untitled WHO Technical Report Series 957 WHO EXPERT COMMITTEE ON SPECIFICATIONS FOR PHARMACEUTICAL PREPARATIONS Forty fourth report WHO Technical Report Series 957 WHO EXPERT COMMITTEE ON SPECIFICATIO.
WHO WHOTechnical TechnicalReport ReportSeries Series 957 957 WHO WHO EXPERT EXPERT COMMITTEE COMMITTEE ON ON SPECIFICATIONS SPECIFICATIONS FOR FOR PHARMACEUTICAL PHARMACEUTICAL PREPARATIONS PREPARATIONS Forty-fourth Forty-fourthreport report The World Health Organization was established in 1948 as a specialized agency of the United Nations serving as the directing and coordinating authority for international health matters and public health One of WHO’s constitutional functions is to provide objective and reliable information and advice in the field of human health, a responsibility that it fulfils in part through its extensive programme of publications The Organization seeks through its publications to support national health strategies and address the most pressing public health concerns of populations around the world To respond to the needs of Member States at all levels of development, WHO publishes practical manuals, handbooks and training material for specific categories of health workers; internationally applicable guidelines and standards; reviews and analyses of health policies, programmes and research; and state-of-the-art consensus reports that offer technical advice and recommendations for decision-makers These books are closely tied to the Organization’s priority activities, encompassing disease prevention and control, the development of equitable health systems based on primary health care, and health promotion for individuals and communities Progress towards better health for all also demands the global dissemination and exchange of information that draws on the knowledge and experience of all WHO’s Member countries and the collaboration of world leaders in public health and the biomedical sciences To ensure the widest possible availability of authoritative information and guidance on health matters, WHO secures the broad international distribution of its publications and encourages their translation and adaptation By helping to promote and protect health and prevent and control disease throughout the world, WHO’s books contribute to achieving the Organization’s principal objective — the attainment by all people of the highest possible level of health The WHO Technical Report Series makes available the findings of various international groups of experts that provide WHO with the latest scientific and technical advice on a broad range of medical and public health subjects Members of such expert groups serve without remuneration in their personal capacities rather than as representatives of governments or other bodies; their views not necessarily reflect the decisions or the stated policy of WHO An annual subscription to this series, comprising about six such reports, costs CHF/US$ 188.00 (CHF/US$ 143.00 in developing countries) For further information, please contact WHO Press, World Health Organization, 20 avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int; order online at http://www who.int/bookorders) 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 957 WHO EXPERT COMMITTEE ON SPECIFICATIONS FOR PHARMACEUTICAL PREPARATIONS Forty-fourth report Geneva 2007 WHO Library Cataloguing-in-Publication DataPublications of the World Health Organization enjoy copyright protection in accordance with the WHO Library Cataloguing-in-Publication Data: Forty-fourth report of the WHO Expert Committee on specifications for pharmaceutical preparations (WHO technical report series; no 957) Pharmaceutical preparations — standards Technology, Pharmaceuticals — standards Drug industry — legislation Quality control I World Health Organization II Series ISBN 978 92 120957 ISSN 0512-3054 (NLM classification: QV 771) © World Health Organization 2010 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 4857; e-mail: bookorders@who.int) 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; e-mail: permissions@who.int) The designations employed and the presentation of the material in this publication not imply the expression of any opinion whatsoever on the part of the World Health Organization 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 specific 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 distributed 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 ii Contents Introduction General policy 2.1 International collaboration 2.1.1 International organizations, agencies and nongovernmental organizations European Directorate for the Quality of Medicines and HealthCare European Medicines Agency The Global Fund to Fight AIDS, Tuberculosis and Malaria Groupement International de la Répartition Pharmaceutique — European Association of Pharmaceutical Full-line Wholesalers International Federation of Pharmaceutical Manufacturers and Associations International Generic Pharmaceutical Alliance International Pharmaceutical Federation United Nations Children’s Fund 2.1.2 Pharmacopoeial Discussion Group 2.1.3 International Conference on Harmonisation 2.1.4 International Conference of Drug Regulatory Authorities 2.2 Cross-cutting issues in pharmaceuticals — quality assurance issues 2.2.1 Herbal medicines 2.2.2 Biologicals and vaccines 2.2.3 Blood products 2.2.4 Essential medicines 2.2.5 Regulatory support 2.2.6 HIV-related activities 2.3 Counterfeit medicines 3 9 10 11 11 13 14 14 Quality control — specifications and tests 3.1 The International Pharmacopoeia 3.2 Current work plan and future work programme 3.3 Specifications for medicines, including children’s medicines 3.3.1 Medicines for HIV and related conditions 3.3.2 Antimalarial medicines 3.3.3 Antituberculosis medicines 3.3.4 Other medicines 3.4 Revision of texts of The International Pharmacopoeia 3.4.1 Antimalarials: artemisinin derivatives 3.4.2 Antibiotics 3.4.3 Other medicines 3.4.4 Heparin 3.5 Review of published general monographs for dosage forms 3.6 General policy topics and general revision issues 3.7 Radiopharmaceuticals 16 16 19 23 23 23 24 25 26 26 27 28 28 29 30 33 3 4 5 6 8 iii Quality control – international reference materials (International Chemical Reference Substances and International Infrared Reference Spectra) 4.1 Annual report of the WHO Collaborating Centre 4.2 Adoption of new International Chemical Reference Substances 4.3 New institution for the establishment of international reference materials 36 36 36 36 Quality control — national laboratories 5.1 External Quality Assurance Assessment Scheme 5.2 WHO good practices for quality control laboratories 5.3 WHO good practices for pharmaceutical microbiology laboratories 37 37 39 42 Quality assurance — good manufacturing practices 6.1 WHO good manufacturing practices: main principles for pharmaceutical products 6.2 WHO good manufacturing practices for active pharmaceutical ingredients 6.3 WHO good manufacturing practices for pharmaceutical products containing hazardous substances 6.4 WHO good manufacturing practices for sterile pharmaceutical products 6.5 Updates of other WHO good manufacturing practices texts 6.6 Good manufacturing practices for blood establishments 42 Quality assurance — new approaches 7.1 Risk analysis 7.2 WHO guidelines on technology transfer 47 47 48 Quality assurance — distribution and trade of pharmaceuticals 8.1 WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce 8.2 WHO good distribution practices for pharmaceutical products 8.3 Regulatory oversight on pharmaceutical cold chain management 49 Prequalification of priority essential medicines 9.1 Prequalification Programme managed by WHO 9.2 Guidelines on requalification of prequalified dossiers 9.3 Guidelines for the preparation of a contract research organization master file 52 52 57 iv 42 43 44 44 45 45 49 50 51 58 10 Nomenclature, terminology and databases 10.1 Quality assurance terminology 10.2 International nonproprietary names 10.3 Pharmacopoeial references 59 59 61 61 11 Miscellaneous 11.1 WHO Model List of Essential Medicines 11.2 Update on stability 11.3 Diethylene glycol 62 62 62 64 12 Summary and recommendations 65 Annex WHO good practices for pharmaceutical quality control laboratories 81 Annex WHO good manufacturing practices for active pharmaceutical ingredients 130 Annex WHO good manufacturing practices for pharmaceutical products containing hazardous substances 192 Annex WHO good manufacturing practices for sterile pharmaceutical products 209 Annex WHO good distribution practices for pharmaceutical products 235 Annex Guidelines on the requalification of prequalified dossiers 265 Annex Guidelines for the preparation of a contract research organization master file 271 v vi WHO Expert Committee on Specifications for Pharmaceutical Preparations Geneva, 12–16 October 2009 Members Professor Saleh A Bawazir, Head of Drug Sector and Vice-President, Saudi Food and Drug Authority (SFDA), Riyadh, Saudi Arabia Mr Jean-Michel Caudron,1 Braine-le-Château, Belgium Professor Theo G Dekker, Research Institute for Industrial Pharmacy, Potchefstroom, South Africa Ms Nilka M Guerrero Rivas, Aseguramiento de la Calidad, Instituto Especializado de Análisis, Ciudad Universitaria Octavio Méndez Pereira, Panamá, Republic of Panama (Co-Rapporteur) Professor Jos Hoogmartens, Laboratorium voor Farmaceutische Analyse, Leuven, Belgium (Chairperson) Professor Jin Shaohong, Executive Deputy Director, National Institute for the Control of Pharmaceutical and Biological Products, Ministry of Public Health, Beijing, People’s Republic of China Dr John H.McB Miller, Strasbourg, France Dr Justina A Molzon, Associate Director for International Programs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA (Co-Chairperson) Ms Metta Treebamroong,1 Senior Pharmacist, Drug Quality and Safety, Bureau of Drug and Narcotics, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand Mr Eshetu Wondemagegnehu Biwota, Addis Ababa, Ethiopia (Co-Rapporteur) Temporary advisers Professor Ivan Addae-Mensah, Professor of Chemistry, University of Ghana, Legon, Ghana Professor Henning G Kristensen,1 Vedbaek, Denmark Ms Marie-Louise Rabouhans, Chiswick, London, England Dr Jean-Louis Robert,1 Service du Contrôle des Médicaments, Laboratoire National de Santé, Luxembourg Dr Saranjit Singh, Professor and Head, Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Nagar, India Mr Robert Tribe, Holder, ACT, Australia Unable to attend vii Special advisers (prequalification) Mr Gordon J Farquharson,2 Guildford, Surrey, England Dr Simon Mills, Ware, Hertfordshire, England Ms Eija Pelkonen,2 Head of Inspectorate, National Agency for Medicines, Helsinki, Finland Dr Birgit Schmauser, Federal Institute for Drugs and Medical Devices, Bonn, Germany Mr Deryck Smith, Guateng, South Africa Dr Angelika Spreitzhofer,2 AGES PharmMed, Institute for Inspections, Medical Devices and Haemovigilance, Vienna, Austria Representation from United Nations Offices33 United Nations Children's Fund (UNICEF) Dr Peter Svarrer Jakobsen, Quality Assurance Officer, UNICEF Supply Division Copenhagen, Denmark Representation from specialized agencies and related organizations44 Global Fund to Fight AIDS, Tuberculosis and Malaria Ms Joelle Daviaud, Senior QA Technical Officer, Pharmaceutical Management Unit, Geneva, Switzerland and Mr Raghu Kumar Krishna Swamy Representation from intergovernmental organizations55 Council of Europe Dr Andrea Lodi, Deputy Head, Laboratory Department, European Directorate for the Quality of Medicines & HealthCare (EDQM), Strasbourg, France European Medicines Agency (EMA) Dr Piotr Kozarewicz, Scientific Administrator, Quality of Medicines Sector, Human Unit Pre-Authorization, London, England Representation from nongovernmental organizations66 International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) Dr Michael G Beatrice, Vice President, Corporate Regulatory & Quality Science, Abbott, Abbott Park, IL, USA Unable to attend Unable to attend: United Nations Development Programme (UNDP), New York, NY, USA Unable to attend: International Atomic Energy Agency (IAEA), Vienna, Austria; United Nations Industrial Development Organization (UNIDO), Vienna, Austria; World Intellectual Property Organization (WIPO), Geneva, Switzerland; World Bank, Washington, DC, USA; World Customs Organization (WCO), Brussels, Belgium; World Trade Organization (WTO), Geneva, Switzerland Unable to attend: European Commission (EC) Brussels, Belgium Unable to attend: Commonwealth Pharmaceutical Association (CPA), London, England; European Chemical Industry Council (CEFIC)/APIC, Brussels, Belgium; International Society for Pharmaceutical Engineering (ISPE), Tampa, FL, USA viii References 264 WHO guide to good storage practices for pharmaceuticals In: WHO Expert Committee on Specifications for Pharmaceutical Preparations Thirty-seventh report Geneva, World Health Organization, 2003, Annex (WHO Technical Report Series, No 908) WHO good pharmacy practice in community and hospital pharmacy settings In: WHO Expert Committee on Specifications for Pharmaceutical Preparations Thirty-fifth report Geneva, World Health Organization, 1999, Annex (WHO Technical Report Series, No 885) WHO good manufacturing practices In: Quality assurance of pharmaceuticals A compendium of guidelines and related materials Good manufacturing practices and inspection, Vol 2, 2nd updated ed Geneva, World Health Organization, 2007 Guidelines for implementation of the WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce In: WHO Expert Committee on Specifications for Pharmaceutical Preparations Thirty-fourth report Geneva, World Health Organization, 1996, Annex 10 (WHO Technical Report Series, No 863) WHO pharmaceutical starting materials certification scheme (SMACS) In: WHO Expert Committee on Specifications for Pharmaceutical Preparations Thirty-eighth report Geneva, World Health Organization, 2004, Annex (Technical Report Series, No 917) Guidelines on import procedures for pharmaceutical products In: WHO Expert Committee on Specifications for Pharmaceutical Preparations Thirtyfourth report Geneva, World Health Organization, 1996, Annex 12 (WHO Technical Report Series, No 863) Good trade and distribution practices for pharmaceutical starting materials In: WHO Expert Committee on Specifications for Pharmaceutical Preparations Thirty-eighth report Geneva, World Health Organization, 2004, Annex (WHO Technical Report Series, No 917) Stability testing of active pharmaceutical ingredients and finished pharmaceutical products In: WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-third report Geneva, World Health Organization, 2009, Annex (WHO Technical Report Series, No 953) (http://www.who.int/medicines/areas/quality_safety/quality_assurance/ regulatory_standards/en/index.html) © World Health Organization WHO Technical Report Series, No 957, 2010 Annex Guidelines on the requalification of prequalified dossiers Introduction Requalification of prequalified dossiers Appendix Summary of key product information Appendix Variations to the product Introduction In accordance with the provisions set out in section 12 (Maintenance of prequalification status) of the Procedure for prequalification of pharmaceutical products1, holders of WHO-prequalified products should submit a quality review years from the date of prequalification of the product, or when requested to so by WHO Prequalification (whichever date is earlier) Section 12 of the above-mentioned guidelines states that: WHO will furthermore arrange for the products and manufacturing sites included in the list to be re-evaluated at regular intervals If, as a result of this re-evaluation, it is found that a product and/or specified manufacturing site no longer complies with the WHO-recommended standards, such products and manufacturing sites will be removed from the list Failure of a manufacturer or applicant to participate in the re-evaluation procedure will also lead to removal from the list Re-evaluation, including re-inspections of manufacturing sites and contract research organizations (CROs), will be done at regular intervals, based on risk assessment, but at least once every years Re-evaluation, including re-inspections, shall also be performed: Procedure for prequalification of pharmaceutical products In: WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-third report Geneva, World Health Organization, 2009, Annex (WHO Technical Report Series, No 953) (http://www.who.int/ medicines/publications/pharmprep/pdf_trs953.pdf#page=145) 265 • if any fraud or omissions by the applicant, manufacturer(s) of a finished pharmaceutical product (FPP) or active pharmaceutical ingredient (API), or CROs in the initial assessment procedure or during the follow-up activities, becomes evident; and • if WHO or any United Nations agency considers that a batch or batches of supplied prequalified pharmaceutical products are not in compliance with the specifications which were found to be applicable upon prequalification Requalification will be applicable to multisource FPPs (generics) where the full dossiers have been submitted, assessed and prequalified by WHO Renewal of marketing authorization for products that have been listed by WHO based on approval by a stringent regulatory agency2 (SRA) remains the responsibility of the relevant SRA Requalification of prequalified dossiers The objective of this quality review submission is to enable WHO to requalify the product based on an assessment of the data and information submitted by the holder of a prequalified product, which includes verification of the acceptability of the product and its conformity to current norms and standards, and assessment of consistency of the quality of the prequalified FPPs, and its manufacturing process(es) over the identified period The holder of a prequalified product should submit the following documents electronically (in pdf format and in also in WinWord where indicated): • A covering letter, which should contain a clear statement by the responsible person submitting the quality review, indicating that the information submitted is true and correct • Summary of key product information (as per Appendix 1) • Variations to the product (as per Appendix 2) • A pharmaceutical quality information form (PQIF)3, completed in WinWord format It should reflect the requirements of current prequalification guidelines and should also take into account technical and Stringent regulatory authority (SRA): a regulatory authority which is: a member of the International Conference on Harmonisation (ICH) (as specified on www.ich.org); or an ICH observer, being the European Free Trade Association (EFTA), as represented by Swiss Medic, Health Canada and World Health Organization (WHO) (as may be updated from time to time); or a regulatory authority associated with an ICH member through a legally-binding, mutual recognition agreement including Australia, Iceland, Liechtenstein and Norway (as may be updated from time to time) Presentation of pharmaceutical quality information In: Guidance for submission of documentation for prequalification of multi-source (generic) finished pharmaceutical products (FPPs) used in the treatment of HIV/AIDS, malaria and tuberculosis Annex (http://apps.who.int/prequal/info_ applicants/Guidelines/GuideGenericSubmitDocFPPs_08_2005_ANNEX8.doc) 266 scientific progress The API and FPP specifications should be provided in tabulated format, comparing the specifications at prequalification and at the time of the requalification submission • Copies of the current API and FPP specifications, duly signed and dated, including the test methods The specifications should indicate the reference number, version number, effective date and change history if any A product quality review may be submitted as supportive documentation It may also be requested by WHO 267 Appendix Summary of key product information This section compares key information on the FPP at the time of prequalification and at the time of the submission for requalification Table A1.1 should be completed by the holder of the prequalified product Include remarks as a footnote to Table A1.1, where deemed necessary, to clarify the information provided Table A1.1 Summary of key product information Item Product number (e.g HA001) INN, strength and pharmaceutical form Applicant (name, physical address and contact numbers) Manufacturing site(s) of FPP, with physical address (including unit and block numbers) and contact numbers (list separately if different steps are performed by different sites, e.g packaging, quality control) Batch size(s) of FPP Product description (visual appearance) Primary and secondary packaging material(s) and pack size(s) Storage conditions of FPP Shelf-life of FPP FPP specification(s) reference number and/or versionb Manufacturer(s) of API(s), with physical address (including unit and block numbers) and contact numbers (list each API separately) Number/version of each APIMF associated with the FPP Storage conditions of API Retest period of API(s) API specification(s) reference number and/or version (for each API)b All commitments and their outcomes 268 Prequalified dossier Current dataa INN, international nonproprietary name; FPP, finished pharmaceutical product; API, active pharmaceutical ingredient; APIMF, active pharmaceutical ingredient master file a If there has been no update of the dossier then indicate “N/A” (not applicable) b According to the latest editions of The International Pharmacopoeia (Ph.Int.), the European Pharmacopoeia (Ph.Eur), the British Pharmacopoeia (BP) and/or the United States Pharmacopeia (USP) Where in-house specifications have been approved and there is now a monograph in any of the internationally-recognized pharmacopoeias (Ph.Int., Ph.Eur, BP, or USP), the specifications should be updated to comply with the new monograph or demonstrated to be at least equivalent In the case that no compendial monograph exists, the applicant should ensure that the approved inhouse specifications are updated, through the variation process, to reflect the requirements of current prequalification guidelines and to take into account technical and scientific progress (e.g current ICH guidelines, general chapters of the Ph.Int.) Each new version of the documents should allow traceability to the prequalified dossier and approved variations 269 Appendix Variations to the product The holder of the prequalified product should submit a review, in tabular format, of any minor and/or major changes (including those pending) to the initially prequalified product or to the terms of the initially prequalified dossier Table A2.1 should be completed by the holder of the prequalified product Table A2.1 Information on variations to the prequalified product Reference no Date of submission Date of approval/ rejection and reference number of the letter Date of implementation Major changes Description of the change, e.g change in the primary packaging site of a sterile product Minor changes Description of the change according to the PQ variation guide Add as many rows as necessary Note Requests for variations should have been submitted in accordance with WHO’s Guidance on variations to a prequalified product dossier4.6 WHO Guidance on variations to a prequalified product dossier In: WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-first report Geneva, World Health Organization, 2007, Annex (WHO Technical Report Series, No 943) (http://apps.who.int/ prequal/info_general/documents/TRS943/TRS943.pdf#page=121) 270 © World Health Organization WHO Technical Report Series, No 957, 2010 Annex Guidelines for the preparation of a contract research organization master file Background General information Quality management system of the contract research organization Personnel Ethics committee Computer systems Equipment and instruments Documentation Safety monitoring Investigational medicinal products and comparator products 10 Pathology 11 Bioanalytical laboratory 12 Biostatistics 13 Study volunteers 14 Other information 271 Background A contract research organization master file (CROMF) is a document prepared by the contract research organization (CRO) containing specific and factual information about the CRO and the conduct of clinical studies as well as the analyses of samples and related operations (including clinical trials, clinical data management, pharmacokinetics and statistical analysis and regulatory affairs) carried out at the named site If only some of the operations referred to below are carried out at the site, the master file (MF) needs to be presented only for those operations In a case where a CRO is responsible for activities pertaining only to bioanalytical procedures, then only sections in the CROMF relating to these should be described Other sections may be marked as “not applicable” Where a CRO performs various activities, separate sections could be prepared for the different units, e.g clinical pharmacology unit (CPU) and bioanalytical laboratory (BAL) A CROMF provides information on the policies, approach and general activities of a CRO It is not trial-specific as trial-specific data are submitted in a product dossier It serves as general information to regulators and can be used during preparation for inspections by regulatory inspectors in addition to the trial-specific data and information submitted for assessment It also provides an overview of the organization’s approach to good clinical practices (GCP), good laboratory practices (GLP) and other guidelines pertaining to its activities A CROMF should be submitted to the national medicines regulatory authority (NMRA) where such a document is requested It should be succinct and as far as possible not exceed 25 A4 pages (where appropriate, supportive documentation may be appended) An updated CROMF should be submitted when requested by the NMRA, or if significant changes have been implemented by the CRO 272 General information 1.1 Name and exact address of the CRO, including telephone, fax, 24-hour telephone numbers and e-mail address 1.2 Short description of the CRO (including size, location, number of beds, layout and plan, areas for handling samples and waste) 1.3 Activities as licensed/authorized by the national authority 1.4 Inspections and approvals 1.4.1 Inspections/approvals/accreditations by any regulatory agency 1.4.2 Audits of subcontractors 1.5 Type of studies (and indications, where appropriate) performed on site (a list of projects conducted at this site may be provided) 1.6 Provisions for insurance 1.6.1 Number of employees engaged in studies, quality, storage and distribution 1.7 Contract services employed 1.7.1 Use of outside scientific, analytical or other technical assistance in relation to studies and analysis (e.g clinical laboratory, bioanalytical laboratory, X-ray facilities and caterers) 1.7.2 Services outsourced, e.g contracts with tertiary care hospital for handling of medical emergencies, ambulance facility, nutrition, biomedical waste, chemical waste, caterers, pest control and pathology laboratory Quality management system of the contract research organization (Short description including, e.g responsibilities of the quality assurance unit A list of quality system documents can be included) 2.1 Organization chart including the arrangements for quality assurance 2.2 Internal audits and self inspection 2.3 Corrective and preventive action plans (CAPA) Personnel (A brief description can be presented in tabular format) 3.1 Qualifications, experience and responsibilities of key personnel as applicable 3.1.1 project manager 3.1.2 principal investigator 3.1.3 analytical investigator 3.1.4 biostatistician 3.1.5 clinical research associates 3.1.6 data manager 273 3.1.7 monitor 3.1.8 the study director(s) 3.1.9 person responsible for quality assurance 3.2 Training of personnel: 3.2.1 training policy and procedure (brief description) 3.2.2 training records Ethics committee 4.1 Constitution and relation to CRO 4.2 Procedures including review and approval of protocols Computer systems (Short description) 5.1 Hardware 5.2 Software (and version number) used (e.g in the bioanalytical laboratory, in pharmacokinetic and statistical analysis) and change control procedure 5.3 Data management systems (include a procedural flow chart and a brief description of query generation and resolution) 5.4 Security procedures 274 5.5 Electronic exchange of confidential information 5.6 Brief description of validation programme 5.7 Back-up and storage of electronic data Equipment and instruments 6.1 Brief description of major equipment and instruments (a list of equipment is not required) 6.2 Qualification, maintenance and calibration programme, including the temperature recording systems Documentation 7.1 Briefly describe document management systems 7.2 Project work flow including quality assurance and control process 7.3 Preparation of protocols 7.4 Preparation of informed consent forms and subject information forms 7.5 Preparation of report forms 7.6 Preparation of final report Safety monitoring (Brief description) Adverse drug reaction reporting procedure Provisions made for emergencies, including protocols and equipment available Investigational medicinal products and comparator products (Brief description) 10 9.1 Acquisition, storage, handling, sampling and disposal 9.2 Pharmacy and dispensing Pathology 10.1 Biological sample collection and storage 10.2 Handling and analysis of biological samples 11 Bioanalytical laboratory (Brief description) 11.1 Method development and validation 11.2 Reference standard materials used for preparation of calibration standards and quality control samples 11.3 Biological matrix storage, and handling of matrix samples 11.4 Analysis of unknown samples 275 11.5 Preparation and labelling of reagents 11.6 Storage of samples 11.7 Stability procedures 11.8 Waste management 12 Biostatistics 12.1 Data processing and analysis 12.2 Data management 13 Study volunteers 13.1 Procedure for recruitment 13.2 Collecting information on volunteers (e.g databank), while confidentiality is maintained 13.3 Procedure for obtaining informed consent 14 Other information 14.1 Power supply system — uninterrupted power supply and generator availability and capacity 14.2 Brief description of any other activities performed on site by the CRO 14.3 Any other information which the CRO may feel it appropriate to add 276 SELECTED WHO PUBLICATIONS OF RELATED INTEREST The International Pharmacopoeia, fourth edition Volume 1: general notices; monographs for pharmaceutical substances (A–O) Volume 2: monographs for pharmaceutical substances (P–Z); monographs for dosage forms and radiopharmaceutical preparations; methods of analysis; reagents 2006 (1500 pages), also available in CD-ROM format and online First supplement: general notices; monographs for pharmaceutical substances; monographs for dosage forms; general and specific monographs; methods of analysis; International Chemical Reference Substances; International Infrared Reference Spectra; reagents, test solutions and volumetric solutions 2008 (309 pages), also available in CD-ROM format and online Basic tests for drugs: pharmaceutical substances, medicinal plant materials and dosage forms 1998 (94 pages) Basic tests for pharmaceutical dosage forms 1991 (134 pages) Quality Assurance of Pharmaceuticals: a compendium of guidelines and related materials Volume 1: 1997 (244 pages) Volume 2: good manufacturing practices and inspection Second updated edition, 2007 (409 pages) Also available on: WHO training modules on GMP A resource and study pack for trainers, 2007 (CD-ROM) WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-third report WHO Technical Report Series, No 953, 2009 (161 pages) International nonproprietary names (INN) for pharmaceutical substances Cumulative list no 13 2010 (available in CD-ROM format only) The selection and use of essential medicines Report of the WHO Expert Committee (including the 16th WHO Model List of Essential Medicines and the 2nd WHO Model List for Children) WHO Technical Report Series, No 958, 2010 (174 pages) WHO Expert Committee on Biological Standardization Fifty-sixth report WHO Technical Report Series, No 941, 2007 (340 pages) Further information on these and other WHO publications can be obtained from WHO Press, World Health Organization, 1211 Geneva 27, Switzerland (tel +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int; order online: http://www.who.int/bookorders) The TheExpert ExpertCommittee Committeeon onSpecifi Specifi cations cationsfor forPharmaceutical Pharmaceutical Preparations Preparationsworks workstowards towardsclear, clear,independent independentand andpractical practical standards standardsand andguidelines guidelinesfor forthe thequality qualityassurance assuranceofofmedicines medicines Standards Standardsare aredeveloped developedby bythe theCommittee Committeethrough throughworldwide worldwide consultation consultationand andan aninternational internationalconsensus-building consensus-buildingprocess process The Thefollowing followingnew newguidelines guidelineswere 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