WHO Technical Report Series 937 SPECIFICATIONS This report presents the recommendations of an international WHO EXPERT COMMITTEE group of experts convened by the World Health Organization to consider matters concerning the quality assurance of ON SPECIFICATIONS FOR pharmaceuticals and specifi cations for drug substances and dosage forms. PHARMACEUTICAL PREPARATIONS FOR The report is complemented by a number of annexes. These include: a list of available International Chemical Reference PHARMACEUTICAL Substances and International Infrared Spectra; supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms; updated supplementary guidelines on good manufacturing practices for the manufacture of herbal medicines; supplementary guidelines on Fortieth Report good manufacturing practices for validation; good distribution practices for pharmaceutical products; a model quality assurance PREPARATIONS system for procurement agencies (recommendations for quality assurance systems focusing on prequalifi cation of products and manufacturers, purchasing, storage and distribution of pharmaceutical products); multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability; a proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral WHO dosage forms; and additional guidance for organizations Technical performing in vivo bioequivalence studies. Report ISBN 92-4-120937-2 Series — 937 Geneva Couverture_ARP.indd 1 8.5.2006 12:10:14 The World Health Organization was established in 1948 as a specialized agency of the United Nations serving as the directing and coordinating authority SELECTED WHO PUBLICATIONS OF RELATED INTEREST for international health matters and public health. One of WHO’s constitutional functions is to provide objective and reliable information and advice in the fi eld of human health, a responsibility that it fulfi ls in part through its extensive The International Pharmacopoeia, third edition. programme of publications. Volume 1: general methods of analysis. 1979 (223 pages) The Organization seeks through its publications to support national health Volume 2: quality specifi cations. 1981 (342 pages) strategies and address the most pressing public health concerns of populations Volume 3: quality specifi cations. 1988 (407 pages) around the world. To respond to the needs of Member States at all levels of Volume 4: tests, methods, and general requirements: quality specifi cations for development, WHO publishes practical manuals, handbooks and training mate- pharmaceutical substances, excipients and dosage forms. 1994 (358 pages) rial for specifi c categories of health workers; internationally applicable guide- Volume 5: tests and general requirements for dosage forms. Quality specifi cations lines and standards; reviews and analyses of health policies, programmes and for pharmaceutical substances and dosage forms. 2003 (371 pages) research; and state-of-the-art consensus reports that offer technical advice and recommendations for decision-makers. These books are closely tied to the Basic tests for drugs: pharmaceutical substances, Organization’s priority activities, encompassing disease prevention and control, medicinal plant materials and dosage forms. the development of equitable health systems based on primary health care, and 1998 (94 pages) health promotion for individuals and communities. Progress towards better health for all also demands the global dissemination and exchange of informa- tion that draws on the knowledge and experience of all WHO’s Member coun- Basic tests for pharmaceutical dosage forms. tries and the collaboration of world leaders in public health and the biomedical 1991 (134 pages) sciences. Quality Assurance of Pharmaceuticals: a compendium To ensure the widest possible availability of authoritative information and guid- ance on health matters, WHO secures the broad international distribution of its of guidelines and related materials. publications and encourages their translation and adaptation. By helping to Volume 1: 1997 (244 pages) promote and protect health and prevent and control disease throughout the Volume 2: good manufacturing practices and inspection. 2004 (236 pages) world, WHO’s books contribute to achieving the Organization’s principal objec- tive — the attainment by all people of the highest possible level of health. WHO Expert Committee on Specifi cations for Pharmaceutical Preparations. Thirty-ninth report. WHO Technical Report Series, No. 929, 2004 (140 pages) The WHO Technical Report Series makes available the fi ndings of various International nonproprietary names (INN) for pharmaceutical substances. international groups of experts that provide WHO with the latest scientifi c and Cumulative list no. 11. technical advice on a broad range of medical and public health subjects. 2004 (available in CD-ROM format only) Members of such expert groups serve without remuneration in their personal capacities rather than as representatives of governments or other bodies; their The use of essential medicines views do not necessarily refl ect the decisions or the stated policy of WHO. Report of the WHO Expert Committee (including the 13th Model List of Essential Medicines). An annual subscription to this series, comprising about six such reports, costs WHO Technical Report Series, No. 920, 2004 (133 pages) Sw. fr. 168.– or US$ 151.– (Sw. fr. 128.40 or US$ 115.– in developing countries). For further information, please contact WHO Press, World Health Organization, WHO Expert Committee on Biological Standardization. 20 avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 Fifty-fourth report. 791 4857; email: [email protected]; order online: http://www.who.int/bookorders). WHO Technical Report Series, No. 927, 2005 (160 pages) Further information on these or other WHO publications can be obtained from WHO Press, World Health Organization, 1211 Geneva 27, Switzerland Couverture_ARP.indd 2 8.5.2006 12:10:16 This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the World Health Organization WHO Technical Report Series 937 WHO EXPERT COMMITTEE ON SPECIFICATIONS FOR PHARMACEUTICAL PREPARATIONS Fortieth Report Geneva 2006 WHO Library Cataloguing-in-Publication DataPublications of the World Health Organization enjoy copyright pro- tection in accordance with the TSR2006.indd i 4.5.2006 15:16:52 © World Health Organization 2006 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4587; email: [email protected]). Requests for permission to reproduce or translate WHO publications — whether for sale or for noncommercial distribution — should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; email: [email protected]). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organiza- tion concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specifi c companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distrib- uted without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This publication contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the World Health Organization. Typeset in Switzerland Printed in Switzerland TSR2006.indd ii 4.5.2006 15:16:53 Contents WHO Expert Committee on Specifi cations for Pharmaceutical Preparations vii 1. Introduction 1 2. General Policy 2 2.1 Cross-cutting pharmaceuticals — quality assurance issues 2 2.1.1 Quality assurance 2 2.1.2 Policy, Access and Rational Use 2 2.1.3 Malaria 2 2.1.4 Biologicals/Vaccines 2 2.1.5 Production of oral rehydration salts 3 2.1.6 Other clusters and departments 3 2.1.7 International collaboration 4 2.1.8 Follow-up report to the Expert Committee 5 2.2 Pharmacopoeial Discussion Group 5 2.3 International Conference on Harmonisation 5 2.4 International Conference of Drug Regulatory Authorities 5 2.5 Counterfeit drugs 5 3. Quality control — specifi cations and tests 6 3.1 The International Pharmacopoeia (Fourth Edition) 6 3.1.1 Dissolution test requirements 6 3.2 Pharmacopoeial monographs on antiretrovirals 6 3.3 Quality specifi cations for antimalarials 7 3.4 Quality specifi cations for antituberculosis drugs 7 3.5 Specifi cations for other