SC I Basis of Pharmacopoeial Requirements

Introduction

This chapter provides explanatory text and guidance on the pharmacopoeial approach to a range of subjects.

Separate, lettered sections of this chapter explain the current approach to a particular aspect of pharmacopoeial control and, where appropriate, give an indication of future developments. The British Pharmacopoeia Commission’s policies continue to evolve and these sections will be updated as and when necessary to reflect further developments.

While these texts outline general policies that are adopted in the Pharmacopoeia, each monograph is considered individually. Departures from the general rule are accepted where justified and are accommodated by appropriate statements in the individual monographs.

In providing these texts to users of the Pharmacopoeia it is emphasised that the specifications of the Pharmacopoeia are one facet of the overall control of the quality of medicinal products and their constituents. Those concerned with the manufacture of medicinal substances and those responsible for their incorporation into pharmaceutical dosage forms must also pay due attention to the requirements and recommendations of other competent authorities. Within the European Community the information required for marketing authorization is laid down in the relevant Directives, Notice to Applicants and associated Notes for Guidance available from the Commission of the European Communities as the series ‘The Rules Governing Medicinal Products in the European Community’.

Dialogue with users is an essential element of pharmacopoeial development and the British Pharmacopoeia Commission hopes that this chapter will provide insight into certain features of pharmacopoeial requirements. The Commission places great value on the assistance it receives from manufacturers and others with the necessary knowledge to assist it in its work. It welcomes suggestions for improvement of published texts and constructive comment on any issues of interest and concern to users.

General considerations

1. A proper understanding of the basis on which the requirements of the Pharmacopoeia are established is essential to the correct interpretation of the requirements.

2. The Pharmacopoeia contributes significantly to the overall control of the quality of medicinal products and provides a publicly available statement concerning the quality that a product or a component of a product is expected to meet at any time during its period of use. Pharmacopoeial specifications are used within licensing systems and by manufacturers, suppliers, purchasers and those acting on behalf of consumers of medicinal products.

3. A manufacturer must recognise that a product or material may be challenged at any time during its claimed period of use by the methods of the Pharmacopoeia and that it must then comply with the pharmacopoeial requirements. These requirements allow for acceptable levels of change that may occur during storage and distribution and reject articles showing unacceptable levels of change. Frequently a manufacturer will need to apply more stringent test limits at the time of release of a batch of the product or material in order to ensure compliance. As stated in the General Notices, a manufacturer may assure himself that the requirements of the Pharmacopoeia will be met by means other than routinely performing all of the tests prescribed in the Pharmacopoeia. It is emphasised that the circumstances under which, and the frequency with which, tests of the Pharmacopoeia should be performed by a manufacturer as part of his overall quality assurance are ultimately matters for agreement between the manufacturer and the competent authority.

4. The requirements included in a monograph, other than any instructions given under the side-heading Production, are designed to provide the means by which an independent judgement can be made as to the overall quality of a particular article. A manufacturer in possession of detailed knowledge of the manufacturing process may have no need to carry out certain tests. The example of some impurity tests in monographs for formulated preparations is discussed in more detail in section A of this chapter. The methods described in the Pharmacopoeia must be robust because they are intended to be used by analysts in a wide range of laboratories, sometimes on an infrequent basis. Understandably, a manufacturer may wish to use other methods that may be more suitable for frequent use or automation and is entitled to do so. However in the event of any doubt or dispute as to whether or not a material is of pharmacopoeial quality, as the General Notice on Assays and Tests makes clear, the methods of the Pharmacopoeia alone are authoritative.

5. This view of pharmacopoeial requirements is also significant when considering the size of sample to be taken for test. In an overall programme designed to give assurance of quality of a manufactured product, the statistical validity of any sampling programme must be beyond doubt. The standards of the Pharmacopoeia, on the other hand, are intended to apply to the sample available, perhaps the container of dispensed tablets provided to a patient in accordance with a prescription. The Pharmacopoeia requires that twenty of those tablets should meet the test for Uniformity of weight. A manufacturer establishing a sampling and testing protocol designed to ensure ultimate compliance with the pharmacopoeial requirements will need to operate at a level designed to show with an acceptable degree of confidence that any twenty tablets, taken at random from a given batch, will meet the requirements.

6. Pharmacopoeial methods and limits are set with the intention that they should be used as compliance requirements and not as requirements to guarantee total quality assurance. An article is not of pharmacopoeial quality if any sample of the size stipulated in the monograph taken at any time during storage, distribution and use within the accepted shelf-life fails to meet all of the requirements.

7. Arising from this it may be useful to underline that compliance of a product with pharmacopoeial requirements demands that the product meets all mandatory aspects of the appropriate monograph and that those requirements shall be interpreted in the light of any relevant General Notices. In certain cases individual requirements of particular tests may seem to be incompatible with those of other tests; where this is apparently the case such requirements have been framed intentionally. For example, the requirement for the overall content of active ingredient in a tablet preparation, as determined on a powdered sample of twenty tablets, might be 95.0 to 105.0% of the stated amount. Thus an assay result of 96.0% would indicate compliance. For the Uniformity of content test a further ten tablets might be individually examined, each tablet being required to contain between 85 and 115% of the mean value, with the possibility of a single exception between 75 and 125%. Thus if nine out of ten tablets fall within the range (assuming the mean to be 96.0%) 81.6 and 110.4% and the tenth falls within the range 72.0 to 120.0% then the tablets examined comply with that requirement. For the Dissolution test each tablet examined might be required to yield at least 70% of the labelled claim into solution within 45 minutes. It has been suggested that since a single outlier tablet might contain as little as 72.0% of the labelled claim and yet still fall within the acceptance limits for content, the requirements for dissolution should be relaxed to take this into account. In framing requirements, however, the view is taken that it is neither realistic nor profitable to attempt to compound the results of various tests in this way. Each test in a pharmacopoeial monograph and the acceptance limit is therefore framed as an individual entity with requirements based on values encountered in practice; compliance with the monograph requires compliance with each and every test.

8. The philosophy outlined above has an important bearing on the construction of a monograph for the Pharmacopoeia. To achieve maximum benefit from the examination of a product the recommended approach is that, wherever possible, a variety of different analytical techniques should be employed. The monographs of the British Pharmacopoeia are, therefore, usually constructed to use fundamentally different procedures for assay and for the examination for impurities. For a medicinal substance the general approach has been to employ spectrophotometric or other appropriate techniques for identification, chromatographic techniques for the control of impurities and a precise, albeit non-specific method for assay. It has been held that this approach confers greater confidence in the verification of the identity and quality of the substance and in the detection of unexpected impurities than would be the case in using, for example, a single stability-indicating liquid chromatographic method for all three purposes. The British Pharmacopoeia Commission recognises, however, that as chromatographic methods become more precise it will become increasingly possible to use them for assay purposes thereby combining precision with specificity and economising upon analytical effort and time. For dosage forms this concept has already been adopted and more specific assay methods, such as those employing liquid chromatography, are being employed increasingly.

9. A discussion of the basis of pharmacopoeial requirements would be incomplete without reminding users that any article described by a name at the head of a monograph in the current edition of the Pharmacopoeia, whether or not it is referred to as ‘BP’, must comply with that monograph. The name at the head of a monograph is to be interpreted in accordance with the General Notice on Titles. In particular, a formulated preparation that is labelled with a title that includes the full nonproprietary name of the active ingredient, where this is not included in the title of the monograph, must also comply with the monograph. Thus, for example, a preparation labelled Labetalol Hydrochloride Tablets must comply with the monograph for Labetalol Tablets.