Good-Laboratory-Practice-(GLP)-HANDBOOK.pdf

UNDP/World Bank/WHOSpecial Programme for Research and Training in Tropical Diseases(TDR)couv.Handbook/14 13.8.2001 23:26 Page 3UNDP/World Bank/WHOSpecial Programme for Research and Training in Tropical Diseases(TDR)HANDBOOKGOOD LABORATORY PRACTICE(GLP)Quality practices for regulated non-clinicalresearch and development 01)2668-OMS-p.tit-contents 13.8.2001 22:54 Page iThe Good Laboratory Practice(GLP)Handbook is designed to serve as an aid forthose countries who wish to upgrade their laboratories to GLP status.It has been devel-oped as part of a significant and wide-ranging technology transfer and capacitybuilding programme in the area of pre-clinical product development for diseaseendemic countries.The GLP Handbook has been produced by a Scientific Working Group(SWG)on GLP issues,convened by the UNDP/World Bank/WHO Special Programme forResearch&Training in Tropical Diseases(TDR),which consisted of independent sci-entific specialists from around the world.The Handbook is broadly based on theOrganisation for Economic Cooperation and Development(OECD)principles of GLP.The Handbook will provide laboratories in disease endemic countries,and trainersthroughout these nations,with the necessary technical aid for implementing GLP pro-grammes.TDR gratefully acknowledges the participation and support of all those involved inthe production of this Handbook and,in particular,the OECD who also kindly per-mitted reprint of both the OECD Principles of Good Laboratory Practice and therelated documents.For all correspondence:Dr Deborah KioyPre-clinical CoordinatorProduct Research and DevelopmentTDR/WHOAvenue Appia 201211 Geneva 27 SwitzerlandTel:[phone]Fax:[phone]E-mail:kioydwho.int 01)2668-OMS-p.tit-contents 13.8.2001 22:54 Page iiivTABLE OF CONTENTSFOREWORD.1CHAPTER1.INTRODUCTION TO THE TDR HANDBOOK ON GLP.5GENERAL INTRODUCTION.5The need for application of quality standards in drug research,development and testing:the situation of developing countries and the role of TDR.5The drug development process and the non-regulated vs.Regulated areas.7INTRODUCTION TO GLP AND ITS APPLICATION.9The history of GLP.9What is GLP?.112.GOOD LABORATORY PRACTICE TRAINING.15INTRODUCTION.15THE FUNDAMENTAL POINTS OF GLP.16Resources.17Rules.18Characterization.18Documentation.19Quality assurance.19 01)2668-OMS-p.tit-contents 13.8.2001 22:54 Page vviRESOURCES.20Facilities:buildings and equipment.20Personnel.25RULES FOR THE CONDUCT OF STUDIES.28General aspects.28The study plan or protocol.29Standard Operating Procedures(SOPs).33CHARACTERIZATION.36The test item.36Test system.44DOCUMENTATION RAW DATA AND DATA COLLECTION.48Carrying out procedures and recording observations.48Records and recording.49QUALITY ASSURANCE UNIT.51Protocol(or study plan)review.52SOP review.52Planning(Master schedule,inspection plan).52Audits and inspections.53Quality assurance statement.55QAU inspections of suppliers and contractors.56The distribution and archiving of QAU files and reports.563.STEPWISE IMPLEMENTATION OF GLP.57INTRODUCTION.57IMPLEMENTATION AS A PROJECT.58STEPWISE IMPLEMENTATION OF GLP REQUIREMENTS.61 01)2668-OMS-p.tit-contents 13.8.2001 22:54 Page viANNEXESOECD SERIES ON PRINCIPLES OF GOOD LABORATORY PRACTICE ANDCOMPLIANCE MONITORINGI.OECD PRINCIPLES OF GOOD LABORATORY PRACTICE(ENV/MC/CHEM(98)17).77II.REVISED GUIDES FOR COMPLIANCE MONITORING PROCEDURES FOR GOOD LABORATORY PRACTICE(OCDE/GD(95)66).109III.REVISED GUIDANCE FOR THE CONDUCT OF LABORATORY INSPECTIONS AND STUDY AUDITS(OCDE/GD(95)67).129IV.QUALITY ASSURANCE AND GLP(ENV/JM/MONO(99)20).151V.COMPLIANCE OF LABORATORY SUPPLIERS WITH GLP PRINCIPLES(ENV/JM/MONO(99)21).161VI.THE APPLICATION OF THE GLP PRINCIPLES TO FIELD STUDIES(ENV/JM/MONO(99)22).169VII.THE APPLICATION OF THE GLP PRINCIPLES TO SHORT-TERM STUDIES(ENV/JM/MONO(99)23).183VIII.THE ROLE AND RESPONSIBILITIES OF THE STUDY DIRECTOR IN GLP STUDIES(ENV/JM/MONO99)24).197IX.GUIDANCE FOR THE PREPARATION OF GLP INSPECTION REPORTS(OCDE/GD(95)114).209X.THE APPLICATION OF THE PRINCIPLES OF GLP TO COMPUTERISED SYSTEMS(OCDE/GD(95)115).215XI.THE ROLE AND RESPONSIBILITIES OF THE SPONSOR IN THE APPLICATION OF THE PRINCIPLES OF GLP(ENV/MC/CHEM(98)16).229XII.REQUESTING AND CARRYING OUT INSPECTIONS AND STUDY AUDITSIN ANOTHER COUNTRY(ENV/JM/MONO(2000)3).237vii 01)2668-OMS-p.tit-contents 13.8.2001 22:54 Page vii1FOREWORDTo enjoy the advantages of new or improved methods for the control of tropical dis-eases,the countries in which these diseases are endemic will need to rely to a largeextent on their own research activities.It is necessary to strengthen the capacity ofthese countries to perform research and drug product development studies at a levelcomparable with that demonstrated in other parts of the world.Good practice rulesgovern drug product development activities in many parts of the world.World HealthOrganization(WHO),which has published documents on good manufacturing prac-tices(GMP)and good clinical practices(GCP),has not previously recommended orendorsed any quality standard governing the non-clinical phases of drug productdevelopment.Good laboratory practices(GLP)are recognized rules governing the con-duct of non-clinical safety studies,ensuring the quality,integrity and reliability of theirdata.To introduce the concepts of GLP to scientists in developing countries,work-shops on GLP have been organized in these regions.As an outcome of the workshops,it became apparent that some formal guidance would be needed for the successfulimplementation of the GLP standards.The first scientific working group on GLP issues was convened on 25 November,1999,in Geneva,to discuss quality issues in general and the necessity for a WHO guid-ance document on GLP in particular.The working group concluded that it was impor-tant to avoid the co-existence of two GLP standards,the Principles of Good Labora-tory Practice of the Organization for Economic Cooperation and Development(OECD)being the internationally recognized and accepted standard,and recommended that the OECD Principles be adopted by WHO/TDR as the basis of this guidance document.The experts also recognized the need to address quality issues in areas other than thestrictly regulated safety studies for regulatory submission,and recommended that someexplanation be included in this guidance document.The working group further rec-ommended that:WHO/TDR should request OECDs permission to publish the existing OECD GLP textwith a WHO endorsement,and to supplement it with an explanatory introduction.02)2668-OMS-Foreword-02m.XP4 13.8.2001 22:53 Page 1 WHO/TDR should promote/participate in GLP training in various regions of theworld.WHO/TDR should prepare a guideline on the practical implementation of GLP inlaboratories.WHO/TDR should prepare a volume containing:Explanatory text to GLP.OECD Principles of GLP.Important issues in the performance of studies that fall outside of the GLP remit.Need for,and development of,compliance monitoring systems.Financial considerations of GLP implementation.Training and education package(s).Guide to stepwise implementation of GLP.At its second meeting(Geneva,4-6 September,2000),the scientific working groupon GLP issues discussed the material which had been prepared in the meantime.It con-cluded that it was not possible to address issues of quality both within and outside ofthe regulated sector of drug development and testing,in one and the same document.It therefore recommended that:Two documents should be developed from the proceedings of the meeting.Thesedocuments would address the quality of research data but at different levels,i.e.non-regulatory and regulatory(GLP).The first document should contain all sections dealing with GLP and should be pub-lished as soon as ready.A second document,addressing quality issues in biomedical research in general,should be produced as a draft and be circulated for comments.The present WHO Handbook on GLP is the result of these deliberations,and itaddresses aspects of regulatory safety studies which are covered and governed by theOECD Principles of GLP.The quality aspects of studies outside this regulated area(e.g.basic research,early development)will be discussed on a broader basis and are there-fore not included here.2GLP HANDBOOKForeword 02)2668-OMS-Foreword-02m.XP4 13.8.2001 22:53 Page 2Participants:Dr J.P.Seiler*(Intercantonal Office for the Control of Medicines(IOCM),Switzerland),chairDr D.Long*(GLP Consultant,France),rapporteurDr D.Turnheim*(OECD,France)Dr N.Gawadi*(H.Lundbeck,Denmark)Dr N.K.Nair*(University of Sains Malaysia,Malaysia)Dr M.T.Ham*(Ministry of Health,Welfare and Sports,The Netherlands)Dr Ch.K.Maitai*(University of Nairobi,Kenya)Dr Ch.O.N.Wambebe*(National Institute for Pharmaceutical Research and Development,Nigeria)Dr M.Arevalo*(Institute de Immunologia del Valle,Colombia)Dr J.F.McCormack*(Food and Drug Administration(FDA),USA)Dr G.Murila*(Kenya Medical Research Institute,Kenya)Dr P.Palittaponkarnpim*(National Center for Genetic Engineering and Biotechnology,Thailand)Dr J.M.Sapin*(Agence franaise de scurit sanitaire des aliments(AFSSA),France)Dr A.Walubo*(University of the Orange Free State,South Africa)Dr P.Withers*(Phoenix International,France)Dr Sansanee Chaiyaroj*(Mahidol University,Thailand)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)*Participant in both meetings*Participant in one meetingCDS:Communicable DiseasesHTP:Health Technology and Pharmaceuticals3ForewordGLP HANDBOOK 02)2668-OMS-Foreword-02m.XP4 13.8.2001 22:53 Page 351.INTRODUCTION TO THE TDRHANDBOOK ON GLPGENERAL INTRODUCTIONThe need for application of quality standards in drug research,development and testing:the situation of developing countriesand the role of TDR Tropical diseases are a major public health problem in developing countries.For manyof these diseases there are no new,effective and affordable medicines,while older ther-apeutic agents are beginning to lose ground on account of the emergence of resistanceagainst them.The multinational pharmaceutical companies have not traditionallyfocused on these indications in their development programmes,which is why WHOhas created research and development programmes in a number of priority areas suchas malaria.WHOs Special Programme for Research and Training in Tropical Diseases(TDR)commissions studies to be conducted in the areas most affected by such dis-eases.If such programmes are to be successful that is to say,result in the successfulregistration of effective and safe new drug products it is evident that the componentstudies must comply with current quality standards in order to ensure the quality,reli-ability and integrity of data and to protect public health.National regulations requiretherefore that internationally accepted rules,i.e.good manufacturing practice,goodlaboratory practice,and good clinical practice,are followed in the respective stages ofthe development and life cycle of a drug product(see the diagram on product devel-opment,page 7).WHO has already published standards for good manufacturing practices(GMP)1(covering the manufacture of drug product)and for good clinical practices(GCP)21Quality assurance of pharmaceuticals:A compendium of guidelines and related materials.Volume 2,GoodManufacturing Practices and Inspection.Geneva,World Health Organization,1999.2Guidelines for Good Clinical Practices(GCP)for trials on pharmaceutical products.Geneva,WorldHealth Organization,1995.03)2668-OMS-Chap.01-03m.XP4 13.8.2001 22:56 Page 5(covering clinical trials in human,to establish efficacy and safety).However WHO has not yet addressed quality standards for non-clinical testing for the safety of potentialproducts,good laboratory practice(GLP).Since the introduction of GLP quality standards in test facilities of developing coun-tries was seen as an urgent issue,TDR set up a working party(Scientific WorkingGroup on GLP issues),which convened in 1999 and 2000 to discuss how to presentthe WHO position on GLP.During the discussions on this issue,it became first of all clear that,for test facilitiesin developing countries,the introduction of GLP quality measures may be impeded by the difficulty of obtaining adequate resources(e.g.facilities,equipment,trained per-sonnel)or the instability of the infrastructure(e.g.water or electricity supply),eitherwithin the testing laboratory itself or in the community as a whole.On the other hand,investments in GLP quality standards would result in tangible returns in the numberof studies placed with research organizations within these developing countries,resulting in an increase in funding.Conversely,it is clear that,where money is scarce,sponsors will not invest in studies if the reliability of results cannot be assured.Specif-ically,WHO/TDR would be reluctant to allocate its limited funding to non-clinicalsafety studies unless the results could be depended on to support decisions taken con-cerning future progress of a particular compound through the clinical stages to even-tual registration.From the deliberations of the Scientific Working Group on GLP issues,it furtherbecame clear that:Demonstrating compliance with GLP will become a prerequisite for clinical testingand drug registration in developing countries,and certainly if drug products are tobe exported to countries other than the country of origin.It is essential to avoid the co-existence of two or more international regulatory GLPstandards for non-clinical safety testing.Guidance is needed for the implementation of GLP.With such considerations in mind,to adopt the revised Organization for EconomicCooperation and Development(OECD)Principles of Good Laboratory Practice as theofficially endorsed WHO/TDR regulation in the area of non-clinical safety testing wasseen as the most rational way forward.In this handbook,these Principles are presentedin their original text,supplemented by a training section and a guideline for imple-menting GLP.6GLP HANDBOOKChapter 1 Introduction to the TDR handbook on GLP 03)2668-OMS-Chap.01-03m.XP4 13.8.2001 22:56 Page 6The drug development process and the non-regulated vs.regulated areasThe drug development process can be divided into a number of distinct phases,whichmay overlap in time(e.g.clinical Phase 1 studies will be started before the toxicologystudies of longer duration will have been finished;carcinogenicity studies may noteven have been started at this time point).Usually,drug research starts with basic research,the results of which may then beused to define efficacy targets for the potential drug.In established pharmaceuticalcompanies,the discovery phase often involves testing thousands or even tens of thou-sands of compounds in screening assays for the desired pharmacological effect.The tenor twenty“survivors”would then be checked for potential toxic effects again inscreening-type tests,reducing further the number of pot