(1999; 168 pages) [Spanish]
In 1975, the WHO Expert Committee on Specifications of Pharmaceutical Preparations recommended "General guidelines for the establishment, maintenance and distribution of chemical reference substances" (1).1 At that time these general guidelines were aimed at fostering greater collaboration and harmonization among various national and regional authorities responsible for collections of chemical reference substances. This aim is still relevant. The guidelines were initially drawn up for particular use by the WHO Collaborating Center for Chemical Reference Substances in Sweden, which provides International Chemical Reference Substances (ICRS). These substances are primarily intended for use with pharmacopoeial monographs included in The international pharmacopoeia (2).
1 The term chemical reference substances, as used in this text, refers to an authenticated uniform material that is intended for use in specified chemical and physical tests, in which its properties are compared with the properties of a product under examination, and which possesses a degree of purity adequate for its intended use.
It became evident that in order to meet particular national or regional pharmacopoeial requirements, it was necessary to establish chemical reference substances external to the WHO Collaborating Centre for Chemical Reference Substances. Another difficulty was to ensure prompt dispatch of the substances. Since the meticulous work of the WHO Collaborating Centre establishing the international collection would have to be duplicated in local or regional laboratories, guidelines were necessary to ensure the integrity of national or regional collections. In order to clarify the need for national and regional collections, the 1975 guidelines were reviewed and modified in 1982 (3). In view of refinements in pharmaceutical and analytical methods since then, the present revision was considered essential.
The purpose of having chemical reference substances is to achieve accuracy and reproducibility of the analytical results required by pharmacopoeial testing and pharmaceutical control in general. These substances are normally prepared and issued by the regional/national pharmacopoeial commission or the regional/national quality control laboratory on behalf of the drug regulatory authority. In the context of these guidelines, the general use of a chemical reference substance should be considered an integral part of a compliance-oriented monograph or test procedure used to demonstrate the identity, purity and content of pharmaceutical substances and preparations.
The establishment of chemical reference substances should be based on reports in which the results of analytical testing have been evaluated. These reports should subsequently be approved and adopted by a certifying body, normally the relevant pharmacopoeial committee or the drug regulatory authority. Such establishment can be on an international, national or regional basis. Each substance is generally established for a specific analytical purpose, defined by the issuing body. Its use for any other purpose becomes the responsibility of the user and a suitable caution is included in the information sheet accompanying a reference substance. The present guidelines are concerned with both primary and secondary chemical reference substances as defined below.
The preparation of a chemical reference substance should comply with the requirements for quality assurance systems, including principles of good manufacturing practices (GMP) and good control laboratory practices (4-6).
Adequate training programmes are also required. Both the WHO Collaborating Centre and other laboratories concerned with the evaluation and establishment of chemical reference substances give assistance in training, subject to the availability of resources.
Primary chemical reference substance
A designated primary chemical reference substance is one that is widely acknowledged to have the appropriate qualities within a specified context, and whose value is accepted without requiring comparison to another chemical substance.
Secondary chemical reference substance
A secondary chemical reference substance is a substance whose characteristics are assigned and/or calibrated by comparison with a primary chemical reference substance. The extent of characterization and testing of a secondary chemical reference substance may be less than for a primary chemical reference substance. This definition may apply inter alia to some substances termed "working standards".