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Henning Gjelstrup Kristensen
Prof DSc Dr hc
Former chair of the European Pharmacopoeia Commission
Department of Pharmaceutics
The Danish University of Pharmaceutical Sciences
The 5th edition of the European Pharmacopoeia will become effective by 1 January 2005. The European Pharmacopoeia was inaugurated in 1964 through the Convention on the Elaboration of a European Pharmacopoeia. The eight founder countries realised that manufacturing and quality control standards for medicinal products had to be harmonised for reasons of public health and to facilitate the free movement of medicines. Today, the Convention has been signed by 34 European countries, including 24 of the Member States of the European Union (EU) and the EU Commission. Figure 1 shows the European members and observers. In addition, Canada, Morocco, Algeria, Tunisia, Senegal, Syria, China, Malaysia and Australia are observers. The Convention requires that the signatory parties implement the Pharmacopoeia standards unchanged within their territories. Accordingly, the European Directives 2001/82/EC and 2001/83/EC on medicines for human and veterinary use make the standards of the Pharmacopoeia mandatory in the preparation of dossiers for marketing authorisation of medicines.
During the past 40 years, the priority of the European Pharmacopoeia Commission has been to harmonise national standards and elaborate new standards to achieve optimal coverage of marketed products. Precedence has been given to standards for raw materials and general methods for evaluation of the quality of raw materials and finished products. The coverage of active ingredients used in two or more member countries is now almost complete, apart from one manufacturer’s substances that are still being patent-protected; the coverage of excipients is less complete.
Two years ago, the European Pharmacopoeia Commission decided to implement, as far as possible, the principles and terminology of the ICH Q3A guideline Impurities in new drug substances in all monographs on active substances, novel as well as already published. The background for this decision is partly the need to adapt Pharmacopoeia standards to current regulatory requirements, and partly the impact of globalisation, which has meant significant imports of active ingredients from countries outside of Europe. Market surveillance by the authorities requires that Pharmacopoeia standards reflect the quality of substances available on the market and, therefore, authorised by regulatory bodies.
The policy decision of the European Pharmacopoeia Commission has many implications. Published monographs must present lists of specified impurities and other detectable impurities that are controlled by the concerned monograph. The related substances tests should limit the contents of specified impurities in accordance with the contents being qualified by the regulatory bodies. Moreover, it means that users of the monograph must be provided with the necessary means to identify impurities present in a particular sample. It follows that those Pharmacopoeia specifications for impurities cannot be established without close collaboration with both manufacturers and regulators, to make sure that the specifications are in agreement with decisions by regulators on marketing authorisation. The current monographs will be updated to the new policy in the next few years, so that policy can be implemented in the 6th edition. Information on columns and reagents used in drafting monographs and type chromatograms are made available on the European Directorate for the Quality of Medicines (EDQM) website.(1) The related substances test in Pharmacopoeia monographs is a limit test based on comparison of peak areas. In the future, hopefully with the 6th edition, this test will progressively be changed to utilise a quantitative acceptance criterion, in order to be in line with licensing practice and international collaborations. Some of the current monographs already satisfy this approach. The first result of the policy decision is the new chapter (5.10) of the 5th edition on the control of impurities in substances for pharmaceutical use. In this chapter, users of the Pharmacopoeia will find guidance on the use and interpretation of the related substances tests in published monographs. Furthermore, users will find instructions on how to proceed when a new impurity occurs in a substance and how to proceed when there is no published monograph. Specific monographs on pharmaceutical substances must be read in conjunction with the general monograph Substances for pharmaceutical use. Specific monographs prescribe acceptance criteria, whereas the general monograph deals with the need for qualification, identification and reporting of any organic impurity. The thresholds for reporting, identification and qualification obtained in the general monograph are identical to those given in the ICH Q3A guideline. They apply to all related substances, even in cases where the (old) monograph does not contain a related substances test. The provisions of the related substances section do not apply to excipients. Also excluded are, for example, biological and biotechnological products, peptides, fermentation products and herbal products, although the general concepts, but not the threshold values, are equally valid for these classes.
The introduction of functionality-related characteristics in monographs on excipients is another new feature of monographs in the European Pharmacopoeia. Information on physical and physicochemical properties of excipient materials that are important to their functionality in pharmaceutical formulations will be included. In the 5th edition, a few monographs contain such a section, which provides useful information on important properties linked to the use of the concerned excipient. For example, the current monograph on magnesium stearate states that the specific surface area is relevant for its uses as a lubricant in solid dosage forms. Accordingly, the section presents a test based on the general method for determination of the specific surface area and a procedure for obtaining the measure. The section on functionality-related tests is non-mandatory. It is meant to provide suppliers and users of excipients with a common language based on standardised methods for determining the characteristics. Limits have to be agreed among suppliers and users, and may be labelled. Moreover, registration authorities need data generated by methods that have been independently assessed. Sections on functionality-related characteristics are now being developed for a range of excipients brought on the market in different physical grades. The Pharmacopoeia Commission has initiated work on the development of general methods for characterisation of physical properties. Such methods are also subject to international harmonisation among the European, Japanese and US Pharmacopoeias (for example, methods for powder characterisation such as particle size, thermal properties, crystallinity).
Manufacture in hospital pharmacies
During the manufacture of medicinal products in a hospital pharmacy, it must be ensured that raw materials meet the European Pharmacopoeia requirements for identity, purity and strength. The provisions of the general monograph on substances for pharmaceutical use, in particular regarding the threshold values for impurities, have to be applied when assessing the quality of any active ingredient. It is the responsibility of the pharmacist to check that the monograph provides adequate control of impurities for a substance from a given source. The new chapter may be most helpful in the interpretation of the monograph. The procedure for certification of suitability of the monograph can in many cases answer questions. Information on certificates granted can be found on the EDQM website(1) or by consulting the lists regularly published in Pharmeuropa.(2) European Pharmacopoeia monographs on raw materials are elaborated only for materials used in products licensed in the member countries, in practice in at least two countries. It is so because specification of impurities has to be in accordance with regulators decisions on the qualification of impurities, or has to be based on “qualification by use”. Extemporaneous preparations containing nonmonographed substances leave a problem for the hospital pharmacy with regard to the acceptable quality of the raw material. The pharmacist has to consult current European and ICH guidelines on raw materials specification and “extrapolate” the current specifications.