Minimizing the Use of Reference Substances

It is policy of the Commission of the European Pharmacopoeia to minimize the use of reference substances/preparations since the production, maintenance and distribution of chemical reference substances is a costly and time-consuming undertaking. Therefore the decision to establish a reference substance shoidd not be taken lightly and consideration should be given to other approaches which could be adopted to avoid the use of reference substances. A number of strategies can be employed to reduce the need for reference substances. 

Non-specific absolute assay methods, e.g. volumetric titration, can be applied to avoid the establishment of a reference substance. This is only appropriate, however, when the monograph describes a separation test for related substances. This approach is certainly valid for the determination of the content of pharmaceutical raw materials but less acceptable for the assay of content of pharmaceutical preparations where the employment of specific assay methods is recommended (ICH Guideline 1994) to take account of decomposition of the active ingredient during the shelf life of the product and to avoid possible interference from excipients. 

A candidate reference substance is selected from the normal production batches of a manufacturer and is not further usually purified. Candidate reference substances/ preparations should be supplied with  

The quantity requested should be sufficient to allow for all the pre-testing required and the preparation of a stock of vials or ampoules which will last for several years. 

Except in rare cases, the quality of the CRS to be established must comply with the requirements of the monograph. The purity of the candidate reference substances 

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