The complexity of biological macromolecules when compared to small molecule therapeutics, differences in manufacturing, and the broad variety of potential degradation pathways lead to special requirements in quality assurance and analytical testing of pharmaceutical proteins. The product-related impurities are molecular variants formed during manufacture, storage, or use, and their properties are different from the desired product with respect to activity, efficacy, and safety.1
Forced degradation studies are designed to generate product-related variants and develop analytical methods to determine the degradation products formed during accelerated pharmaceutical studies and long-term stability studies. Any significant degradation product should be evaluated for potential hazard and the need for characterization and quantitation.2
A one-time forced-degradation study on a single batch is not considered part of the normal stability protocol.4 However, the design of the stress studies and the results are to be provided to regulatory authorities as part of the stability section of the application.5,6
OBJECTIVES OF STRESS STUDIES The best samples of product-related degradants for the specificity evaluation would be retrieved throughout the pharmaceutical stability study.7 The duration of most stability studies makes this ideal situation untenable. Thus, an analyst is faced with the necessity to artificially generate degraded samples.
Forced degradation or stress testing studies are part of the development strategy5 and are also an integral component of validating analytical methods that indicate stability and detect impurities. This relates to the specificity section of the validation studies.5,6 It is important to recognize that forced degradation studies are not designed to establish qualitative or quantitative limits for change in drug substance (DS) or drug product (DP).8
Testing of stressed samples is required to demonstrate the following abilities of analytical techniques employed in stability studies:1,5,9
The forced degradation studies are also expected
Stress studies may be useful in determining whether accidental exposures to conditions other than normal ranges (e.g., during transportation) are deleterious to the product, and also for evaluating which specific test parameters may be the best indicators of product stability.2,9