WHO Expert Committee on Specifications for Pharmaceutical Preparations - WHO Technical Report Series, No. 885 - Thirty-fifth Report
(1999; 168 pages) [Spanish] View the PDF document
Table of Contents
View the documentWHO Expert Committee on Specifications for Pharmaceutical Preparations
View the document1. Introduction
Open this folder and view contents2. The international pharmacopoeia and related issues
Open this folder and view contents3. International Chemical Reference Substances and Infrared Reference Spectra
Open this folder and view contents4. Quality control - national laboratories
Open this folder and view contents5. Good manufacturing practices
Open this folder and view contents6. Quality systems and inspection
Open this folder and view contents7. Other quality assurance topics
Open this folder and view contents8. Nomenclature and terminology
Open this folder and view contents9. Legal aspects of pharmaceuticals
Open this folder and view contents10. Regulatory issues
Open this folder and view contents11. Training activities
View the document12. Pharmaceuticals contaminated with diethylene glycol
View the documentAcknowledgements
View the documentReferences
View the documentAnnex 1. List of available International Chemical Reference Substances1
View the documentAnnex 2. List of available International Infrared Reference Spectra1
Close this folderAnnex 3. General guidelines for the establishment, maintenance and distribution of chemical reference substances
View the documentIntroduction
Close this folderPart A. Primary chemical reference substances
View the document1. Assessment of need for the establishment of chemical reference substances
View the document2. Obtaining source material
Open this folder and view contents3. Evaluation of chemical reference substances
Open this folder and view contents4. Chemical and physical methods used in evaluating chemical reference substances
View the document5. Assignment of content
Close this folder6. Handling and distribution of chemical reference substances
View the document6.1 Packaging operations
View the document6.2 Storage
View the document6.3 Stability
View the document6.4 Information to be supplied with chemical reference substances
View the document6.5 Distribution and supply
View the document6.6 Period of use
View the documentPart B. Secondary chemical reference substances
View the documentReferences
Open this folder and view contentsAnnex 4. Good manufacturing practices: authorized person - role, functions and training
Open this folder and view contentsAnnex 5. Good manufacturing practices: supplementary guidelines for the manufacture of pharmaceutical excipients
Open this folder and view contentsAnnex 6. Guidelines for inspection of drug distribution channels
View the documentAnnex 7. Good pharmacy practice in community and hospital pharmacy settings
Open this folder and view contentsAnnex 8. National drug regulatory legislation: guiding principles for small drug regulatory authorities
Open this folder and view contentsAnnex 9. Provisional guidelines for developing training programmes: inspection and examination of counterfeit pharmaceuticals
View the documentWorld Health Organization Technical Report Series
View the documentSelected WHO Publications of Related Interest
View the documentBack Cover
 
6.3 Stability

A chemical reference substance is an integral part of the drug specification. Thus, if the reference substance deteriorates, this will change the specification of the drug. It is therefore of the utmost importance that the stability of chemical reference substances should be monitored by regular re-examination and that they should be replaced as soon as a significant change in a property is noted.

The definition of what is a "significant change" differs according to the intended use of the chemical reference substance. Several per cent of degradation products found in a substance may not impair the usefulness of the material in identification tests. For chemical reference substances that are used in chromatographic assays, however, even small amounts of impurities may be unacceptable. When establishing a chemical reference substance, consideration must be given to its intended use and to the performance characteristics of the analytical methods in which it will be used. The tolerable degree of degradation will be different from case to case.

Laboratories in charge of collections of chemical reference substances should have a system for regular re-examination of the materials in stock. The frequency of re-testing may be modified according to the need. It must be borne in mind that the stability of a specially prepared chemical reference substance may not always be the same as that of commercial samples of the same material.

The selection of suitable analytical methods for monitoring the stability of chemical reference substances depends on the nature and intended use of the substance. A substance used solely for identification purposes will normally only require demonstration that it is still suitable for this use, e.g. that the IR spectrum is identical to that obtained during establishment. If substances are employed for other purposes, the testing must be more extensive but should use methods which are rapid and sensitive so as not to consume too much of the existing stock. It is important to check that there has been no significant uptake of moisture, which could result in degradation by hydrolysis and/or a decrease in the assigned content of the substance. Chromatography is employed extensively, as well as absolute methods such as differential scanning calorimetry where applicable. Changes in the impurity profile or purity determination usually mean that the batch must be replaced. Changes which compromise the integrity of the batch indicate it should immediately be withdrawn from use. Sometimes a batch of a chemical reference substance will discolour or otherwise change in appearance. Steps should be taken to replace this substance whether or not the results of subsequent analyses indicate significant degradation. Such changes in physical appearance reduce the confidence of the user in the suitability of the chemical reference substance. Appropriate testing of active bulk substance should be carried out before further dispensing into vials or ampoules.

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