Pharmacopoeial Reference Substances

Thus, it can he seen that ISO type reference materials or certified reference materials are intended to he employed for a number of purposes using a variety of different analytical procedures, whilst pharmacopoeial reference substances/preparations are intended for a specific purpose and are not to be used for methods or procedures which are not described in the particular monograph. 

Pharmacopoeial reference substances/preparations are an integral part of a monograph and employed for a variety of purposes within the monograph (Table 5.3). 

Pharmacopoeial reference substances are increasingly employed as assay standards since assay of content is determined more and more frequently by separation techniques. 

A pharmacopoeial reference substance is intended for the determination of the main component of a substance or for the active ingredient of a pharmaceutical formulation which is usually present at a high proportion of the total. The reference substance is to be used as a primary standard in a specific method validated as prescribed in the ICH Guideline Validation of Analytical Procedure Methodology" (Technical Guide for the Elaboration of Monographs 1996 ICH Guideline 1997). the reproducibility of which is known. This is taken into account when the limits of acceptance (tolerance) for the substance or product are fixed (Daas and Miller 1997,1998). 

Guidance concerning the extent of testing required is also given in the Technical Guide for the elaboration of monographs (1996) of the European Pharmacopoeia. These guidelines are specifically addressed to the establishment of reference substances for pharmacopoeial use. 

Exchanges between pharmacopoeias are co-ordinated by the Pharmacopoeial Discussion Group (PDG) (International Harmonisation 1995) and it is frequent that one pharmacopoeia participates in a collaborative study organized by another pharmacopoeia, or that several pharmacopoeias share the same batch of reference substance to be used in their respective monographs nevertheless, in this case the reference substance can not be considered as harmonized. A new batch of erythromycin was shared between the United States Pharmacopoeia and the European Pharmacopoeia and was established in a common coEaborative study both for the microbiological assay (used in the USP for formulations) and the liquid chromatographic assay (used in the Ph. Eur. and USP for bulk material). 

The Pharmacopoeial Forum fulfills a vital role in promoting industry-wide communication between those involved with quality assurance, the development of standards and analytical methods. It contains an up to date list of official USP Reference Substances, with current and recently changed lot numbers. Reference Substances not yet available and those under development are also described. The publication acts as an international open forum in which scientists are invited to express their views, suggestions, ideas and comments regarding new drug standard development and revisions to existing monographs. Pharmacopoeial Forum is published, on a subscription basis, six times a year, back issues are available for USP website see Table 84. 

The preliminary draft guidelines for the establishment of secondary reference substances were presented to the Committee. The Committee endorsed the general approach and agreed that a definition of a pharmacopoeial reference standard should be included before the text was circulated for comment. 

National and international compendial [pharmacopoeial] authorities publish authenticated reference spectra. Authentic infrared IR reference spectra are required for proof of identity of official substances by direct comparison with observed IR spectra obtained with the test substance examined in a prescribed manner. 

For nonpharmacopoeial substances, or in-house specifications, all the specifications and anal5dical and other control procedures must be fully described. General pharmacopoeial methods may be referred to if applicable, in which case these should be referenced clearly. 

Pharmacopoeial content requirements, with reference to the anhydrous substances, are ... 

Compliance with monographs of the European Pharmacopoeia (Ph Eur) applies to all substances appearing in it and, for other substances, national pharmacopoeias may be enforced. Thus, where a pharmacopoeial monograph for an active substance or pharmaceutical excipient employs NMR spectroscopy in a test method, the substance must comply with this test. However, a test other than the pharmacopoeial test may be used if proof is supplied that the starting material meets the quality requirements of the relevant pharmacopoeia. If a pharmacopoeial monograph is applicable to a substance, then there is no need for the applicant to provide full details of the analytical tests or their validation, as reference to the pharmacopoeia in question is deemed sufficient. 

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