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SECONDEDITIONSpecial Programme for Research & Trainingin Tropical Diseases (TDR) sponsored byUNICEF/UNDP/World Bank/WHOHANDBOOKGOOD LABORATORYPRACTICE (GLP)Quality practicesfor regulated non-clinicalresearch and development

WHO Library Cataloguing-in-Publication DataHandbook: good laboratory practice (GLP): quality practices for regulated non-clinical research and development 2nd ed.1.Laboratories - organization and administration. 2.Laboratories - handbooks. 3.Laboratories techniques and procedures.4.Manuals. I.UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases.ISBN 978 92 4 154755 0(NLM classification: QY 25)Copyright World Health Organization on behalf of the Special Programme for Research andTraining in Tropical Diseases 2009All rights reserved.The use of content from this health information product for all non-commercial education, training and information purposes is encouraged, including translation, quotation and reproduction, in any medium, but the content must not be changedand full acknowledgement of the source must be clearly stated. A copy of any resulting product with such content should besent to TDR, World Health Organization, Avenue Appia, 1211 Geneva 27, Switzerland. TDR is a World Health Organization(WHO) executed UNICEF/UNDP/World Bank/World Health Organization Special Programme for Research and Training inTropical Diseases.The use of any information or content whatsoever from it for publicity or advertising, or for any commercial or income-generating purpose, is strictly prohibited. No elements of this information product, in part or in whole, may be used to promoteany specific individual, entity or product, in any manner whatsoever.The designations employed and the presentation of material in this health information product, including maps and otherillustrative materials, do not imply the expression of any opinion whatsoever on the part of WHO, including TDR, the authors or any parties cooperating in the production, concerning the legal status of any country, territory, city or area, or of itsauthorities, or concerning the delineation of frontiers and borders.Mention or depiction of any specific product or commercial enterprise does not imply endorsement or recommendation byWHO, including TDR, the authors or any parties cooperating in the production, in preference to others of a similar naturenot mentioned or depicted.The views expressed in this health information product are those of the authors and do not necessarily reflect those of WHO,including TDR. WHO, including TDR, and the authors of this health information product make no warranties or representations regarding the content, presentation, appearance, completeness or accuracy in any medium and shall not be held liablefor any damages whatsoever as a result of its use or application. WHO, including TDR, reserves the right to make updatesand changes without notice and accepts no liability for any errors or omissions in this regard. Any alteration to the originalcontent brought about by display or access through different media is not the responsibility of WHO, including TDR, or theauthors. WHO, including TDR, and the authors accept no responsibility whatsoever for any inaccurate advice or informationthat is provided by sources reached via linkages or references to this health information product.Printed in SwitzerlandDesign: Lisa SchwarbLayout: OnProd, Lausanne

HANDBOOKGOOD LABORATORY PRACTICE(GLP)Quality practices for regulated non-clinicalresearch and development

FOREWORDIn order to assist countries in conducting non-clinical research and drug development,TDR developed a Good Laboratory Practices (GLP) series in 2001, comprising a GLP Handbookas well as GLP Training manuals for trainers and trainees.The demand for this series was so substantial that it became one of the most frequent “hits”on the TDR website, generating interest and demand for a second edition. This Second-editionGLP series is presented here in a revised and updated format. It supports continued technology transfer and capacity-building in disease endemic countries (DECs) in line with theaims of the recent World Health Assembly Resolution (WHA 61.21) on a Global strategy andplan of action on public health, innovation and intellectual property (www.who.int/phi).This Second-edition GLP Handbook contains all of the required support material forimplementing GLP in a laboratory. The handbook comprises four parts, all updated,including: 1) explanation of the fundamentals of GLP; 2) support for GLP training; 3) methodology for GLP implementation in DEC research institutions; 4) GLP principles and guidance produced by the Organisation of Economic Co-operation and Development (OECD),and reproduced here with OECD permission.Since publication of the initial GLP edition, TDR-fostered GLP training efforts throughoutthe world, and particularly in Asia, Latin America and Africa, have led to the formation ofa network of GLP trainers. These trainers, acting as testers and critics, had a significantimpact on the revision and expansion of this Second-edition GLP series, and particularly inthe creation of a section on ‘stepwise’ implementation of GLP, identifying clear milestonesfor the process.A key aim of TDR is to empower disease endemic countries to develop and leadresearch activities at internationally-recognized standards of quality. This revised GLPseries will support that goal, assisting DEC institutions in performing research and drugdevelopment studies to international standards. This, in turn, will also help institutionscontinue research initiatives into the clinical phases of development, in partnership withboth the public and private sectors.iii

GLP HANDBOOK ForewordWe anticipate that the use of these GLP resources will help promote cost-effective andefficient preclinical research with a long term positive effect on the development of products for the improvement of human health. In this way, the revised GLP series contributesto TDR’s primary mission of “fostering an effective global research effort on infectious diseasesof poverty in which disease endemic countries play a pivotal role”.ivDr R. RidleyDirector TDR

The Development of this HandbookTo enjoy the advantages of new or improved methods for the control of tropical diseases, disease endemic countries (DECs) will need to rely to a large extent on their ownresearch activities. It is therefore necessary to strengthen the capacity of these countries toconduct research and drug product development studies at a level comparable to that inother parts of the world.The pertinent regulations in the preclinical scenario are the Good Laboratory Practice(GLP) regulations. These regulations are the subject of this handbook, which is a referenceand support document, to help in the implementation of GLP. The Principles of GoodLaboratory Practice of the Organisation for Economic Cooperation and Development(OECD) form the basis of this series of guidance documents.This is the second version of the WHO Handbook on GLP. It is the result of experiencegained since the first version was published. It also refers to material related to GLP developments over the last seven years. Since the publication of the first GLP Handbook andtraining manuals, many training programmes have been conducted all over the world. TheWHO-TDR Network of GLP Trainers was formed to continue propagating training andimplementation of GLP in DECs. The network recommended the revision of this guidancedocument in order to reflect the progress in international GLP.The modifications in this second version are as indicated below:Chapter 1. Introduction to the WHO/TDR Handbook on GLP has been the subjectof minor modifications to help understanding and facilitate reading.Chapter 2. GLP Training: This has been reorganised and updated. The order of thefive fundamental points now reads “resources – characterisation -– rules – results (insteadof documentation) – quality assurance”. Minor corrections have been made and extraexplanations added to this part dealing with the fundamentals of GLP.Notable changes include: New section on the role of the Study Director in the Multi-Site situation. Reference to the prescriptive and descriptive documents in GLP studies. Reference to Principal Investigators. Reference to the Validation of Computerised Systems. New section on the role of Quality Assurance in the Multi-Site situation.v

GLP HANDBOOK The developmentChapter 3. Stepwise implementation now identifies clearer milestones in the processof setting up GLP, as requested by the GLP Network of Trainers.viChapter 4. OECD guidance documents has been expanded to include thosepublished since the first edition of the handbook. These represent entirely new itemscompared with the first version. At the time of going to press, all the OECD guidancedocuments on GLP are included in the handbook. The guidance documents are: the application of the OECD Principles of GLP to the organisation and managementof multi-site studies; the application of the principles of GLP to in vitro Studies; establishment and control of archives that perate in compliance with the principlesof GLP.Thus, this second edition of the GLP Handbook represents an up-to-date GLP referencedocument which we trust will be useful to support future deployment of GLP in researchcentres of DECs.Contributors to the first edition:Scientific Working Group on GLP issues:Dr J. P. Seiler** (International Office for the Control of Medecines (IOCM),Switzerland), ChairMr D. Long** (GXP Consultant, France), RapporteurDr D. Turnheim** (OECD, France)Dr N. Gawadi** (H. Lundbeck, Denmark)Dr N. K. Nair** (University of Sains malaysia, Malaysia)Dr P. Palittaponkarnpim* (National Center for Genetic Engineering andBiotechnology, Thailand)Dr Ch. O. N. Wambebe** (National Institute for Pharmaceutical Research anddevelopment, Nigeria)Dr M. T. Ham** (Ministry of health, Welfare and Sports, The NetherlandsDr A. Walubo* (University of the Orange Free state, South Africa)Mr P. Withers* (Phoenix International, France)Dr G. Murilla* (Kenya Medical Research Institute, Kenya)Dr J.-M. Sapin* (Agence française de sécurité des aliments (AFSSA), France)

The development GLP HANDBOOKDr Sansanee Chaiyaroj* (Mahidol University, Thailand)Dr M. Arevalo* (Institute de Immunologia del Valle, Colombia)Dr J. F. McCormack* (Food and Drug Administration (FDA), USA)Dr Ch. K. Maitai** (University of Nairobi, Kenya)WHO Secretariat:Dr D. Kioy** (Preclinical Coordinator, TDR/CDS)Dr B. Halpaap** (TDR/CDS)Dr E. Griffiths** (HTP)Dr H. Engers** (TDR/CDS)Dr S. Kopp-Kubel* (HTP)Dr C. Heuck* (HTP)Dr T. Kanyok* (TDR/CDS)Dr M. Demesmaeker* (HTP)** Participation in both meetings* Participation in one meetingCDS: Communicable DiseasesHTP: Health Technology and PharmaceuticalsContributors to the second editionWHO/TDR Network of GLP TrainersDr Deepak Kumar AGRAWAL (Industrial Toxicology Research Centre, Lucknow,INDIA)Dr Myriam AREVALO (Instituto de Immunologia del Valle, COLOMBIA1061)Dr Sarita BHALLA (Central Insecticide Laboratory, Faridad, INDIA)Dr Daniel CHAI Chivatsi (Institute of Primate Research (IPR), Nairobi, KENYA)Dr K.S. GAMANIEL (National Institute for Pharmaceutical Research andDevelopment, Abuja, NIGERIA)Dr Sandhya KULSHRESTHA (Central Insecticide Laboratory, New Delhi, INDIA)M. David LONG, (Facilitator Consultant, Paris, FRANCE)Dr Lazara MARTINEZ (Centro para el Control Estatal de la Calidad de losMedicamentos – CECMED, CUBA)Dr Paul N. MBUGUA (University of Nairobi, KENYA)vii