Stability stress testing

Table 12.3 Examples of physical stability stress testing of drug substances...

The use of stress tests to study the stability of emulsions has been described in Sec. V.C. 

Although determination of a complete pH-degradation rate profile is desired, it may not always be practical due to limitations of drug supply and time. Also, insufficient solubility in purely aqueous systems may limit determination of pH-degradation rate profiles. Organic cosolvents may be used to increase solubility however, extrapolation to aqueous conditions must be done with caution. Stability of the drug in a suspended form in the desired buffer can be tested in lieu of solution stability. The stress test results must however, be interpreted in relation to the solubility in the suspension medium. The test may provide an empirical indication of pH stability in the presence of excess water. Satisfactory stability in the GI pH range (1 to 7.5) is important for oral absorption. While there are examples of... 

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 (drug substance) — Studies undertaken to elucidate the intrinsic stability of the drug substance. 

Data on the chemical stability at room temperature have been compiled almost exclusively for vitamins. A stress test was almost always performed for PVP-iodine preparations, and this corresponds to at least one year at room temperature. 

Data on the chemical stability are scanty. Preparations with PVP-iodine as disinfectant are an exception, in which case a stress test was always performed whose results represent a period of much more than 12 months at room temperature (20-25 °C). 

Stress testing is used to determine the intrinsic physical and chemical stability of the pharmaceutical ingredient under accelerated, elevated temperature storage conditions, such as 50°C- 75% RH, 40°C- 75% RH, and 30°C- 60% RH. 

Stress testing is used to help identify degradation pathways under the influence of accelerated heat, light, and RH conditions in the presence or absence of air or oxygen. Such stability testing protocols represent an important aspect of a pharmaceutical ingredient process validation program. 

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... 

An important aspect of this definition is that the studies are part of the formal, definitive, storage program. In contrast, ICH, in Annex 1, Glossary and Information of the revised stability guideline (6) defined stress testing (drug substance) as ... 

A more detailed description of stress testing is provided near the beginning of the ICH Stability guideline, under the Drug Substance heading ... 

The description of stress testing was slightly modified in the revised stability guideline from the original description in ICH Q1A (5). The original Q1A description contained this additional paragraph ... 

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