecule, providing the scientific foundation for developing stability-indicating analytical methods (SAIMs). The use of validated SAIMs for long-term stability studies provide the definitive stability information. A representation of the overall strategy is shown in Figure 1.

Typically, stress testing is not a “one time” event;²² rather it is performed at several stages in the “life cycle” of a novel drug candidate with different goals, strategies, and levels of thoroughness. The regulatory guidance of the FDA does not explicitly require stress testing to be performed or reported during Phase 1–2 stages, although it is encouraged to facilitate the development of stability-indicating methods.^23,24 The FDA guidance does require drug substance stress testing for Phase 3 and suggests these studies be conducted on drug products as well. For the New Drug Application (NDA), the guidance requires a summary of DS and DP stress studies including elucidation of degradation pathways, demonstration of the stability-indicating nature of the analytical methods, and identification of significant degradation products.^25,26

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