An Update for Pharmaceutical Stress Testing Enabled by Modern Informatics Technologies

I. Introduction

A. Background on Stress Testing

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