Stress testing degradation studies

Similar to accelerated studies, stress tests give a general picture of the chemical stability and degradation pathways under exaggerated conditions, such as under extreme pH conditions (acids and bases), heat, oxidative or reductive conditions, hydrolysis, and light irradiation (light irradiation tests at not less than 1.2 million lux hours are formalized as described in ICH QIB). These mostly non-formalized stress tests are only evaluated over a short term, e.g., 1 month. 

The stress studies should demonstrate that impurities and degradants from the active ingredient do not interfere with the quantitation of the API [12]. Stress testing of the API, in addition to validating the stability-indicating power of the analytical method, can also help establish the degradation pathways and the intrinsic stability of the molecule [7]. 

Stress testing is the main tool that is used to predict stability problems, develop analytical methods, and identify degradation products and pathways. Since there are no detailed regulatory guidelines that describe how to carry out stress testing studies (nor has there ever been a textbook or reference book devoted to the subject), stress testing has evolved into an artful science that is highly dependent on the experience of the company... 

As these examples illustrate, historically there has been tremendous variation in the conditions employed in acid/base and oxidative stress testing studies. There has also been tremendous variation in defining the appropriate endpoint of the stress testing studies, i.e., what length of time (and temperature) or amount of degradation is sufficient to end the stress exposure. 

Recent publications on the topic of stress testing/forced degradation studies reveal that there is still a tremendous variability in the conditions... 

Figure 1 Cartoon illustration of hypothetical chromatograms from stress testing (upper) and accelerated or long-term stability studies. Peaks A-I represent all the degradation products from stress-testing studies under various stress conditions and are therefore classified as potential degradation products. Peaks B-E and G represent the products that form at significant levels during formal stability studies and are therefore classified as the actual or relevant degradation products.

As described in the PhRMA Available Guidance and Best Practices article on forced degradation studies (12), stress testing should include condi-... 

The use of elevated temperature is appropriate (though not required) for aqueous solution stress-testing studies. As discussed in Section III. A, elevated temperatures up to 70°C should accelerate the hydrolytic degradation... 

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