(1997; 248 pages) [French]
4.2 Stability and periodic re-evaluation
It should be recognized that a reference substance is an integral part of the drug specification. Thus, if the reference substance deteriorates, this also implies a change in the specification of the drug. It is therefore of the utmost importance that the stability of reference substances should be monitored by regular re-examination and that replacement should be made as soon as a significant change in a property is noted.
The definition of what is a “significant change” differs, however, with the intended use of the reference substance. Degradation products in a substance amounting to several per cent may not impair the usefulness of the material in an infrared identification test. For reference substances that are used in chromatographic tests or in assays, however, even small amounts of impurities may be quite unacceptable. In the establishment of standards for reference substances, consideration must be given to the intended use of the substance and to the performance characteristics of the analytical methods for which it is to be used. It must be recognized, however, that the tolerable degree of degradation will be different from case to case.
Laboratories in charge of collections of reference standards should have a system for regular re-examination of the materials in stock. When sufficient experience has been gained, the frequency of retesting may be modified. In this context, however, it is appropriate to bear in mind that the stability of a specially prepared reference substance may not always parallel that of commercial samples of the same material.
The selection of suitable analytical methods for monitoring the stability of reference substances depends on the nature of the substance. Thin-layer chromatography is used extensively and often simple tests, such as determination of water or pH, are useful for recognizing the onset of degradation.
When quantitative estimation of the degree of degradation is needed, more complicated techniques, such as phase solubility analysis, differential scanning calorimetry, or chromatography coupled with quantitative determination of the separated components, must be used.
Change in the moisture content of reference substances is a phenomenon that is difficult to control. To establish suitable conditions for packing operations and storage that might minimize such changes, it is recommended that, for each substance, data be obtained relating to moisture content and relative humidity.