Reference substances and Reference Materials

Reference substances (primary reference substances or secondary reference substances (8)) are used for the testing of a sample.

Note: Pharmacopoeial reference substances should be employed when available and appropriate for the analysis. When a pharmacopoeia reference substance has not been established then the manufacturer should use its own reference substance.

Reference materials may be necessary for the calibration and/or qualification of equipment, instruments or other devices.

Registration and labeling

An identification number should be assigned to all reference substances, except for pharmacopoeia reference substances.

A new identification number should be assigned to each new batch.

This number should be marked on each vial of the reference substance.

The identification number should be quoted on the analytical worksheet every time the reference substance is used (see Part three, section 15.5). In the case of pharmacopoeial reference substances the batch number and/or the batch validity statement should be attached to the worksheet.

The register for all reference substances and reference materials should be maintained and contain the following information:

(a) the identifi cation number of the substance or material; (b) a precise description of the substance or material; (c) the source;

1. the date of receipt;
2. the batch designation or other identifi cation code;
3. the intended use of the substance or material (e.g. as an infrared reference substance or as an impurity reference substance for thin-layer chromatography);
4. the location of storage in the laboratory, and any special storage conditions;
5. any further necessary information (e.g. the results of visual inspections);
6. expiry date or retest date;
7. certificate (batch validity statement) of a pharmacopoeial reference substance and a certified reference material which indicates its use, the assigned content, if applicable, and its status (validity); and
8. in the case of secondary reference substances prepared and supplied by the manufacturer, the certificate of analysis.
   1. A person should be nominated to be responsible for reference substances and reference materials.
   2. If a national pharmaceutical quality control laboratory is required to establish reference substances for use by other institutions, a separate reference substances unit should be established.
   3. In addition a file should be kept in which all information on the properties of each reference substance is entered including the safety data sheets.
   4. For reference substances prepared in the laboratory, the fi le should include the results of all tests and verifi cations used to establish the reference substances and expiry date or retest date; these should be signed by the responsible analyst.

Retesting (monitoring)

All reference substances prepared in the laboratory or supplied externally should be retested at regular intervals to ensure that deterioration has not occurred. The interval for retesting depends on a number of factors, including stability of the substance, storage conditions employed, type of container and extent of use (how often the container is opened and closed). More detailed information on the handling, storage and retesting of reference substances is given in the WHO General guidelines for the establishment, maintenance and distribution of chemical reference substances (8).

The results of these tests should be recorded and signed by the responsible analyst.

In the case that the result of retesting of a reference substance is noncompliant, a retrospective check of tests performed using this reference substance since its previous examination should be carried out. For evaluation of outcomes of retrospective checks and consideration of possible corrective actions, risk analysis should be applied.

Pharmacopoeial reference substances are regularly retested and the validity (current status) of these reference substances is available from the issuing pharmacopoeia by various means, e.g. web sites or catalogues. Retesting by the laboratory is not necessary, provided the reference substances are stored in accordance with the storage conditions indicated.