Quality Assurance of Pharmaceuticals - A Compendium of Guidelines and Related Materials - Volume 1
(1997; 248 pages) [French] View the PDF document
Table of Contents
Open this folder and view contentsIntroduction
Open this folder and view contents1. National drug regulation
Open this folder and view contents2. Product assessment and registration
Open this folder and view contents3. Distribution
Close this folder4. The international pharmacopoeia and related activities
View the documentGuidance for those preparing or commenting on monographs for preparations to be included in The international pharmacopoeia1
View the documentValidation of analytical procedures used in the examination of pharmaceutical materials1
Close this folderGeneral guidelines for the establishment, maintenance, and distribution of chemical reference substances1
View the document1. Criteria for determining the need for the establishment of chemical reference substances
View the document2. Evaluation of reference substances
Open this folder and view contents3. Chemical and physical methods used in evaluating reference substances
Close this folder4. Handling and distribution of reference substances
View the document4.1 Packing and storage
View the document4.2 Stability and periodic re-evaluation
View the document4.3 Information to be supplied with reference substances
View the document4.4 Expiry of reference substances
View the document4.5 Distribution problems
View the document5. Reference materials calibrated against International Chemical Reference Substances
View the document6. Means of promoting effective exchange of information and ensuring cooperation between organizations establishing reference substances
View the documentGeneral recommendations for the preparation and use of infrared spectra in pharmaceutical analysis1
View the documentList of available International Chemical Reference Substances1
View the documentList of available International Infrared Reference Spectra1
Open this folder and view contents5. Basic tests
Open this folder and view contents6. Laboratory services
Open this folder and view contents7. International trade in pharmaceuticals
Open this folder and view contents8. Counterfeit products
Open this folder and view contents9. Training
View the documentSelected WHO publications of related interest
View the documentBack cover
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.

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