Pharmacopoeial Reference

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). 

Abstract The current situation in the pharmaceutical industry is discussed, when the traceability of measurement (analytical) results to certified values of pharmacopoeial reference standards is required, without evaluating their uncertainties. It is shown that the evaluation of measurement uncertainty is necessary for understanding the level of confidence of the analytical results and their comparability, particularly during preparation and characterisation of the reference standards. 

An interesting example is die assay of clonidine hydrochloride in injections and tablets (British Pharmacopoeia, 1980). In 0.01 Mhydrochloric acid, clonidine exhibits two sharp maxima ne - 272 nm and 279 nm, which are not suitable for precise measurement. However, clonidine forms an ion pair with bromothymol blue, and this can be readily extracted into chloroform for subsequent measurement of the broad maximum near 420 nm. Because of the intiinsic variabihty of reagents used in such methods, a pharmacopoeial reference standard is employed for cahbration. A similar policy is adopted for assays involving chemical modification of the drug, as in the tetrazolium assay for corticosteroids, the assay for folic acid involving hydrolysis, diazotisation, and coupling with N-(l-naphthyl)ethylenediamine, and the reaction of penicillins with imidazole and mercuric salts. 

More than one recognised pharmacopoeial reference may be used as references for active and inactive ingredients, provided that different individual parameters may not be used selectively with the intention to comply with the less strict criteria of each pharmacopoeia. 

Pharmacopoeial specifications and control procedures must be in line with the latest editions. Where pharmacopoeial references are given without an edition date (in order to obviate updating the dossier with every new publication), the latest edition will apply within twelve months of that edition becoming effective. 

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. 

Fiedler Encyclopedia of Excipients describes the properties of more than 17,000 excipients that are used in pharmaceutical and cosmetic industry. The descriptions contain chemical name, synonyms, structural formula, pharmacopoeial references, CAS Registry number (Chemical Abstract Service), synthesis, properties, use, toxicology, analysis. Published by Editio Cantor Verlag... 

Chemical and pharmaceutical manufacturers must establish their own internal reference materials, when no pharmacopoeial monograph exists, to satisfy the requirements of Good Manufacturing Practice (European Commission 1997). 

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. 

It is clear today that the issue discussed above should be taken into account by pharmacopoeial committees and regulatory bodies involved in drug quality assurance for harmonization of requirements to analytical results and improvement of their quality, first of all while developing the reference standards. 

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. 

Spectrofluorimetry differs from absorption spectrophotometry in not yielding an absolute scale of values. For this reason it is essential to employ a reference standard for quantitative measurements. For example, some pharmacopoeial tests, such as the test for uniformity of content for digitoxin tablets, employ a spectrofluorimefric assay and comparison wi an ofticial reference standard. Quantitative Spectrofluorimetry has been proposed for a munber of naturally fluorescent compoimds, including ergometrine, riboflavine, tiie catechol-amines, phenothiazines, the barbiturates (at pH 13), and certain antibiotics such as chlortetracycline and oxytetracycline. 

Reference to pharmacopoeial monograph for medicinal plant included in recognised pharmacopoeias or submissions of a monograph. 

Validity Study (refer to section 14 of GUIDE) Please enclose validation documents for critical manufacturing processes and analytical methods (if non-pharmacopoeial). ... 

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. 

Pyrogenicity or endotoxin content. The pyro-genicity of a specified dose of product when administered to rabbits can be assayed by a standard pharmacopoeial method but the trend is to replace this with an in vitro assay for endotoxin (Chapter 19). The capacity of the product to induce gelation of Limulus polypbemus amoebocyte lysate is determined against a reference endotoxin preparation and the result is expressed as IU of endotoxin. 

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

Specifications for starting materials (and also of primary or printed packaging materials) should include, if applicable, reference to a pharmacopoeial monograph. 

Reference to pharmacopoeial monographs or similar official references. 

For many established biopharmaceutical compounds, either international (World Health Organization), national (NIBSC) or pharmacopoeial (USP, Ph. Fur.) reference... 

---