The current regulatory guidances governing forced degradation studies of biological pharmaceuticals are extremely general.
They itemize broad principles and approaches with few practical instructions. There is no single document that comprehensively
addresses issues related to stress studies such as objectives, timing, selection of stress conditions, and extent of degradation.
We will attempt to fill that gap by summarizing regulatory guidance for stress studies of biological products and present
some examples of their practical applications.
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
Regulatory guidance is open to interpretation. Detailed information and specific instructions for conducting forced degradation
studies of biologics and biotechnology products are close to non-existent. The most recent workshop was held in 2001 by the
Pharmaceutical Research and Manufacturers of America Analytical Research and Development Steering Committee. The conclusion
was that there is little information about strategies and principles. The summary provides useful definitions and general
comments about degradation studies, while guidance concerning the scope, timing, and best practices is very general.3 This article shows a way to reduce these generalities to practice.
Michael Kats, Ph.D.
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
- to evaluate stability of DS and DP in solution
- to determine structural transformations of the drug substance and drug product
- to detect low concentrations of potential degradation products
- to detect unrelated impurities in the presence of the desired product and product-related degradants
- to separate product-related degradants from those derived from excipients and intact placebo.3
The forced degradation studies are also expected
- to elucidate possible degradation path-ways
- to identify degradation products that may be spontaneously generated during drug storage and use
- to facilitate improvements in the manufacturing process and formulations in parallel with accelerated pharm-aceutical studies.
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