STABILITY TESTING METHODS
- REAL-TIME STABILITY TESTING
It is usually performed for longer duration of the test period, to allow significant product degradation under recommended storage conditions. The test period depends upon the stability of the product which should be long enough to indicate clearly that no measurable degradation occurs and must permit one to distinguish degradation from inter-assay variation.
During testing, data is collected at an appropriate frequency such that a trend analysis is able to distinguish instability from day-to-day ambiguity. The reliability of data interpretation can be increased by including a single batch of reference material for which stability characteristics have already been established. Stability of the reference material also includes the stability of reagents as well as consistency of the performance of the instrument to be used throughout the period of stability testing. However, system performance and control for drift and discontinuity resulting from changes in both reagents and instrumentation must be monitored (Anderson et al., 1991).
- ACCELERATED STABILITY TESTING
In this testing, a product is stressed at several high (warmer than ambient) temperatures and the amount of heat input required to cause product failure is determined. This is done to subject the product to a condition that accelerates degradation. This information is then projected to predict shelf life or used to compare the relative stability of alternative formulations. This usually provides an early indication of the product shelf life and thus shortening the development schedule. In addition to temperature, stress conditions applied during accelerated stability testing are moisture, light. agitation, gravity, pH and package (Kommanaboyina et al., 1999).
In accelerated stability testing the samples are subjected to stress, refrigerated after stressing, and then assayed simultaneously. Because duration of the analysis is short, the likelihood of instability in the measurement system is reduced in comparison to the real-time stability testing. Further, in accelerated stability testing, comparison of the unstressed product with stressed material is made within the same assay and the stressed sample recovery is expressed as percent of unstressed sample recovery. For statistical reasons, the treatment in accelerated stability projections is conducted at four different stress temperatures. However, for thermolabile and proteinaceous components, relatively accurate stability projections are obtained when denaturing stress temperatures are avoided (Anderson et al., 1991).
Conference on Harmonization (ICH) guideline (e.g., 40% for products to be stored at controlled room temperature) were developed from a model that assumes energy of activation of about 83 kJ per mole (Anderson et al., 1991).
A common practice of manufacturers in Pharmaceutical industries was to utilize various shortcuts such as Q rule and bracket tables for prediction of shelf life of the products but these methods are not official either in ICH or FDA.
The Q rule states that a product degradation rate decreases by a constant factor Q10 when the storage temperature is decreased by 10°C. The value of Q10 is typically set at 2, 3 or 4 because these correspond to reasonable activation energies. This model falsely assumes that the value of Q does not vary with temperature.
The bracket table technique assumes that, for a given analyte, the activation energy is between two limits (e.g., between 10 and 20 kcal). As a result, a table may be constructed showing days of stress at various stress temperatures. The use of a 10 to 20 kcal bracket table is reasonable because broad experience indicates that most analytes and reagents of interest in pharmaceutical and clinical laboratories have activation energies in this range (Kommanaboyina et al., 1999; Anderson et al. 1991).
