European Pharmacopoeia - 8th Edition


The European Pharmacopoeia is prepared under the auspices of the Council of Europe in accordance with the terms of the Convention on the Elaboration of a European Pharmacopoeia (European Treaty Series No. 50) (‘the Convention’) as amended by the protocol to the Convention (European Treaty Series No. 134), signed by the governments of 37 member states

(Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Montenegro, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovak Republic, Slovenia, Spain, Sweden, Switzerland, ‘the former Yugoslav Republic of Macedonia’, Turkey, Ukraine and United Kingdom) and by the European Union.

Volumes 1 and 2 of this publication 8.0 constitute the 8th Edition of the European Pharmacopoeia. They will be complemented by non-cumulative supplements that are to be kept for the duration of the 8th Edition. 2 supplements will be published in 2013 and 3 supplements in each of the years 2014 and 2015. A cumulative list of reagents will be published in supplements 8.4 and 8.7. 

For legal reasons, the official publication date of a European Pharmacopoeia edition is 6 months ahead of its application date. However, in practice, an edition may be made available before its official publication date. Note that the early availability of an edition does not modify its official publication and application dates.

If you are using the 8th Edition at any time later than 1 April 2014, make sure that you have all the published supplements and consult the index of the most recent supplement to ensure that you use the latest versions of the monographs and general chapters.

GENERAL MONOGRAPHS

The European Pharmacopoeia contains a number of general monographs covering classes of products. These general monographs give requirements that are applicable to all products in the given class or, in some cases, to any product in the given class for which there is a specific monograph in the Pharmacopoeia (see 1. General Notices,Generalmonographs). Where no restriction on scope of a general monograph is given in a preamble, it isapplicabletoallproducts in the class defined, irrespective of whether there is an individual monograph for the product in the Pharmacopoeia.

Whenever a monograph is used, it is essential to ascertain whether there is a general monograph applicable to the product in question. The general monographs listed below are published in the General Monographs section (unless otherwise stated). This list is updated where necessary and republished in each supplement.


Members of the European Pharmacopoeia Commission: 


Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Montenegro, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, ‘the former Yugoslav Republic of Macedonia’, Turkey, Ukraine, United Kingdom and the European Union.

Observers to the European Pharmacopoeia Commission: Albania, Algeria, Argentina, Armenia, Australia, Brazil, Canada, China, Georgia, Israel, Madagascar, Malaysia, Moldova, Morocco, Republic of Belarus, Republic of Guinea, Republic of Kazakhstan, Republic of Singapore, Russian Federation, Senegal, Syria, Tunisia, United States of America and WHO (World Health Organization).

European Pharmacopoeia - 8th Edition


Work under the P4 procedure has successfully continued during the elaboration of the 7th Edition. Already

59 P4 monographs for chemical substances have been adopted by the European Pharmacopoeia Commission. Under the P4 procedure for chemical substances, a pilot project on bilateral prospective harmonisation of active substance monographs with the USP was initiated and so far has resulted in the adoption of 4 harmonised monographs. As the P4 procedure for chemical substances has been such a success, the European Pharmacopoeia Commission decided in 2009 to initiate a similar process for biological substances. The so-called P4-BIO procedure takes account of the increasing number and importance of biologically-derived active substances and biosimilars on the European market. Two monographs elaborated by the P4-BIO procedure have already been adopted by the European Pharmacopoeia Commission.

The work on controlling impurities, a particular strength of the European Pharmacopoeia, has continued. Monographs are evaluated and approved by the Competent Authorities of member states, and the impurity profiles covered by these monographs reflect the existing, approved routes of synthesis. A revision mechanism is in place for newly-approved products (e.g. new sources, new routes). The analytical methods in monographs are robust and validated and are based on collaborative laboratory testing. The monographs reflect regulatory practice by applying ICH guideline Q3A R to the pharmacopoeial substances. The guideline of the European Medicines Agency (EMA) concerning the control of genotoxic impurities, which came into force in 2007, has also been taken into account and has resulted in a revision of the general monograph on Substances for Pharmaceutical use (2034) and adoption of 3 general methods for genotoxic impurities.

The European Pharmacopoeia Commission is also continuing its efforts to reduce the number of animals needed to perform tests (implementation of the 3Rs principle, i.e. replacing, refining and reducing the use of animals in tests). It has aligned pharmacopoeial texts with VICH Guidelines 41 (test for reversion to virulence) and 44 (developmental safety tests), which came into force in 2008 and 2009, respectively, and with Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes. Furthermore, to ensure consistency with European regulations the European Pharmacopoeia Commission has harmonised all the veterinary vaccine monographs, including monographs on vaccines intended for species that were outside the scope of the VICH Guidelines. As a consequence, the safety tests and the tests for increased virulence performed during development of the vaccines have been harmonised, which will greatly reduce the number of animals used for testing.

The European Pharmacopoeia Commission continuously revises general texts and monographs, re-evaluates

the relevance of animal tests mentioned in European Pharmacopoeia texts and, if deemed appropriate, includes alternative methods. The general monograph on Vaccines for veterinary use (0062) was revised to delete the TABST (target animal batch safety test), except in ‘particular circumstances’ to cover the need to perform, on an ad hoc basis, further testing and safety tests in particular. In the interest of the 3Rs, the European Pharmacopoeia Commission also adopted the deletion of the TABST from the European Pharmacopoeia for all veterinary vaccines. Currently, at the European Pharmacopoeia level, animals are no longer used in the testing of medicinal products derived from human blood and plasma. In many cases, in vivo testing has been replaced by in vitro methods for human and veterinary vaccines. For the remaining in vivo assays, different strategies are being used to promote reduction and refinement of animal use, e.g. serology assays or single dilution assays for diphtheria, tetanus, acellular pertussis and rabies (veterinary/human) vaccines.

A number of important European Pharmacopoeia activities have been initiated over the last few years, such as the establishment of a PAT (Process Analytical Technology) Working Party based on a request from the EMA. PAT tools make it possible to use additional information collected throughout the production process, e.g. use of NIR

(near-infrared spectrophotometry) to determine tablet content. Chapter 2.2.40 Near Infrared Spectrophotometry was revised to introduce PAT-related concepts such as in-line and on-line measurements. This was done in close consultation with the EMA’s CVMP/CHMP Quality Working Party so that it would be aligned with the on-going revision of the EMA’s Note for guidance on NIR. The revised chapter was adopted by the European Pharmacopoeia Commission at its November session in 2012 and it will be complemented by the revised EMA Guideline on the use of near infrared spectroscopy by the pharmaceutical industry and the data requirements for new submissions and variations, which is expected to be finalised in 2013. The General Notices will be updated to take account of real-time release testing, which will be done once the EMA Guideline has been adopted. The alternative, optional Chapter 2.9.47. Demonstration of Uniformity of Dosage Units (UDU) using large sample sizes that could be used to replace conventional UDU testing has also been adopted. The PAT Working Party is now reflecting on the need for new general chapters.

A Heavy Metals Working Party has been created to implement the EMA’s Guideline on metal catalysts and metal reagent residues and the future ICH Q3D guideline. The terms of reference for this working party are to draft a general chapter to implement the guideline, to assess the capability of the current Chapter 2.4.8. Heavy metals to appropriately limit the priority metals mentioned in the guideline and to consider the introduction of instrumental screening methods, whilst also allowing other means of ensuring compliance where possible and justified. Since the ICH guideline has not yet been published, it was decided to introduce a new General Chapter 5.20. Metal catalyst or metal reagent residues and a new General Method 2.4.20. Determination of metal catalyst or metal reagent residues. General Chapter 5.20 reproduces the EMA’s guideline on the specification limits for residues of metal catalysts or metal reagents. It is applicable to all excipients and APIs, except those for veterinary use only, but not to starting materials or herbals. General Method 2.4.20 describes the general approach for the determination of metal catalyst or metal reagent residues in substances for pharmaceutical use. As the chemical composition of the substances and the specification limits for the metal(s) of interest vary considerably, it is not possible to describe all suitable sample preparation and measurement methods. Therefore, any method that fulfils the requirements described in this chapter may be used. Both General Chapter 5.20 and General Method 2.4.20 have been published in European Pharmacopoeia supplement 7.7. A cross-reference is to be introduced into the general monograph on Substances for Pharmaceutical Use (2034) to make General Chapter 5.20 legally-binding.

As a follow-up to the Workshop on the future of monographs in the field of biologicals organised by the EDQM in February 2011, 2 new working parties have been created: (1) the Raw Materials for the Production of Cellular and Gene Transfer Products Working Party, which will elaborate texts on raw materials such as antibodies, basal media (for cell culture), serum/serum replacements, growth factors and cytokines, and (2) the Host Cell Proteins Working Party, which will draft recommendations with regard to the development, validation and use of in-house or commercial kits or test methods

for the detection and quantification of host cell-derived proteins. In addition, the scope of the P4-BIO pilot projecthas been extended in order to elaborate monographs on one monoclonal antibody, one hormone/enzyme and one pegylated protein. The P4-BIO working party has also been asked to elaborate one finished product monograph. The terms of reference of the Cell Therapy Products Working Party have also been extended in order to elaborate a general text dealing with microbiological control of organs and tissues for human use, including preservation and other related media. As a consequence, the Working Party has been renamed the Cell Therapy Products, Tissues and Organs Working Party.

The production section of the monograph Human normal immunoglobulin for intravenous administration (0918) has been revised due to experience with an immunoglobulin preparation that caused an increased rate of thromboembolic complications. In light of concerns for public health associated with these thromboembolic events, the revised monograph will be implemented by the accelerated procedure.

Due to the increasing number of fraudulent activities and cases of adulteration, the European Pharmacopoeia Commission has decided to add a new section, Potential Adulteration, under § 1.4. MONOGRAPHS of the General Notices. The need to include this section in individual monographs will be decided by the European Pharmacopoeia Commission on a case-by-case basis. The objective of this section is to make relevant information available to users of the European Pharmacopoeia to ensure the proper quality of medicinal products (i.e. active substances, excipients, intermediate products, bulk products and finished products). The new version of the General Notices was adopted by the European Pharmacopoeia Commission at its 140th session. In relation to this issue of adulteration, the Council of Europe and

its EDQM have adopted a multi-level, anti-counterfeiting strategy comprising various aspects, such as legislative actions against pharmaceutical crime by means of the Medicrime Convention. This Convention is the first international treaty against counterfeit medical products and similar crimes involving threats to public health. In addition, the EDQM is developing eTACT; an anti-counterfeiting traceability service for medicines. The aim of eTACT is to ensure the traceability of individual packs of medicines using mass serialisation. It would allow each pack of medicine to be traced and verified by the different stakeholders in the legal supply chain. Patients would also be allowed to verify the authenticity of their medication. Governance of the eTACT system would be the responsibility of the EDQM as a public, inter-governmental organisation that is able to ensure the confidentiality of the data handled by the system.

Two additional new working parties have also recently been created: (1) the Finished Product Monographs Working Party, which aims to draft 2 monographs (i.e. on one single-sourceand one multi-source product) allocated to it by the European Pharmacopoeia Commission, while addressing issues related to the elaboration of chemically-defined finished products monographs in order to assess whether such monographs should be elaborated by the European Pharmacopoeia in the future, and (2) the Second Identification Test Working Party, which will prepare a guidance document that defines the criteria for inclusion of a second series of identification tests (solely intended to be carried out in pharmacies) in individual monographs and will review the methods and instrumentation available in pharmacies for this purpose.

Compliance with the EU REACH (Registration, Evaluation, Authorisation and Restriction of Chemical substances) Regulation has posed a significant challenge and this issue has been high on the agenda of the current Presidium.

The European Pharmacopoeia Commission approved the request for the revision of 215 monographs as a consequence of the EU REACH Regulation and already several revised monographs have been adopted.

During the past 3 years I have had the honour, pleasure and privilege to serve the European Pharmacopoeia Commission as its 16th elected Chair. The task has been challenging, but also interesting and rewarding because of the insights it has given me into the various aspects of the development work that goes into the drafting of the quality standards provided by the texts of the Pharmacopoeia. It has also given me an insight into the many other important areas in which the EDQM is involved.

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