(1999; 168 pages) [Spanish]
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.