SC III D. Monograph Development: Methods of Analysis

1. This Supplementary Chapter concerns the methods described in the Pharmacopoeia for the analysis of medicinal and pharmaceutical substances, pharmaceutical dosage forms and other articles. It provides information on the development, validation and use of pharmacopoeial methods so that users of the Pharmacopoeia may understand the purpose and limitations of a monograph and to guide manufacturers and other users when participating in the development of new monographs and the revision of existing monographs.

2. For further information regarding the elaboration of European Pharmacopoeia monographs, users may also consult the “Technical guide for the elaboration of monographs”, which is published by the European Pharmacopoeia.

3. The Chapter does not set out the nature and extent of validation required in particular instances. Guidelines on such matters with respect to product registration are available from other sources such as the International Conference on Harmonisation (ICH) and are published as guideline Q2(R1), “Validation of Analytical Procedures: Text and Methodology”. The terms used, and illustrations of the data requirements to demonstrate that a method satisfies the definitions, are provided in Supplementary Chapter III F.

Method origin

3. Proposals for new or revised methods for inclusion are often provided by manufacturers and other users of the Pharmacopoeia either in response to a request from the Secretariat or Laboratory or, for revised methods, when a published method has been found to be unsuitable for any reason. A method may become unsuitable when, for example, a reagent or piece of apparatus is no longer readily available, knowledge of the material has increased, regulatory requirements have altered or a more specific or sensitive test has been developed.

4. Any method that is to be considered for inclusion in a monograph has to be suitable for pharmacopoeial purposes and, wherever possible, be accompanied by appropriate supporting data.

4.1 Guidance on the suitability of any method for inclusion in the Pharmacopoeia may be obtained by reference to the General Notices (in particular, those dealing with official standards, excipients, identification and assays and tests) and Supplementary Chapter I concerning the basis of pharmacopoeial requirements. Each monograph, taken as a whole, should provide a reliable basis for making an independent judgement as to the quality of an article in the interests of the protection of the public.

4.2 A pharmacopoeial monograph applies throughout the shelf-life of a formulated preparation or throughout the period of use of a medicinal or pharmaceutical substance and the monograph when taken as a whole must be stability indicating and must be able to assure the quality of the substance throughout its claimed shelf life. Methods for inclusion in the Pharmacopoeia should therefore have been shown to be stability indicating where appropriate by means of forced degradation studies.

4.3 Other than in exceptional circumstances, methods should not specify the use of apparatus that is not widely available in reasonably equipped laboratories nor should they require extensive additional training of laboratory staff. Reagents and reference materials required for a proposed pharmacopoeial method should be generally available from the common sources of supply in the United Kingdom or a manufacturer should be able to supply sufficient quantity for use as a British Pharmacopoeia Chemical Reference Substance (BPCRS). The method should be described in sufficient detail that a competent analyst is able to repeat it.

4.4 Methods proposed by manufacturers should have been adequately validated in accordance with appropriate guidelines (paragraph 2 refers). Exceptionally, full validation data may not be available in some circumstances. For example, not all contributors to the Pharmacopoeia are able to demonstrate the specificity of a test method for application to a monograph for a formulated preparation since the nature of the excipients may be unknown; in this case a note of the extent of any validation carried out, with its limitations, is helpful.

4.5 It is of particular importance that method proposals include a robust and reliable identity test(s) for the active component in a substance or formulated preparation. Infrared spectrophotometry is preferred.

4.6 It is also of particular importance that any pharmacopoeial method is robust and reproducible. Data that demonstrate the transferability of a method are, therefore, especially helpful.

Method elaboration

5. All proposals for new and revised methods for publication are carefully examined. The nature and extent of the evaluation is determined by a number of factors including the following:

— whether the proposal is for a new monograph or for revision of an existing monograph,

— extent of validation and batch data available,

— how many specifications and/or samples are available for examination,

— complexity of the proposed method.

6. The evaluation of methods is carried out by the Commission’s Expert Advisory Groups and Panels of Experts, the Secretariat and the Laboratory; practical evaluation is included in many cases. If necessary, more extensive practical work is carried out in consultation with the proposer of the method. Such practical work may be necessary, for example, where a proposed method is not directly applicable to other sources of the material or preparation or is shown to be insufficiently robust for pharmacopoeial use.

7. After initial evaluation, the method is drafted in the style of the Pharmacopoeia and those known to have an interest in the material or preparation are invited to comment. If necessary, further modifications may be made to the method and the consultation process repeated before the method is published. A diagrammatic representation of the process of monograph elaboration is provided as Supplementary Chapter III B.

Published methods

8. The user can expect that published methods:

are suitable for the purpose for which they are described in the Pharmacopoeia, have been evaluated and, where necessary, modified as described in the preceding section,

have been shown to be adequately validated, as appropriate to the type of test, and include tests to demonstrate the continuing suitability of the method, where necessary,

are described in sufficient detail that a competent analyst can perform the test using readily available apparatus and reagents and that any necessary reference materials are available, will be reviewed and revised when experience shows this to be necessary.

9. The user cannot, however, assume that a method forming part of a pharmacopoeial monograph will have been applied to all sources of a raw material or to all formulations of a dosage form currently available. The user is responsible for confirming that the method is applicable to the particular material being examined. It is essential that a manufacturer carries out sufficient checks to demonstrate that, for example, impurities arising from a new route of synthesis are controlled by the methods described in the monograph or that the excipients in a formulated preparation do not interfere with any of the tests in a monograph. It should be noted that an article cannot claim to be of pharmacopoeial quality unless it can be shown to comply with all of the tests specified in a monograph (see General Notice on Official Standards).

Feedback

The British Pharmacopoeia Commission welcomes constructive comments from users on the tests of the Pharmacopoeia and it is through such feedback that revision of the tests is initiated. A list of contact points in the Secretariat is to be found in Supplementary Chapter III A.