The Principles of Good Laboratory Practice: Application to...

The Principles of Good Laboratory Practice:Application to In Vitro Toxicology Studies

The Report and Recommendations of ECVAM Workshop 371,2

Robin Cooper-Hannan,3 John W. Harbell,4 Sandra Coecke,5 MichaelBalls,5 Gerard Bowe,5 Miroslav Cervinka,6 Richard Clothier,7 FraukeHermann,8 Lynn K. Klahm,9 Jan de Lange,5 Manfred Liebsch10 andPhilippe Vanparys11

3Qualitas, Danworth Lane, Hurstpierpoint, West Sussex BN6 9LN, UK; 4Institute for InVitro Science, 21 Firstfield Road, Suite 220, Gaithersburg, MD 20878, USA; 5ECVAM,Institute for Health and Consumer Protection, European Commission Joint Research Centre,21020 Ispra (VA), Italy; 6Charles University Faculty of Medicine, Simkova 870, HradecKrálové, Czech Republic; 7FRAME Alternatives Laboratory, University of NottinghamMedical School, Queen�s Medical Centre, Nottingham NG7 2UH, UK; 8RCC Cytotest CellResearch, In den Leppsteinwiessen 19, 64380 Rossdorf, Germany; 9Human andEnvironmental Safety Division, The Procter and Gamble Company, Cincinnati, OH, USA;10ZEBET, BgVV, Diedersdorfer Weg 1, 12277 Berlin, Germany; 11Genetic and In VitroToxicology, Janssen Pharmaceutica, Turnhoutse Weg 30, 2340 Beerse, Belgium

ATLA 27, 539�577, 1999 539

Address for correspondence and reprints: Dr S. Coecke, ECVAM, JRC Institute for Health & Consumer Protec-tion, 21020 Ispra (VA), Italy.1ECVAM � European Centre for the Validation of Alternative Methods. 2This document represents the agreedreport of the participants as individual scientists and quality assurance personnel.

CONTENTS

PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 542

1 INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543

1.1 SCOPE OF THE PRINCIPLES OF GOOD LABORATORY PRACTICE . . . . . 543

1.2 HISTORY OF THE PRINCIPLES OF GOOD LABORATORY PRACTICE . . . 543

1.3 CLAIMING GOOD LABORATORY PRACTICE COMPLIANCE . . . . . . . . . . . 544

1.4 REGULATORY AND NON-REGULATORY STUDIES . . . . . . . . . . . . . . . . . . 544

2 STUDY ORGANISATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544

2.1 SINGLE-SITE STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544

2.2 MULTI-SITE STUDIES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545

2.3 MULTI-STUDY TRIALS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545

3 THE PRINCIPLES OF GOOD LABORATORY PRACTICE AND IN VITRO STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545

3.1 TEST FACILITY ORGANISATION AND PERSONNEL . . . . . . . . . . . . . . . . . 5463.1.1 Test Facility Management�s responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . 5463.1.1.1 Study Director . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5463.1.1.2 Principal Investigator. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5473.1.1.3 Organisation chart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5473.1.1.4 Master Schedule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5483.1.1.5 Site plans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5483.1.1.6 Personnel records. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5483.1.1.7 Standard Operating Procedures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5493.1.2 Test Site Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5493.1.3 Study Director�s responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5493.1.4 Principal Investigator and study personnel . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5513.1.4.1 Principal Investigator. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5513.1.4.2 Study personnel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552

3.2 QUALITY ASSURANCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553

3.3 FACILITIES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553

3.4 APPARATUS, MATERIAL AND REAGENTS . . . . . . . . . . . . . . . . . . . . . . . . . 556

3.5 TEST SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 558

3.6 TEST, REFERENCE AND CONTROL ITEMS. . . . . . . . . . . . . . . . . . . . . . . . . 560

3.7 STANDARD OPERATING PROCEDURES . . . . . . . . . . . . . . . . . . . . . . . . . . . 562

540 R. Cooper-Hannan et al.

3.8 PERFORMANCE OF THE STUDY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5623.8.1 Controls and acceptance criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5623.8.2 Study preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5623.8.3 Study plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5653.8.4 Study plan amendments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5663.8.5 Notes to file . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5663.8.6 Raw data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5663.8.7 Quality control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5663.8.8 Confidentiality issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567

3.9 REPORTING OF STUDY RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567

3.10 STORAGE AND RETENTION OF RECORDS AND MATERIALS . . . . . . . . . 567

4 MULTI-STUDY TRIALS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567

4.1 TRIAL MANAGEMENT TEAM. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567

4.2 TRIAL PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569

4.3 TRIAL COORDINATOR�S RESPONSIBILITIES . . . . . . . . . . . . . . . . . . . . . . . 569

4.4 TRIAL REPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570

4.5 QUALITY ASSURANCE OF MULTI-STUDY TRIALS. . . . . . . . . . . . . . . . . . . 571

5 CONCLUSIONS AND RECOMMENDATIONS. . . . . . . . . . . . . . . . . . . . . . 572

5.1 GOOD LABORATORY PRACTICE PROMOTES CONFIDENCE IN THE DATA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572

5.2 GOOD LABORATORY PRACTICE COMPLIANCE . . . . . . . . . . . . . . . . . . . . . 572

5.3 STUDY CONDUCT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573

5.4 QUALITY ASSURANCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573

5.5 VALIDATION AND MULTI-STUDY TRIALS . . . . . . . . . . . . . . . . . . . . . . . . . 573

6 ACKNOWLEDGEMENTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573

7 REFERENCES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574

8 APPENDIX 1: TERMINOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575

ECVAM Workshop 37: Good Laboratory Practice 541


PREFACE

This is the report of the thirty-seventh of a series of workshops organised by the EuropeanCentre for the Validation of Alternative Methods (ECVAM). ECVAM�s main goal, as definedin 1993 by its Scientific Advisory Committee, is to promote the scientific and regulatoryacceptance of alternative methods which are of importance to the biosciences and whichreduce, refine or replace the use of laboratory animals. One of the first priorities set byECVAM was the implementation of procedures which would enable it to become well-informed about the state-of-the-art of non-animal test development and validation, and thepotential for the possible incorporation of alternative tests into regulatory procedures. It wasdecided that this would be best achieved by the organisation of ECVAM workshops on specifictopics, at which small groups of invited experts would review the current status of in vitrotests and their potential uses and make recommendations about the best ways forward (1). Inaddition, other topics related to the Three Rs (reduction, refinement, replacement) concept ofalternatives to animal experiments have been considered in several ECVAM workshops.

ECVAM brought together experts in the field of cell culture technology and Good LaboratoryPractice (GLP) to stimulate the use and acceptance of in vitro toxicology data during the humanrisk assessment process, at both the European and world levels. The ECVAM workshop on ThePrinciples of Good Laboratory Practice: Application to In Vitro Toxicology Studies was held inAngera, Italy, on 6�9 December 1998. The workshop was chaired by Robin Cooper-Hannan(Qualitas, Hurstpierpoint, UK) and John Harbell (Institute for In Vitro Science, Gaithersburg,MD, USA), and was attended by cell culture technologists, toxicologists and quality assurancepersonnel from industry, academia and government. The aim of the workshop was to discussand make recommendations on the application of the OECD Principles of GLP to good qualitycell and tissue culture practices. In addition to reviewing the application of GLP to single-siteand multi-site studies, this document pays specific attention to multi-study in vitro toxicologytrials, including ECVAM�s prevalidation/validation studies which employ blind-coded chemi-cals. The consensus reached at the workshop was that validation efforts for in vitro toxicologystudies should be carried out under GLP, to facilitate the regulatory acceptance of high qualityvalidated in vitro tests.

1 INTRODUCTION

The Principles of GLP are intended to iden-tify the GLP requirements for test facilities(laboratories) which perform studies for reg-ulatory purposes. These principles define aquality system concerned with the organisa-tional process and the conditions underwhich studies are planned, performed, moni-tored, recorded, reported and archived. GLPis concerned with the quality of test data andthe management of quality studies. The gen-eration of test data according to current sci-entific knowledge and good managementpractices has been seen as the best way ofpromoting the reliability, and hence theinternational acceptability, of data. GLPaddresses an overall structure intended topromote and maintain quality data. Being amanagement practice, these principles donot interfere with the use of scientific knowl-edge or practices, but rather complement it.

The Principles of GLP were originallywritten to address animal-based toxicology.However, there has been a growing appreci-ation that certain additions/modificationsare required to meet the current state-of-the-art for in vitro studies and to assure the qual-ity of the data they provide. To this end,ECVAM and the Institute for In Vitro Sci-ences (IIVS) convened the workshop on GLP.It should be emphasised that this workshopwas not an effort to diminish the Principlesof GLP, but to enhance them. It drew on suc-cessful approaches used by industry, qualityassurance professionals and regulatory agen-cies with in vitro bioassays. The primarygoals were: a) to recommend additions/modi-fications to the OECD Principles of GLPneeded to address the specific needs of invitro bioassays (for example, test systemcharacterisation, facilities); b) to formalisestandards of practice to ensure quality datafrom in vitro studies (for example, use of con-trols and performance standards); c) to pro-vide assistance in the implementation of thePrinciples of GLP; and d) to address the spe-cific needs of prevalidation and validationwith respect to in vitro toxicology multi-study trials.

The current OECD Principles of GLP,which were adopted by the OECD in 1997(2), were used as the primary GLP referencefor this workshop report.

The report commences with a generalaccount of GLP, including the history of

GLP, and outlines the types of studies whichthis document addresses (single-site andmulti-site studies and multi-study trials).The OECD Principles of GLP are presented,in tabular form, with additions and modifica-tions applicable to in vitro studies. TheOECD Principles of GLP primarily addressthe needs of single-site and multi-site studies(2�5). The application of GLP to prevalida-tion and validation in multi-study trialsinvolving blind-coded chemicals is a specialcase, for which additional guidelines are nec-essary. Therefore, this report also discussesthe organisation of multi-study trials, includ-ing the terms �trial plan� and �trial report�.

Definitions of terms used in the OECDPrinciples of GLP are presented in Appendix1. Amendments and additional terms, asdefined by the workshop participants, arepresented as bold and underlined text.

1.1 SCOPE OF THE PRINCIPLES OFGOOD LABORATORY PRACTICE

The OECD Principles of GLP are intended tobe applied to the non-clinical safety testing oftest items contained in pharmaceuticals, pes-ticides, cosmetics and veterinary drugs, aswell as medical devices, food additives, feedadditives and industrial chemicals. Thesetest items are frequently synthetic chemi-cals, but can be of natural or biological originand, in some circumstances, can be livingorganisms. The purpose of testing theseitems is to obtain data on their propertiesand/or their safety with respect to humanhealth and/or the environment.

The OECD has stated that �Data gener-ated in the testing of chemicals in an OECDMember Country in accordance with OECDTest Guidelines and OECD Principles ofGood Laboratory Practice shall be acceptedin other Member Countries for purposes ofassessment and other uses relating to theprotection of man and the environment�.Therefore, it is relevant to validate theincreasing numbers of in vitro toxicologystudies in accordance with GLP, in order tofacilitate their acceptance by Member Coun-tries (6, 7).

1.2 HISTORY OF THE PRINCIPLES OFGOOD LABORATORY PRACTICE

In 1975, the US Food and Drug Administra-tion (FDA) raised concerns about the qualityand integrity of some safety studies submit-



ted to them. This inquiry resulted in the pro-duction by the FDA of proposals for GLP reg-ulations in 1976, to provide guidance to testfacilities for promoting the development ofquality data. A task force of FDA investiga-tors was set up to conduct a pilot programmeof inspections. Between 1976 and 1978, theinspectors looked at 98 laboratories (mostlyin the USA, but some in Europe) to deter-mine conformity with the proposed GLP reg-ulations. These investigations showed thatthe integrity of some studies was open toquestion, revealing problems so severe thatstudies could not be relied upon for regula-tory decision-making. The conclusion of theFDA�s review of laboratories was that therewas an obvious need for improving standardsacross industry as a whole.

In 1978, the FDA issued the regulationsspecifying the principles of GLP for adequatesafety testing. These regulations became lawin the USA in 1979. This established the FDAas the first government agency to assess labo-ratory compliance with GLP regulations. In1987, the FDA regulations on GLP wererevised. The FDA�s action stimulated muchinterest in the US Environmental ProtectionAgency (EPA), in other countries and in inter-national organisations such as the OECD.

The FDA Principles of GLP provided thebasis for the OECD Principles of GLP pub-lished in 1981. These OECD Principles of GLPwere set out as an integral part of the OECDDecision on Mutual Acceptance of Data in theAssessment of Chemicals. The OECD identi-fied three essential elements on which themutual acceptance of data can be based,namely: the application of the OECD Princi-ples of GLP; the establishment of harmonisednational GLP compliance programmes andguidance for national inspectors in the perfor-mance of inspections and audits; and the useof the OECD Test Guidelines.

Since the OECD Principles of GLP wereadopted by Member Countries, including theEuropean Economic Community (notably viaDirectives 87/18/EEC, 88/320/EEC and90/18/EEC), the interpretation of GLP isessentially the same among OECD MemberCountries (8, 9). After a decade and a half ofuse, the OECD Member Countries consid-ered that there was a need to review andupdate the Principles of GLP to account forscientific and technical progress in the areaof safety testing. This led to the revisedOECD Principles of 1997 (2).

1.3 CLAIMING GOOD LABORATORYPRACTICE COMPLIANCE

The requirements of national GLP compli-ance programmes can vary among countries.It can be the case that a test facility mightonly be able to claim formal GLP complianceif it is within a compliance programme runby the relevant national GLP MonitoringAuthority. It is recommended that a testfacility should clarify this, as appropriate,with the applicable national GLP MonitoringAuthority. Test facilities within a nationalGLP compliance programme are periodicallyvisited by government inspectors who under-take a comprehensive assessment and deter-mine the status of GLP compliance (10).

The quality assurance (QA) monitoring ofa participating test site in a study, which isnot within a national GLP compliance pro-gramme, might not confer formal GLP com-pliance. If work is conducted in a non-GLPcompliant facility, in support of a GLP study,consideration should be given to informingthe relevant national GLP MonitoringAuthority. Study reports and trial reportsmust clearly identify facilities which do notadhere to formal GLP, and must address anyimpact that non-compliance could have hadon integrity of the study.

1.4 REGULATORY AND NON-REGULATORY STUDIES

A test facility can conduct both �regulatorystudies�, intended for review by the regulatoryauthorities, and �non-regulatory studies�(including test development and fundamentalresearch) which are not intended for submis-sion to the regulatory authorities. Where thisis the practice in the same GLP area, it will benecessary for the non-regulatory work to alsobe conducted in compliance with GLP. Essen-tially, the main differences between such reg-ulatory and non-regulatory studies is that thelatter can be subject to reduced QA monitor-ing and can have fewer specific GLP docu-mentation requirements.

2 STUDY ORGANISATION

2.1 SINGLE-SITE STUDIES

The original OECD Principles of GLP, issuedin 1981, were primarily considered for sin-gle-site studies (Figure 1). A single-site studyis one in which the test facility, the Study

Director and all study procedures are basedin one location. The Study Director is theindividual responsible for the overall conductof a study. The role of Study Director is ofcentral importance in GLP (see section onStudy Director�s responsibilities). Each sin-gle-site study, conducted in accordance withGLP, has one Study Director, one study planand one study report.

2.2 MULTI-SITE STUDIES

Safety studies in a variety of disciplines, mostnotably in studies examining the fate of chem-ical substances in the environment (fieldstudies) are often undertaken as multi-sitestudies. A multi-site study is one study withone Study Director, but involving several testsites, which can be geographically remoteand/or in separate institutions (Figure 2).Each multi-site study, conducted in accor-dance with GLP, has one Study Director, onestudy plan and one study report (3, 4).

A multi-site study can present a challengewith respect to the need for the Study Direc-tor to maintain responsibility for the overallconduct of the study. The OECD recognisedthis and introduced the role of PrincipalInvestigator into the revised OECD Princi-ples of GLP of 1997 (2). In a multi-site study,the Principal Investigator is an individualwho acts on behalf of the Study Director andwho has defined responsibilities for dele-gated phases of the study. Principal Investi-gators prepare contributory reports on theirwork for the Study Director. The role andresponsibilities of the Principal Investigatorare discussed in section 3.1.4.

2.3 MULTI-STUDY TRIALS

A multi-study trial, such as interlaboratoryprevalidation/validation blind trials (11�13),will consist of two or more related studies inrelation to each test undergoing prevalida-tion/validation, with each study being inde-pendent and separate from the other studies.Therefore, each study will have its own StudyDirector, study plan and study report, andeach study might be conducted as either a sin-gle-site or a multi-site study (Figure 3). Theblind nature of these trials means that theStudy Director and study personnel are notfully aware of details about the test items dur-ing the conduct of the study, or during thepreparation and finalisation of the studyreport.

The study reports are forwarded to anindependent facility for data and statisticalanalyses and for preparation of the trialreport. Through necessity, the participat-ing laboratories will be reporting results oncoded test items, and so cannot address theanalytical requirements of GLP compli-ance. The management and reporting ofmultistudy trials are further discussedlater.

3 THE PRINCIPLES OF GOODLABORATORY PRACTICE ANDIN VITRO STUDIES

This section discusses the Principles of GLPand their application to in vitro studies. Thetext should be read together with the tablesand Appendix 1.

The OECD Principles of GLP have beenpresented by the OECD in ten GLP topics.The OECD text for these topics is presentedin Tables 1�10 (the first topic is covered byTables 1A�1C). The additions and modifica-tions recommended by the workshop partici-pants are shown as bold and underlined text,and the topics not considered relevant to invitro studies are shown as italicised andunderlined text.

Figure 1: Organisation of a single-sitestudy

Sponsor

Management

Study Director

Qualityassurance


Dashed lines indicate quality assurance staffinvolvement.


3.1 TEST FACILITY ORGANISATIONAND PERSONNEL

The Principles of GLP relevant to the testfacility are presented in Table 1A�1C.

3.1.1 Test Facility Management�sresponsibilities

The Principles of GLP related to Test Facil-ity Management�s responsibilities areshown in Table 1A.

The primary GLP responsibility of TestFacility Management is to ensure that a suffi-cient number of qualified personnel, andappropriate facilities, equipment and materi-als, are available for the timely and properconduct of studies. The test facility includesthe persons, premises and operational unitsnecessary for the conduct of a study. The testsite is the location(s) at which a phase(s) of astudy is conducted in a multi-site study. It isimportant to document the name of the per-son who acts as Test Facility Management, in

terms of GLP. In general, it will be the level ofmanagement which has overall responsibilityfor ensuring GLP compliance. The roles ofTest Facility Management, Study Directorand QA manager should each be performed bydifferent persons, so that there are checks andbalances in the overall programme. Test Facil-ity Management is not the same as the TrialManagement Team, which has responsibilitiesfor the overall conduct of a multi-study trial,and is discussed later in this document.

3.1.1.1 Study Director

The Study Director is appointed by TestFacility Management. When appointing aStudy Director to a study, managementshould be aware of that individual�s currentor anticipated workload. The Master Sched-ule, as described below, lists the studiesplanned, in progress and completed, andshould be used as a reference when appoint-ing a Study Director.

Figure 2: Organisation of a multi-site study

aQuality assurance staff will also have communication links with each laboratory.

Dashed lines indicate quality assurance staff involvement.

Sponsor

Management

Study DirectorLaboratory 1

PrincipalInvestigatorLaboratory 2



Etc.

Qualityassurancea

In the event that a Study Director has tobe replaced during a study (for example,because of a career change), it will be neces-sary for Test Facility Management to issue astatement detailing the change and the rea-son, and naming the replacement StudyDirector. The date on which the change is totake effect should also be noted. A study planamendment should be prepared to recordthis change, and should be signed by thereplacement Study Director, Test FacilityManagement and, if applicable, the sponsor.

At the time of replacement, it is theresponsibility of the replacement StudyDirector to determine whether the study hasbeen conducted in compliance with GLP. Ifany GLP deficiencies are noted during thisreview, it is the responsibility of the replace-ment Study Director to fully document them.

3.1.1.2 Principal Investigator

Test Facility Management should ensure in amulti-site study, that, if needed, a PrincipalInvestigator is designated who is appropri-ately trained, qualified and experienced, andwhose understanding of GLP is sufficient forsupervision of the delegated phase(s) of thestudy. The replacement of a Principal Inves-tigator should be done according to proce-dures established by Test Site Managementand be similar to those for the replacementof a Study Director.

3.1.1.3 Organisation chart

An organisation chart for the test facilityshould be available, which should include theidentity of the most senior manager who hasoverall responsibility for GLP compliance

Figure 3: Good Laboratory Practice organisation for a multi-study trial(including prevalidation and validation studies)

aSeveral quality assurance units might be involved in a multi-study trial.


Trialmanagement and

co-ordinator

Sponsor

Statistics

Test 1: study 1Study DirectorLaboratory 1


Etc.Test 1: study 2Study DirectorLaboratory 2


Quality assurancea



and should include the lines of reporting andcommunication in the test facility. The chartshould identify the main job areas associatedwith GLP, and should identify the individu-als who have designated responsibilities withrespect to GLP organisation. This includesthe maintenance of lists of individuals whocan be appointed as a Study Director and,where appropriate, a list of those individualswho can be appointed as Principal Investiga-tors. Other positions appropriate for the org-anisation chart are laboratory manager, testsubstance controller, Standard OperatingProcedure (SOP) administrator, archivistand QA personnel. Superseded organisationcharts and superseded lists of designatedStudy Directors and Principal Investigatorsshould be retained in the archives.

3.1.1.4 Master Schedule

Reference to the Master Schedule is a usefulmeans for Test Facility Management to iden-tify the allocation of resources. The MasterSchedule is used to assess the volume ofwork being performed and by which individ-uals. It also permits an awareness of studiesplanned, in progress and completed.

The Master Schedule should normally pro-vide the following study information: uniquestudy identification, test system, test item,nature of study, name of Study Director/Principal Investigator and start and comple-tion study dates. The inclusion of furtherinformation, such as the date of the issue ofthe study report and the date of archiving, isconsidered appropriate.

The Master Schedule at the test facilitymust show overall dates and the identity ofthe Study Director, whereas a Master Sched-ule at a test site need only show local datesand local activities, and the identity of therelevant Principal Investigator.

In some test facilities, there is the conductof both regulatory studies, intended for sub-mission to the regulatory authorities, andnon-regulatory studies, for example, testdevelopment and fundamental researchstudies. Non-regulatory studies can be con-ducted under GLP, but can have a reducedamount of QA monitoring and reduced spe-cific GLP documentation requirements.Where a laboratory has these two types ofstudies, it is appropriate to identify in theMaster Schedule which are the regulatorystudies and which are the non-regulatorystudies.

3.1.1.5 Site plans

Site plans are relevant documents for TestFacility Management, since they can be usedto demonstrate that laboratories are wellorganised and that there is adequate andappropriate separation of activities and func-tions. Site plans need not be detailed, such asin engineering site plans, but they should bedated and should indicate the main func-tional areas, such as test item store, formu-lation area and archives. Superseded siteplans should be archived.

3.1.1.6 Personnel records

Test Facility Management must ensure themaintenance of a record of the qualifications,training, experience and job description ofeach professional individual with GLPresponsibilities. Also, there must be assur-ance that personnel clearly understand thefunctions they are to perform and, wherenecessary, are provided with training forthese functions.

It is usual for the qualifications, togetherwith a brief account of education, employ-ment history and experience, to be recordedin the form of a curriculum vitae.

Job descriptions will be presented in aGLP-compliant manner, if they include jobtitle, qualifications and experience necessaryfor the position, reporting relationships andan outline of the key objectives of the jobposition, especially those objectives affectingGLP. Job descriptions should be signed byboth employee and manager.

Training is usually documented in theform of an on-going training record listingspecific tasks which need to be signed offbefore an individual can undertake suchtasks without direct supervision. Trainingrecords are considered to be key GLP docu-ments, since they demonstrate those proce-dures which an individual can undertake.One method that can be used by Test Facil-ity Management, or the Study Director orQA personnel, to determine whether an indi-vidual has been trained in a given procedure,is to check the training record.

The need for re-training, for example,after a period of absence or when there havebeen procedural and technical revisions,should always be considered.

Training records should be described in aStandard Operating Procedure (SOP), whichshould address who should have training

records and who can authorise trainingrecords. Training records should be consid-ered for all grades of professional staff withGLP duties, to at least the level of StudyDirector. The SOP should describe where thetraining records are to be located, and shouldidentify that a training record should be for-warded to the archives when an individualno longer has GLP responsibilities. The SOPshould also outline the documentation forattendance at courses and conferences.

In certain cases, especially for personnelwith advanced training, self-education andself-certification may be possible. Test Facil-ity Management should judge whether andwhen this is appropriate.

3.1.1.7 Standard Operating Procedures

It is appropriate for Test Facility Manage-ment to ensure an individual has beenassigned responsibility for the administra-tion of the SOP system. Such a role servesto ensure that SOPs are reviewed at appro-priate time intervals, that new and revisedSOPs are authorised and issued in a timelymanner, that SOPs are appropriately dis-tributed, and that a historical file of super-seded SOPs is maintained. In multi-sitestudies it might be decided to assign an indi-vidual with SOP responsibilities for ensur-ing the administration and control ofcertain SOPs across test sites. SOP admin-istration of this nature would need to beclarified in the study plan.

3.1.2 Test Site Management

In a multi-site study, Test Site Manage-ment will have the responsibilities definedin Table 1A, with the following exceptions:a) the appointment of the Study Director,and the replacement of the Study Director,if applicable; b) ensuring documentedapproval of the study plan by the StudyDirector; c) ensuring that the Study Direc-tor has made the approved study plan avail-able to the QA personnel; and d) ensuringthat clear lines of communication existbetween the Study Director, PrincipalInvestigator(s), study personnel and QApersonnel.

3.1.3 Study Director�s responsibilities

The Principles of GLP relevant to the StudyDirector�s responsibilities are shown inTable 1B.

The role of Study Director is of fundamen-tal importance, and it is the Study Directorwho is accountable for ensuring the GLP com-pliance in the conduct of the study and in thestudy report. The Study Director is the singlecritical point of study control and mustensure clear lines of communication betweenthe Study Director and study personnel.

Before any work on a study is undertaken,the Study Director should ensure that TestFacility Management have committed ade-quate resources, that study personnel are ade-quately trained, and that the equipment to beused in the study has been appropriately cali-brated and maintained. The Study Directorshould also ensure that appropriate arrange-ments have been made for the supply of the testsystems, and test, control and reference items,which meet the requirements of the study, andthat there are appropriate SOPs for the study.

It is the responsibility of the Study Direc-tor to approve the study plan, and anyamendments to the study plan, by dated sig-nature. It is also the Study Director�s respon-sibility to ensure that copies of the studyplan, any amendments, and relevant SOPsare readily available to personnel, that per-sonnel are properly briefed, and that anydeviations from the study plan or SOPs aredocumented and acted upon. The StudyDirector should ensure that QA personnelhave a copy of the study plan, and anyamendments, in a timely manner and com-municate effectively with them, as requiredduring the conduct of the study.

Study Director involvement during thecourse of a study should include reviewing pro-cedures and data, in order to ensure compli-ance with the study plan and the SOPs. Todemonstrate the monitoring activities of theStudy Director, the type and frequency of thereviews should be documented in the studyrecords. The impact of any deviations from thestudy plan on the quality and integrity of thestudy should be assessed and appropriate cor-rective action should be taken, if necessary.The Study Director should acknowledge alldeviations from SOPs during the conduct ofthe study.

The Study Director must sign and date thestudy report to indicate acceptance ofresponsibility for the validity of the data andthat the study report accurately reflects thework conducted and all the results obtained.

The Study Director should ensure that allrelevant raw data and records are properly



Table 1A: Test Facility Organisation and Personnel

1.1 Test Facility Management�s Responsibilities

1. Each Test Facility Management should ensure that the Principles of Good LaboratoryPractice are complied with in its test facility.

2. At a minimum it should:a) ensure that a statement exists which identifies the individual(s) within a test facility

who fulfils the responsibilities of management as defined by these Principles of GoodLaboratory Practice;

b) ensure that a sufficient number of qualified personnel, appropriate facilities, equip-ment and materials are available for the timely and proper conduct of the study;

c) ensure the maintenance of a record of the qualifications, training, experience and jobdescription for each professional and technical individual;

d) ensure that personnel clearly understand the functions they are to perform and, wherenecessary, provide training for these functions;

e) ensure that appropriate and technically valid Standard Operating Procedures areestablished and followed, and approve all original and revised Standard Operating Pro-cedures;

f) ensure that there is a Quality Assurance programme with designated personnel, andassure that the Quality Assurance responsibility is being performed in accordance withthese Principles of Good Laboratory Practice;

g) ensure that for each study an individual with the appropriate qualifications, trainingand experience is designated by the management as the Study Director before thestudy is initiated. Replacement of a Study Director should be done according to estab-lished procedures, and should be documented;

h) ensure, in the event of a multi-site study, that, if needed, a Principal Investigator isdesignated who is appropriately trained, qualified and experienced to supervise thedelegated phase(s) of the study. Replacement of a Principal Investigator should bedone according to established procedures, and should be documented;

i) ensure documented approval of the study plan by the Study Director;j) ensure that the Study Director has made the approved study plan available to the

Quality Assurance personnel;k) ensure the maintenance of a historical file of all Standard Operating Procedures;l) ensure that an individual is identified as responsible for the management of the

archive(s);m) ensure the maintenance of a master schedule;n) ensure that test facility supplies meet requirements appropriate to their use in a study;o) ensure for a multi-site study that clear lines of communication exist between the Study

Director, Principal Investigator(s), the Quality Assurance programme(s) and studypersonnel;

p) ensure that test, reference and control items are appropriately characterised;q) establish procedures to ensure that computerised systems are suitable for their

intended purpose, and are validated, operated and maintained in accordance withthese Principles of Good Laboratory Practice.

3. When a phase(s) of a study is conducted at a test site, test site management (if appointed)will have the responsibilities as defined above with the following exceptions: 2g, 2i, 2j and2o.

Recommended additions to the test are in bold and underlined.

maintained, to ensure data integrity, andthat upon completion, or termination, of thestudy, these records are transferred in atimely manner to the archives.

3.1.4 Principal Investigator and studypersonnel

3.1.4.1 Principal Investigator

The Principles of GLP related to the Princi-pal Investigator are shown in Table 1C.

In a multi-site study, it is unreasonable toexpect a Study Director to maintain directsupervision over all test sites. Therefore, it isappropriate to have a Principal Investigatorappointed at test sites which are remotefrom the Study Director. The PrincipalInvestigator must be an appropriately quali-fied individual at the test site, who can effec-

tively carry out the technical phase of thestudy in conformance with the study plan,applicable SOPs, the Principles of GLP andthe specific technical requirements. It mustbe noted that, although a Study Director candelegate duties to a Principal Investigator,the Study Director�s responsibilities cannotbe delegated.

There should not be a need to appoint aPrincipal Investigator to work on the studyat the Study Director�s geographical andmanagerial location.

The Principal Investigator should indicateacceptance of the study plan, and anyamendments to the study plan, by dated sig-nature. Management and sponsor dated sig-natures should be provided, as appropriate.

In a situation where a Principal Investiga-tor undertakes a specialist activity, the Prin-

Table 1B: Test Facility Organisation and Personnel

1.2 Study Director�s Responsibilities

1. The Study Director is the single point of study control and has responsibility for the over-all conduct of the study and for its study report.

2. These responsibilities should include, but not be limited to, the following functions. TheStudy Director should:a) approve the study plan and any amendments to the study plan by dated signature;b) ensure that the Quality Assurance personnel have a copy of the study plan and any

amendments in a timely manner and communicate effectively with the Quality Assur-ance personnel as required during the conduct of the study;

c) ensure that study plans and amendments and Standard Operating Procedures areavailable to study personnel;

d) ensure that the study plan and the study report for a multi-site study identify anddefine the role of any Principal Investigator(s) and any test facilities and test sitesinvolved in the conduct of the study;

e) ensure that the procedures specified in the study plan are followed, and assess and doc-ument the impact of any deviations from the study plan on the quality and integrity ofthe study, and take appropriate corrective action if necessary; acknowledge deviationsfrom Standard Operating Procedures during the conduct of the study;

f) ensure that all raw data generated are fully documented and recorded;g) ensure that computerised systems used in the study have been validated;h) sign and date the study report to indicate acceptance of responsibility for the validity

of the data and to indicate the extent to which the study complies with these Princi-ples of Good Laboratory Practice;

i) ensure that after completion (including termination) of the study, the study plan, thestudy report, raw data and supporting material are archived.

Recommended additions to the text are in bold and underlined.



cipal Investigator can prepare, if necessary,an amendment to the study plan, in consul-tation with the Study Director. However, theStudy Director must be responsible for thenumbering, approval and issue of all studyplan amendments. All study plan amend-ments should be issued to all recipients ofthe original study plan.

The Principal Investigator is responsible forensuring that QA personnel are kept informedabout study activities for which the PrincipalInvestigator is responsible, so that QA person-nel can plan the inspection schedule. It is alsonecessary for the Principal Investigator torespond, in a timely manner, to QA reports.

On completion of a Principal Investigator�sstudy activity, the Principal Investigatorshould sign and date the contributory report,to confirm that it accurately reflects the workconducted and all the results obtained. Suffi-cient commentary should be included to

enable the Study Director to write the studyreport. The Principal Investigator shouldinclude a signed GLP compliance statementconfirming compliance with GLP, or indicat-ing clearly where there were any deviationsfrom GLP.

If study documents and/or materials are tobe archived locally, the archiving arrange-ments should be confirmed in the contribu-tory report.

3.1.4.2 Study personnel

All study personnel involved in the conductof the study must be knowledgeable in theaspects of the Principles of GLP which areapplicable to their involvement in the study,and should be sure they are undertakingonly duties in which they have been ade-quately trained (Table 1C).

Study personnel should have ready accessto the study plan and relevant SOPs. It is

Table 1C: Test Facility Organisation and Personnel

1.3 Principal Investigator�s Responsibilities

The Principal Investigator will ensure that the delegated phases of the study are conductedin accordance with the applicable Principles of Good Laboratory Practice.

1.4 Study Personnel�s Responsibilities

1. All personnel involved in the conduct of the study must be knowledgeable in those partsof the Principles of Good Laboratory Practice which are applicable to their involvement inthe study.

2. Study personnel will have access to the study plan and appropriate Standard OperatingProcedures applicable to their involvement in the study. It is their responsibility to com-ply with the instructions given in these documents. Any deviation from these instructionsshould be documented and communicated directly to the Study Director, and/or if appro-priate, the Principal Investigator(s).

3. All study personnel are responsible for recording raw data promptly and accurately and incompliance with these Principles of Good Laboratory Practice, and are responsible for thequality of their data.

4. Study personnel should exercise health precautions to minimise risk to themselves and toensure the integrity of the study. They should communicate to the appropriate person anyrelevant known health or medical condition in order that they can be excluded from oper-ations that may affect the study.

their responsibility to comply with theinstructions given in these documents. Anydeviations from these instructions should bedocumented and communicated directly tothe Study Director and/or, if appropriate, tothe Principal Investigator.

All study personnel are responsible forrecording raw data promptly and accuratelyand in compliance with GLP, and are respon-sible for the quality of their data.

Study personnel should take the necessarypersonal and health precautions to avoid anycontamination of test systems and test items,and should take adequate safety precautionswhen handling materials of known, orunknown, hazard.

3.2 QUALITY ASSURANCE

The Principles of GLP specific to QA are pre-sented in Table 2. The establishment andeffective operation of a QA programme is arequirement of GLP and is one of the princi-pal means by which study personnel, Man-agement, sponsors and ultimately theregulatory authorities are assured of theGLP compliance status of studies. The QAfunction is based on organisational, ratherthan scientific, procedures. Therefore, QAdoes not interfere with the technical and sci-entific conduct of studies.

Test Facility Management has ultimateresponsibility for compliance with the Prin-ciples of GLP. This includes the appointmentand effective organisation of a QA function.Persons undertaking QA activities must beindependent of the studies inspected, andshould report to a level of managementwhere the overall responsibility for GLPresides. In small facilities, it might not befeasible to maintain full-time QA personnel.However, Management must appoint at leastone individual to have permanent, albeitpart-time, coordination of QA. Managementcan contract out the QA function, so the QAfunction need not be in-house.

QA inspections include reviews of proce-dures to assure compliance with the studyplan, SOPs and the Principles of GLP. Theypay attention to the flow of information andthe chain of custody of samples and dataacross interfaces. This is particularly relevantto multi-site studies, where it is necessary tocoordinate QA activities across sites, to ensurethat all critical phases and interfaces are sub-ject to QA monitoring. In the case of a labora-tory that is not within a national GLP

compliance programme, but which is partici-pating in a GLP study, increased QA monitor-ing of that laboratory should be considered.

Inspections of facilities, procedures andstudy reports result in QA reports, which areforwarded to relevant study personnel,including the Study Director and Test Facil-ity Management. QA reports should be seenas a way of promoting awareness of GLPissues. There should be an agreed time-frame for recipients to respond to QAreports, for example, within 2 weeks. Signif-icant findings should be reported, andresponses should be made, as quickly as pos-sible.

QA personnel should prepare and sign aQA statement for inclusion in the studyreport. The QA statement specifies theinspections undertaken, their dates, and thedates when the QA findings were reported.This statement also serves to confirm thatthe study report reflects the raw data. TheQA statement is usually presented as astand-alone document, within the studyreport, to confirm the independence of QA.

3.3 FACILITIES

The Principles of GLP specific to facilitiesare presented in Table 3. The basic require-ments for facilities will be dictated by thetypes of test systems employed and the typesof studies to be performed. Facilities includeall of the buildings, individual room(s) andequipment provided to maintain the speci-fied, controlled environment for the test sys-tem(s). Initial quarantine, diagnosis/treatment of disease, maintenance beforeand after treatment with the test item, andisolation from external disturbances, mustbe provided. External disturbances mightcome in the form of contamination fromother studies/test systems (across species),dust from the preparation of test or controlitems for dosing (for example, dose feedpreparation, treatment or harvest of individ-ual test subjects, environmental sourcessuch as noise, light and bioburden). A testfacility appropriate for one type of test sys-tem might be wholly insufficient for another.

GLP was originally developed for facili-ties in terms of rooms or areas (portion ofa room), since those units are appropriatefor most in vivo studies where test systemsare exposed to room air, so environmentalconditions for maintenance and isolationneed to be directed at that level. In con-



trast, most in vitro (especially cell andorgan culture) systems are manipulated invertical laminar flow biological safety cabi-nets to protect both the test system andthe operator. The test system is main-tained within an incubator, which providesthe required environmental conditions. Itis further isolated from other cultures by

the flasks, tubes or plates in which it isgrown or treated. Therefore, modificationsare necessary to the wording of the OECDPrinciples of GLP for facilities conductingin vitro studies. The addition of the term�or equipment� in the facilities� require-ments is intended to remedy this situation(Table 3).

Table 2: Quality Assurance Programme

2.1 General

1. The test facility should have a documented Quality Assurance programme to assure thatstudies performed are in compliance with these Principles of Good Laboratory Practice.

2. The Quality Assurance programme should be carried out by an individual or by individu-als designated by, and directly responsible to, management, who are familiar with the testprocedures.

3. Such individuals should not be involved in the conduct of the study being assured.

2.2 Responsibilities of the Quality Assurance Personnel

1. The responsibilities of the Quality Assurance personnel include, but are not limited to, thefollowing functions. They should:a) maintain copies of all approved study plans and Standard Operating Procedures in use

in the test facility and have access to an up-to-date copy of the Master Schedule;b) verify that the study plan contains the information required for compliance with these

Principles of Good Laboratory Practice. This verification should be documented;c) conduct inspections to determine whether all studies are conducted in accordance with

these Principles of Good Laboratory Practice. Inspections should also determine thatstudy plans and Standard Operating Procedures have been made available to studypersonnel and are being followed. Inspections can be of three types as specified byQuality Assurance programme Standard Operating Procedures: i) study-based inspec-tions; ii) facility-based inspections; and iii) process-based inspections. Records of suchinspections should be retained;

d) inspect the study reports to confirm that the methods, procedures and observationsare accurately and completely described, and that the reported results accurately andcompletely reflect the raw data of the studies;

e) promptly report any inspection results in writing to management and to the StudyDirector, and to the Principal Investigator(s) and the respective management, whenapplicable;

f) prepare and sign a statement, to be included with the study report, which specifiestypes of inspections and their dates, including the phase(s) of the study inspected, andthe dates inspection results were reported to management and the Study Director andPrincipal Investigator(s), if applicable. This statement would also serve to confirm thatthe study report reflects the raw data.


Table 3: Facilities

3.1 General

1. The test facility should be of suitable size, construction and location to meet therequirements of the study and to minimise disturbance that would interfere with thevalidity of the study.

2. The design of the test facility should provide an adequate degree of separation of thedifferent activities to assure the proper conduct of each study.

3.2 Test System Facilities

1. The test facility should have a sufficient number of rooms, areas or appropriateequipment (for example, biological safety cabinets) to assure the isolation of testsystems and the isolation of individual projects, involving substances or organismsknown to be or suspected of being, biohazardous.

2. Suitable rooms, areas, or equipment (for example, biological safety cabinets)should be available for the treatment and cultivation of the in vitro test systems,in order to ensure that there is no contamination of the test system(s).

3. There should be storage rooms or areas as needed for supplies and equipment. Storagerooms, areas or equipment should be separated from rooms, areas or equipmenthousing the test systems and should provide adequate protection against infestation,contamination, and/or deterioration

4. The facilities should provide adequate equipment (for example, biohazardhoods, ventilated cabinets), for the protection of the study personnel, envi-ronment and test system.

3.3 Facilities for Handling Test, Reference and Control Items

1. To prevent contamination or mix-ups, there should be separate rooms, areas or stor-age cabinets for receipt and storage of the test, reference and control items. Mixingof the test, reference and control items with a vehicle should be performedso as to preclude contamination and mix-up.

2. Storage rooms, areas or storage cabinets for the test, reference and control itemsshould be separate from rooms, areas, or storage equipment containing the test sys-tems. They should be adequate to preserve identity, concentration, purity and stability,and ensure safe storage for hazardous substances.




The handling of test, reference and controlitems (7) for an in vitro study is generallyperformed in containment equipment to pro-tect the items and the operator. The volumesof sample being prepared are quite smallcompared to those used in many in vivo stud-ies. Changes to Table 3 focus on the need forthe absence of contamination and mix-up,and reflect the facilities used for in vitrostudies and the volumes of material to bemanipulated.

There should be adequate storage facilitiesfor supplies and equipment (for example,refrigerators, freezers, cryopreservators,ventilated cabinets, storage rooms). Storagefacilities should be adequately separatedfrom the test system and should provide ade-quate protection against infestation, contam-ination, and/or deterioration.

Some facilities work with dedicated GLPand non-GLP areas, while others will con-duct both regulatory and non-regulatorystudies within a single GLP-compliant area.If a test facility carries out both regulatoryand non-regulatory studies, it is essentialthat the GLP compliance of the regulatorystudies is not compromised by the non-regu-latory studies.

Management must clearly establish poli-cies and procedures which preclude compro-mising the GLP compliance of regulatorystudies by non-regulatory studies. If a testfacility does have dedicated GLP and non-GLP areas, a base level of GLP compliancefor the complete facility could be established,

in order to introduce a general GLP workingpractice among all laboratory personnel (forexample, for weighing, labelling and calibra-tion).

Personnel should not undertake activitieswithin a GLP area unless they have beentrained in the appropriate GLP require-ments. The presence of both GLP and non-GLP activities within the same facilityrequires constant vigilance on the part ofTest Facility Management, Study Directors,supervisors and QA personnel, to ensurecontinual GLP compliance.

The GLP practices in the non-regulatorystudies must not run counter to those for theregulatory studies. For example, cell culturesassociated with a non-regulatory studyplaced in a GLP-compliant incubator musthave the same labelling and freedom fromadventitious agents as those used for theGLP studies.

3.4 APPARATUS, MATERIAL ANDREAGENTS

The Principles of GLP specific to this areaare presented in Table 4. Procedures on howapparatus is inspected, cleaned, maintainedand calibrated must conform to the needs ofthe study plan and SOPs. This conformitymust be documented as raw data.

The apparatus used to maintain test sys-tem isolation and environment is particu-larly critical for in vitro studies. Forexample, a study plan should specify anacceptable temperature range for the incuba-

Table 3: continued

3.4 Archive Facilities

Archive facilities should be provided for the secure storage and retrieval of study plans,raw data, study reports, samples of test items and specimens. Archive design and archiveconditions should protect contents from untimely deterioration.

3.5 Waste Disposal

Handling and disposal of wastes should be carried out in such a way as not to jeopardisethe integrity of studies. This includes provision for appropriate collection, storage and dis-posal facilities, and decontamination and transportation procedures.


tor. The incubator must be able to conformto that range, and a record of the monitoringmust be maintained. There will usually beseveral parameters that should be main-tained and documented daily (temperature,humidity, CO2 concentrations), and otherswhich can be assessed and documented peri-odically (cleaning and bioburden).

Clearly, the quality of the apparatus mustmeet the expected and established levels ofaccuracy and precision. The specific require-ments for a certain piece of apparatus (forexample, frequency of cleaning or calibra-tion) might not be the same in all laborato-ries or for all assay systems. Managementand the Study Director should establishappropriate requirements. As a minimumrequirement, the manufacturer�s specifica-tions should be met. The implementation ofa monitoring/calibration programme is rec-ommended.

The acceptance testing of new, or changed,computer systems for data capture, manipu-lation and storage is complex, involving bothhardware and software components, andshould be conducted and documented in aGLP-compliant manner. Before a computersystem is used for GLP studies, it must bedemonstrated that it is suitable for itsintended use and that there are procedures

for maintaining and controlling the system.The raw data for each computer systemshould be defined, and the system designshould always provide for the retention ofaudit trails, to show all changes to data,without obscuring the original data. Respon-sibilities for computer systems must beclearly defined before a study begins.

The focus of the acceptance testing effortshould be on the application(s) being used,rather than on the computer system itself.That is, do the hardware and softwaretogether produce the desired result whenchallenged by rigorous testing with knowndata sets? For example, a spreadsheet mightbe prepared to manipulate data in a study.The performance of that spreadsheet, for itsintended purpose, would be tested and docu-mented, rather than an attempt to evaluatean entire commercial spreadsheet program.Any data transfer steps between platformsand any direct data capture functions frominstrumentation would be included in theevaluation. In such cases, it will be essentialto define precisely the form of the raw data.If the raw data are in the form of an elec-tronic file, electronic signatures and datestamps must meet GLP standards, asdefined by the appropriate regulatoryauthorities.

Table 4: Apparatus, Materials and Reagents

1. Apparatus, including validated computerised systems, used for the generation, storageand retrieval of data, and for controlling environmental factors relevant to the study,should be suitably located and of appropriate design and adequate capacity.

2. Apparatus used in a study should be periodically inspected, cleaned, maintained, moni-tored for its performance and calibrated according to Standard Operating Procedures.Records of these activities should be maintained. Calibration should, where appropriate,be traceable to national or international standards of measurement.

3. Apparatus and materials used in a study should not interfere adversely with the test sys-tems.

4. Chemicals, reagents and solutions should be labelled to indicate identity (with concentra-tion if appropriate), expiry date and specific storage instructions. Information concerningsource, preparation date and stability should be available. The expiry date may beextended on the basis of documented evaluation or analysis.



The requirement that the apparatus andmaterials used in a study do not interferewith a test system is also critical for in vitrostudies. As study plans, and equipmentmaintenance, cleaning and decontaminationprocedures (i.e. SOPs) are developed, consid-eration must be given to avoidance of theintroduction of chemical residues, tempera-ture fluctuations or other environmental fac-tors which will affect the test system. Forexample, consideration must be given to theeffects of bright sunlight on culture media,or of incubator vibration on cell culture uni-formity.

The labelling of chemicals, reagents andsolutions, including commercially preparedmedia and reagent solutions, should be con-ducted in such a way as to ensure compliancewith GLP requirements. Revised labellingshould be prepared when appropriate; forexample, supplementation of a medium witha labile component could change the expirydate.

3.5 TEST SYSTEMS

The Principles of GLP in relation to test sys-tems are presented in Table 5. Several addi-tions to this table have been made, which aredirected toward cell/tissue culture systems.These address the needs to authenticate theorigin of the test system, its freedom fromadventitious agents and its condition uponarrival. Also, within the facility, the test sys-tem must be propagated and maintained inorder to preserve its biological integrity forits intended application.

Many in vitro test systems are not directlyisolated by the facility from the originalspecies and tissue of origin, but are cell linesobtained from other sources. In some cases,the primary isolation might have occurredseveral decades earlier. In other cases, par-ticularly with human cells and tissues, thedonor records are not available to the end-user of the test system. Thus, the agency(cell repository or commercial source) pro-viding the test system might be the primarysource of data on the species and tissue oforigin. It might also provide data on anytests performed to demonstrate the absenceof adventitious agents and the purity(species and tissue type) of the test system. Itis essential that the test facility is able totrace the lineage of the test system to itsimmediate source and to document the han-dling of that system within the test facility.

This requirement is similar to documenta-tion of the origin and basic health of an invivo test system.

In vitro test systems are often propagatedwithin test facilities. Both prokaryotic andeukaryotic systems can be expanded andbanked to provide a continuous source ofmaterial. Since the study plan will have beenprepared with certain expectations of thetest system and specific performance criteriafor the assay (see section 3.8), the test sys-tem must be maintained in such a way as topromote stability over time. Test systemmaintenance and propagation should beaddressed in the planning of a study (orstudy type) and documented in sufficientdetail for the critical elements required tomaintain stability to be included. Records oftest system maintenance should also includeall critical elements.

Characterisation of the in vitro test systemis of the utmost importance. The handling ofin vitro systems is perhaps more critical thanthat of in vivo systems. The following pointsshould be considered.

1. Proper conditions should be establishedand maintained for the storage, handlingand care of test systems, in order toensure the quality of the data. High qual-ity cell and tissue culture practices andgood aseptic techniques, which are anessential part of in vitro work, should beenforced.

2. Characterisation of the test system isnecessary, to ensure that it is what itclaims to be, and any significant changesin the test system should be evaluated.

3. Newly received test systems should becontrolled for their purity, lack of contam-ination, suitability and identity. Until thetest system has met these pre-defined cri-teria, it should not be used in GLP-com-pliant studies and should be appropriatelytreated or destroyed. Any future contami-nation or defects which could affect thequality of the data should be investigated,and the test system returned to quaran-tine until it is �cleared�. When beginningthe experimental work in a study, the testsystem should be free of any contamina-tion or defects, or any conditions whichmight interfere with the purpose or con-duct of the study. Test systems that do notconform (for example, those with contam-ination, defects) during the course of a


Table 5: Test Systems

5.1 Physical/Chemical

1. Apparatus used for the generation of physical/chemical data should be suitably locatedand of appropriate design and adequate capacity.

2. The integrity of the physical/chemical test systems should be ensured.

5.2 Biological

1. Proper conditions should be established and maintained for the storage, housing, handlingand care of biological test systems, in order to ensure the quality of the data.

2. The absence of contamination or defects in test systems should be demon-strated. If any damage or defect occurs (for example, contamination), this lotshould not be used in studies and should be appropriately destroyed. At theexperimental starting date of a study, test systems should be free of any diseaseor condition that might interfere with the purpose or conduct of the study. Testsystems that become contaminated or damaged during the course of a studyshould be appropriately destroyed, if necessary, to maintain the integrity of thestudy.

3. The origin (for example, species and tissue), source, arrival condition andmaintenance requirements of the in vitro test system should be documented.

4. Biological test systems should be acclimatised to the test environment for an adequateperiod before the first administration/application of the test, reference or control item.

5. All information needed to properly identify the test systems should appear on their hous-ing or containers. Individual test systems that are to be removed from their housing orcontainers during the conduct of the study should bear appropriate identification, wher-ever possible.

6. During use, housing or containers for test systems should be cleaned and sanitised atappropriate intervals. Any material that comes into contact with the test system shouldbe free of contaminants at levels that would interfere with the study. Bedding for animalsshould be changed as required by sound husbandry practice. Use of pest control agentsshould be documented.

7. Test systems used in field studies should be located so as to avoid interference in the studyfrom spray drift and from past usage of pesticides.

Recommended additions to the text are in bold and underlined. Recommended deletions are initalics and underlined.



study should be appropriately treated, ifpossible, or destroyed, if necessary, tomaintain the integrity of the study. Anydiagnosis and treatment of non-confor-mity before, or during, a study should berecorded.

4. Records of origin (for example, species,tissue), maintenance requirements, iden-tity, source, date of arrival, and arrivalcondition of in vitro test systems shouldbe maintained.

5. Test systems should be acclimatised (ifnecessary) to the test environment for anadequate period before the first adminis-tration or application of the test, controlor reference item. The propagation of thein vitro test system after receipt by thetest facility should be consistent with thestudy plan and/or SOPs.

6. All information needed to properly iden-tify the in vitro test system should be ade-quately recorded throughout the courseof the study. Individual test materials(for example, flasks, plates) that are pre-pared and used during the course of thestudy, should bear appropriate identifica-tion, wherever possible. Individual testsystem containers (i.e. transwells) toosmall to be individually labelled, shouldbe contained in a properly labelled outercontainer.

7. Any material that comes into contactwith the test system should be free ofcontaminants. Sterile equipment andgood culture techniques should be usedwhere appropriate (14).

3.6 TEST, REFERENCE AND CONTROLITEMS

The Principles of GLP specific to these mat-ters are presented in Table 6. The category ofcontrol items has been added to the table,since control items do not meet the definitionof reference items. Control items serve inmonitoring the performance of the test sys-tem(s), but might not necessarily be comparedwith the test item(s) in the same way as a ref-erence item (bench mark material). In manysituations, only the positive control items areclassed as separate item(s), since the negativecontrol items might just be thediluent/medium used to prepare the testitems, the positive controls and/or the refer-ence items.

Procedures must be established that aredesigned to prevent errors in the identifica-tion and cross-contamination of test, control,and reference items and their preparations.These procedures might include, for exam-ple, the separation of storage and handlingareas for control and reference items fromstorage and handling areas for test items.There might also be separation of storageand handling areas for negative controlitems and for test and positive control sub-stances. In addition, other procedures mightbe used to limit the risk of contamination ordegradation; for example, limitations on thenumber of materials which might be manip-ulated at any one time and the strict colourcoding of samples and receiving vessels.

Test, reference and control item account-ability and supervision begin with receipt ofthe materials and continue throughout thelife of the study until the final disposition(archiving, return and/or disposal) of thematerial. Test, reference and control itemaccounting encompasses the systems forreceipt, storage, issue and use (by date andstudy), and final disposition. Once the studyis completed, these records are archived.Good test substance control is demonstratedby a well documented audit trail, supple-mented by checks of operations at criticalpoints.

Demonstration of the concentration, sta-bility and homogeneity of the test, controlor reference item in the vehicle might notbe possible or practical in short-term stud-ies. Unlike many studies where largebatches of material must be prepared andheld for some time (for example, feedingstudies), most in vitro studies involve dilu-tion of the items immediately before useand in relatively small volumes. The studyplan must carefully address the preparationand handling requirements of test, controland reference items in the vehicles used topresent the substance to the test system. Ifanalysis is not to be performed, its exclu-sion should be clearly stated in the studyplan and study report. It might be appro-priate to state this exclusion as part of theGLP compliance statement (see section 3.9)in the study report.

In many situations (including prevalida-tion and validation studies), the laboratorymight be testing test, reference and controlitems which are provided under code fromthe sponsor. In this case, the sponsor would

be responsible for characterisation and forproviding the laboratory with sufficientinformation to handle the test and refer-ence items appropriately. Laboratory safetyis also an issue when testing coded materi-als. It is common practice for the sponsor to

provide some information directly to thelaboratory if there is a particular hazardwhich must be addressed. Safety instruc-tions (for example, material safety datasheets) may be sent to the laboratory safetyofficer or another appropriate agency (for

Table 6: Test, Reference and Control Items

6.1 Receipt, Handling, Sampling and Storage

1. Records including test, reference and control item characterisation, date of receipt,expiry date, and quantities received and used in studies should be maintained.

2. Handling, sampling and storage procedures should be identified in order that the homo-geneity and stability are assured to the degree that possible contamination or mix-up areprecluded.

3. Storage container(s) should carry identification information, expiry date and specific stor-age instructions.

6.2 Characterisation

1. Each test, reference and control item should be appropriately identified (for example,code, Chemical Abstracts Service Registry Number [CAS number], name, biological para-meters).

2. For each study, the identity, including batch number, purity, composition, concentrationsor other characteristics to appropriately define each batch of the test, reference or con-trol items should be known.

3. In cases where the test, reference or control item is supplied by the sponsor, thereshould be a mechanism, developed in cooperation between the sponsor and the test facil-ity, to verify the identity of the test item subject to the study, as appropriate.

4. The stability of test, reference and control items under storage and test conditionsshould be known for all studies.

5. If the test, reference or control item is administered or applied in a vehicle, the homo-geneity, concentration and stability of the test item in that vehicle should be determined,as appropriate. For test items used in field studies (for example, tank mixes), these maybe determined through separate laboratory experiments.

6. A sample from each batch should be retained for analytical purposes for all studies exceptshort-term studies.



example, a poisons control centre) in asealed envelope which is opened only in thecase of an emergency (spill or exposure). Itis important that the supplier of the blindcoded materials takes on these responsibil-ities and provides sufficient information tohelp ensure that the handling of the testitems under code does not affect the out-come of the study.

3.7 STANDARD OPERATINGPROCEDURES

The Principles of GLP specific to SOPs arepresented in Table 7. SOPs are the writtenbody of procedures that govern the proce-dural aspects of the GLP-compliant labora-tory. They should address all the categorieslisted in Table 7. Collectively, they should setthe standards by which the test facility oper-ates, reflecting the expectations of TestFacility Management, the Study Director,and QA.

The procedure for preparing, distributingand maintaining SOPs should be addressedin an SOP. This SOP should describe SOPformat, including section headings and sec-tion numbering, in order to promote consis-tency. SOPs can be written by a variety ofauthors, reflecting the expertise of manyindividuals within the organisation. Inturn, the SOPs should be reviewed and ulti-mately approved by the appropriate signa-tory.

SOPs are controlled to ensure that onlycurrent authorised SOPs are available.Given that they are controlled documents, itis appropriate for every SOP page to have theSOP identifier and version number. Manage-ment should ensure that a responsible indi-vidual has been assigned, such as an SOPadministrator, who is accountable for ensur-ing that SOPs are current, authorised,appropriately distributed, and reviewed on aregular basis.

A copy of each superseded or withdrawnSOP should be maintained in a designatedarchive. In this manner, when reconstruct-ing studies, the SOPs which were current atthe time of a study can be referenced.

If common SOPs are to be issued to all lab-oratories in a multi-site study, it is necessaryto establish, before beginning the study, howSOPs are to be authorised, issued and even-tually archived. Where there are differencesbetween a study plan and SOPs, it should beclarified whether it is the study plan or the

SOPs which are the primary reference forthe study. In multi-site studies, it may behelpful for the lead laboratory to providestudy SOPs to the other laboratories. Thisreduces the workload and helps to assuregreater uniformity in procedures among theparticipating laboratories.

3.8 PERFORMANCE OF THE STUDY

This section includes discussion on the studyplan and performance of a study. The Princi-ples of GLP specific to this area are pre-sented in Table 8.

3.8.1 Controls and acceptance criteria

One of the major additions to the Principlesof GLP proposed by the workshop is the con-cept of assay acceptance criteria for end-points (Table 8).

The responses of a test system to controlitems usually provides the basis for deter-mining the acceptability of an assay. Insome assays, both negative and positivecontrol items are used to determine accep-tance. In other assays, only positive controlresponses are used. The observed positivecontrol response is compared to historicalvalues for the assay to determine whetheror not the response falls within the prede-fined limits given in the study plan�s accep-tance criteria. The range of acceptablevalues is generally derived as a function ofthe historical mean and standard deviationfor the controls. They must also addressthe required precision of the assay. Ideally,each endpoint in an assay should beaddressed by a positive control and have anacceptable range of values. The perfor-mance of the controls also allows compari-son of an assay�s performance in differentlaboratories and over time.

3.8.2 Study preparation

Before the commencement of a study, it canbe useful for the Study Director to have apre-study meeting to discuss the proposedstudy plan. Such a meeting should clarifycommunications throughout the study. Theestablishment of open, two-way communica-tion between the Study Director and studypersonnel is essential to the proper control ofa study. In addition to a discussion of thestudy plan, such a meeting can include prac-tical demonstrations of applicable tech-niques.


Table 7: Standard Operating Procedures

7.1 A test facility should have written Standard Operating Procedures approved by Test Facil-ity Management that are intended to ensure the quality and integrity of the data generatedby that test facility. Revisions to Standard Operating Procedures should be approved byTest Facility Management.

7.2 Each separate test facility unit or area should have immediately available current StandardOperating Procedures relevant to the activities being performed therein. Published textbooks, analytical methods, articles and manuals may be used as supplements to these Stan-dard Operating Procedures.

7.3 Deviations from Standard Operating Procedures related to the study should be docu-mented, and should be acknowledged by the Study Director and Principal Investigator(s),as applicable.

7.4 Standard Operating Procedures should be available for, but not be limited to, the followingcategories of test facility activities. The details given under each heading are to be consid-ered as illustrative examples.

1. Test, Reference and Control ItemsReceipt, identification, labelling, handling, sampling and storage.

2. Apparatus, Materials and Reagentsa) Apparatus

Use, maintenance, cleaning, performance check and calibration.b) Computerised Systems

Validation, operation, maintenance, security, change control and back-up.c) Materials, Reagents and Solutions

Preparation and labelling.

3. Record Keeping, Reporting, Storage and RetrievalCoding of studies, data collection, preparation of reports, indexing systems, handling of data,including the use of computerised systems.

4. Test System (where appropriate)a) Room, area and equipment preparation and environmental room, area and equip-

ment conditions for the test system.b) Procedures for receipt, transfer, proper placement, characterisation, identification and

care of the test system.c) Test system preparation, observations and examinations, before, during and at the con-

clusion of the study.d) Tests for contamination or defects of the test system. Handling of test system indi-

viduals found moribund or dead during the study.e) Collection, identification and handling of specimens (including necropsy and histopathology).f) Siting and placement of test systems in test plots.

5. Quality Assurance ProceduresOperation of Quality Assurance personnel in planning, scheduling, performing, documentingand reporting inspections.




Table 8: Performance of the Study

8.1 Study Plan

1. For each study, a written plan should exist prior to the initiation of the study. The studyplan should be approved by dated signature of the Study Director and verified for GLP com-pliance by Quality Assurance personnel as specified in Table 2. The study plan should alsobe approved by the Test Facility Management and the sponsor, if required by national reg-ulation or legislation in the country where the study is being performed.

2. a) Amendments to the study plan should be justified and approved by dated signatureof the Study Director and maintained with the study plan.

b) Deviations from the study plan should be described, explained, acknowledged and dated in a timely fashion by the Study Director and/or Principal Investigator(s) and maintained with the study raw data.

3. For short-term studies, a general study plan accompanied by a study-specific supplementmay be used.

8.2 Content of the Study Plan

The study plan should contain, but not be limited to, the following information.

1. Identification of the study, the test item(s), reference item(s), negative control item(s),and positive control item(s):a) a descriptive title;b) a statement which reveals the nature and purpose of the study;c) identification of the test item(s) by code or name (IUPAC; CAS number, biological para-

meters, etc.);d) the reference item(s) to be used (if applicable);e) negative control item(s);f) positive control item(s).

2. Information concerning the sponsor and the test facility:a) name and address of the sponsor;b) name and address of any test facilities and test sites involved; c) name and address of the Study Director;d) name and address of the Principal Investigator(s), and the phase(s) of the study dele-

gated by the Study Director and under the responsibility of the Principal Investigator(s);

3. Dates:a) the date of approval of the study plan by signature of the Study Director. The date of

approval of the study plan by signature of the test facility management and sponsor ifrequired by national regulation or legislation in the country where the study is beingperformed;

b) the proposed experimental starting and completion dates.

4. Test methods. Reference to the OECD Test Guideline or other test guideline or method to be used.


3.8.3 Study plan

Sufficient information should be available toprepare a detailed study plan which elimi-nates as much uncertainty in the execution

of the study as possible. It would be hard toover-emphasise the need for careful, detailedpreparation of the study plan. The studyplan includes the conceptual design of thestudy (what is tested and how it is tested),

Table 8: continued

5. Issues (where applicable):a) the justification for selection of the test system(s);b) characterisation of an in vitro test system(s), such as species and tissue of

origin, source of supply, cell designation, culture conditions and other per-tinent information;

c) the method for administration and the reason for its choice;d) the dose levels and/or concentration(s), frequency and duration of administration/

application. Numbers of treatment groups and replicate determinationswithin each treatment group;

e) detailed information on the experimental design, including a description of the chrono-logical procedure of the study, all methods, materials and conditions, use of positiveand negative controls, type and frequency of analysis, measurements, observationsand examinations to be performed, and statistical methods to be used;

f) assay acceptance criteria for endpoints.

6. Records. A list of records to be retained, including their location.

8.3 Conduct of the Study

1. A unique identification should be given to each study. All items concerning this studyshould carry this identification. Specimens from the study should be identified to confirmtheir origin. Such identification should enable traceability, as appropriate for the speci-men and study.

2. The study should be conducted in accordance with the study plan.

3. All data generated during the conduct of the study should be recorded directly, promptly,accurately and legibly by the individual entering the data. These entries should be signedor initialled and dated.

4. Any change in the raw data should be made so as not to obscure the previous entry, shouldindicate the reason for change, and should be dated and signed or initialled by the indi-vidual making the change.

5. Data generated as a direct computer input should be identified at the time of data inputby the individual(s) responsible for direct data entries. Computerised system designshould always provide for the retention of full audit trails to show all changes to the datawithout obscuring the original data. It should be possible to associate all changes to datawith the persons having made those changes, for example, by use of timed and dated (elec-tronic) signatures. Reason for changes should be given.




the raw data to be obtained, the manipula-tions of the raw data to produce the studyendpoint values, the interpretation schemefor endpoints, and the acceptance criteria forthe study. The study plan must be written insuch a way as to preclude misinterpretationby the study personnel. This requirement isparticularly important when more than onelaboratory will use the same study plan.

In a multi-site study, the study planshould include the name and address of thePrincipal Investigator, the location of thetest site(s), the study-part(s) performed, themethods and statistical parameters used, thelocation where the documentation relating tothe part for which the Principal Investigatoris responsible is archived, the GLP regula-tions followed (according to national require-ments), and any time schedules necessary forthe conduct of the study. A study planamendment will be necessary if a new Prin-cipal Investigator and new test site becomeinvolved in the study. The study plan shouldinclude procedures for the recording of studydata to ensure consistency of data recordingat all of the sites in a multi-site study, and tomeet the requirements of data management.

In addition to the study plan which identi-fies the records to be retained or archived, itis also appropriate to address at which loca-tions archived records will be kept.

The study plan becomes an authoriseddocument when it is signed by the StudyDirector, Test Facility Management and thesponsor, if applicable. The study plan shouldbe distributed to study personnel and QApersonnel, who need to be informed of stud-ies so that QA inspections can be planned.Obtaining signatures in a multi-site studycan be a lengthy process. It might be accept-able, subject to written procedures, for fac-similied signatures to be used in order toallow the study plan and amendments to beissued in a timely manner.

A study plan is distinct from the trial plan,which is specific to multi-study trials and isdiscussed later.

3.8.4 Study plan amendments

If a change to the original study plan is pro-posed, a study plan amendment should beissued before the change occurs. An amend-ment may also be issued as a result of unex-pected occurrences during a study, whichwill require significant action. Study planamendments should be sequentially num-

bered, indicate the reason for the change,and include the dated signature of the StudyDirector and, if applicable, those of the Prin-cipal Investigators and Test Facility Man-agement. All amendments should bedistributed to all recipients of the originalstudy plan.

3.8.5 Notes to file

A note to file provides a means of recordingstudy information, such as a study plan devi-ation. Notes to file can be initiated by anystudy personnel, but should be acknowl-edged by the Study Director, who shouldapprove any corrective action and decideupon the recipients of notes to file. Sequen-tial numbering of notes to file assists studycontrol. Significant deviations from thestudy plan might be best documented asstudy plan amendments.

3.8.6 Raw data

Study personnel must have a clear under-standing of what constitutes raw data. Thedefinition of raw data (see Appendix 1) mustbe documented.

Raw data records should enable the recon-struction of the study. They should also beable to explain who did what, when, by whatmeans, why and where. To do so, data mustbe generated completely, accurately, legiblyand promptly. Entries should be signed orinitialled and dated. Corrections should bemade without obscuring the original entry.Corrections should also be dated and signed,and the reason for the correction should begiven. Raw data not only involve study-spe-cific documentation (performance of astudy), but also the more general recordsconcerning apparatus, material andreagents, and handling of test, control andreference items and of test systems. During astudy, raw data should be maintained in safestorage areas prior to transfer to archives forlong-term secure retention.

3.8.7 Quality control

The conduct of the study should includequality control (QC) steps, undertaken bystudy personnel, as described in SOPs. QCsteps should be undertaken when there is aneed for verification, especially at a datainterface. For example, manual entry of rawdata should be checked by another studymember. If the data being checked are criti-

cal, i.e. one error in the data could affectstudy integrity, all such data should be con-sidered for checking. If the data beingchecked are non-critical, consideration canbe given to checking samples of data (forexample, a sample from each analyticalbatch).

3.8.8 Confidentiality issues

In multi-site studies, it should be ensuredin advance that confidentiality issues willnot impede the flow of information betweeninstitutions. It may be appropriate forstudy personnel to sign confidentialitystatements.

3.9 REPORTING OF STUDY RESULTS

The Principles of GLP specific to the report-ing of study results are presented in Table 9.The OECD Principles of GLP employ theterm �final report�. In the current docu-ment, �study report� is used instead of finalreport, in order to keep study report distinctfrom the trial report, i.e. the report of amulti-study prevalidation and validationtrial (see section 4.4).

Study reports should be prepared in atimely manner. The Study Director shouldsign and date the study report to indicateacceptance of responsibility for the validityof the data and that the study report accu-rately reflects work conducted and all theresults obtained. The study report for amulti-site study should identify and definethe role of any Principal Investigators andtest sites involved in the conduct of thestudy.

The study report should include a GLPcompliance statement, which is a formalrecord to confirm that the study was con-ducted and reported in accordance withGLP, clearly identifying, as appropriate,where the study deviated from GLP. TheGLP compliance statement is signed anddated by the Study Director and shouldaddress, in particular, the GLP status of anytest sites not within a national GLP compli-ance programme.

In a multi-site study, it might be appropri-ate for the Principal Investigator to include asigned GLP compliance statement in thecontributory report that is forwarded to theStudy Director.

The GLP compliance statement should notbe confused with the QA statement, also pre-

sented in the study report, which is a distinctand separate record of QA study monitoring.

The Study Director should authorise andsign any subsequent corrections and/or addi-tions to the study report.

3.10 STORAGE AND RETENTION OFRECORDS AND MATERIALS

The principles of GLP specific to records arepresented in Table 10.

On completion of a study, the Study Direc-tor is responsible for ensuring that all studydata are transferred in a timely manner tothe archives, as described in the studyreport. If study data are archived at severallocations, it should be remembered that, ifthe study is subject to regulatory audit, itcould be necessary, at short notice, for allstudy data to be transferred to one locationfor the audit.

Once archived, the responsibility for thesafe keeping of study data passes from theStudy Director to Test Facility Manage-ment, which has responsibility for ensuringthat there are designated personnel respon-sible for the archives, and that the archivesare secure areas with the contents indexedin an orderly manner. The duration ofarchiving should be in accordance with reg-ulatory requirements or as specified byTest Facility Management.

4 MULTI-STUDY TRIALS

4.1 TRIAL MANAGEMENT TEAM

The sponsor of a multi-study trial appointsa Trial Management Team to have respon-sibility for overseeing the organisation,conduct and reporting of the trial (6, 15).The Trial Management Team does not haveimmediate responsibility for ensuring GLPcompliance, since it is Test Facility Man-agement which has direct GLP responsibil-ity. However, there are some Principles ofGLP which can be usefully applied to theTrial Management Team. For example, thetrial plan should identify the key responsi-bilities of specific members of the TrialManagement Team, including that of thechairperson and Trial Coordinator. Itmight be appropriate to designate an indi-vidual in the Trial Management Team tocoordinate GLP compliance issues; how-ever, the responsibility for GLP at a test



Table 9: Reporting Study Results

9.1 General

1. A study report should be prepared for each study. In the case of short-term studies, astandardised study report accompanied by a study-specific extension may be prepared.

2. Reports of Principal Investigators or scientists involved in the study should be signed anddated by them.

3. The study report should be signed and dated by the Study Director to indicate acceptanceof responsibility for the validity of the data. The extent of compliance with these Princi-ples of Good Laboratory Practice should be indicated.

4. Corrections and additions to a study report should be in the form of amendments.Amendments should clearly specify the reason for the corrections or additions and shouldbe signed and dated by the Study Director.

5. Reformatting of the study report to comply with the submission requirements of anational registration or regulatory authority does not constitute a correction, addition oramendment to the study report.

9.2 Content of the Study Report

The study report should include, but not be limited to, the following information.

1. Identification of the study, the test item(s), reference item(s) and control items:a) a descriptive title; b) identification of the test items by code or name (IUPAC, CAS number, biological para-

meters, etc.);c) identification of the reference and control items, by name;d) characterisation of the test item including purity, stability and homogeneity.

2. Information concerning the sponsor and the test facility:a) name and address of the sponsor;b) name and address of any test facilities and test sites involved;c) name and address of the Study Director;d) name and address of the Principal Investigator(s) and the phase(s) of the study dele-

gated, if applicable;e) name and address of scientists having contributed reports to the study report.

3. Dates. Experimental starting and completion dates.

4. Statement. A Quality Assurance programme statement listing the types of inspectionsmade and their dates, including the phase(s) inspected, and the dates any inspectionresults were reported to management and to the Study Director and Principal Investiga-tor(s), if applicable. This statement would also serve to confirm that the study reportreflects the raw data.


facility remains with Test Facility Manage-ment. Some of the required responsibilitiesof the Trial Management Team are illus-trated in Figure 4 (6, 13). The Trial Man-agement Team is responsible for theselection of participating laboratories, butnot for the appointment of Study Directors,who are appointed by Test Facility Man-agement.

4.2 TRIAL PLAN

The trial plan outlines the trial goals andproposed time-scales, and identifies the stud-ies, all the participating facilities and thenames of Test Facility Management, StudyDirectors and Principal Investigators. Wherethere is no formal Study Director or Princi-pal Investigator, as might be the case forfacilities undertaking test item supply, datamanagement and statistics, the personresponsible for the technical conduct of thework should be identified.

The trial plan should include: a) the iden-tity of the Trial Coordinator; b) SOP admin-istration, if common SOPs are to be usedacross studies; c) arrangements for QA mon-itoring of study activities, including any pre-trial inspections; and d) the identity ofarchiving locations.

The trial plan must be signed by at leastthe chairperson of the Trial ManagementTeam. The final trial plan should be identi-fied as final, be fully authorised, and issued

on a need-to-know basis. Any changes to thetrial plan should result in a trial plan amend-ment, in the same manner that any changesto a study plan result in a study plan amend-ment. Trial plan amendments must be num-bered, sequentially, and should be issued toall the original recipients of the trial plan.

4.3 TRIAL COORDINATOR�S RESPONSIBILITIES

The name and location of the Trial Coordi-nator should be identified in each of the indi-vidual study plans as the person responsiblefor coordinating the supply and analysis oftest, reference and control items and thecoordination and preparation of the trialreport. It should be clarified whether theTrial Coordinator has direct access to thetest item coding.

The Trial Coordinator�s responsibilitiesinclude:

1. Responsibility for the coordination andcommunication network for test, refer-ence and control item supply and analy-sis, data management and statistics forall the studies in a multi-study trial.

2. Ensuring that document and data flowbetween facilities are recorded.

3. Ensuring that QA monitoring is beingundertaken in accordance with the trialplan.

Table 9: continued

5. Description of materials and test methods:a) description of methods and material used; b) reference to OECD Test Guideline or other test guideline or method.

6. Results:a) a summary of results;b) all information and data required by the study plan;c) a presentation of the results, including calculations, determinations of statistical sig-

nificance (if appropriate) and historical control data;d) an evaluation and discussion of the results and, where appropriate, conclusions.

7. Storage: The location(s) where the study plan, samples of test, reference and controlitems, specimens, raw data and the study report are to be stored.




4. Assessing and documenting the impact ofany amendments and/or deviations fromthe trial plan and study plans on the qual-ity and integrity of the multi-study trial.

5. Ensuring that the individual studyreports are forwarded, in a timely man-ner, for data and statistical analysis.

6. Preparing the trial report, which can beallocated to a Study Director or an inde-pendent person.

7. Ensuring that the trial report is an accu-rate reflection of the overall multi-studytrial. The Trial Coordinator signs anddates the final trial report to confirm thatthe trial report is an accurate account ofthe multi-study trial.

8. Ensuring that the trial documentation isproperly archived.

4.4 TRIAL REPORT

The trial report summarises the trial goals,procedures, results and conclusions of a multi-study trial. This represents the whole multi-study trial, including archiving and, as such,will cover several study reports, as well asreports for test item supply, data managementand statistics. The preparation of the trialreport is outlined in Figure 5. The Trial Coor-dinator oversees the preparation of the trialreport. The Trial Coordinator might also beresponsible for preparation of the scientificconclusions. Signatories to the trial reportinclude the Trial Coordinator, the chairperson

Table 10: Storage and Retention of Records and Materials

10.1 The following should be retained in the archives for the period specified by the appro-priate authorities:a) the study plan, raw data, samples of test, reference and control items, specimens

and the study report of each study;b) records of all inspections performed by the Quality Assurance programme, as well as

Master Schedules;c) records of qualifications, training, experience and job descriptions of personnel;d) records and reports of the maintenance and calibration of apparatus;e) validation documentation for computerised systems;f) the historical file of all Standard Operating Procedures;g) environmental monitoring records.

In the absence of a required retention period, the final disposition of any study materialsshould be documented. When samples of test, reference and control items and specimens aredisposed of before the expiry of the required retention period for any reason, this should bejustified and documented. Samples of test, reference and control items and specimensshould be retained only as long as the quality of the preparation permits evaluation.

10.2 Material retained in the archives should be indexed in order to facilitate orderly storageand retrieval.

10.3 Only personnel authorised by management should have access to the archives. Move-ment of material in and out of the archives should be properly recorded.

10.4 If a test facility or an archive-contracting facility goes out of business and has no legalsuccessor, the archive should be transferred to the archives of the sponsor(s) of thestudy(s).


of the Trial Management Team, the statisti-cian, and the Study Directors. Although theStudy Directors may not be involved with thepreparation of the trial report, their signa-tures confirm that the trial report is an accu-rate reflection of study events. The trial reportshould contain a statement, signed by theTrial Coordinator, commenting on the accu-racy and completeness of the trial report andidentifying any significant issues which couldhave affected the integrity of the trial, includ-

ing matters of GLP compliance. A QA state-ment could be included in the trial report, inorder to identify what QA monitoring wasdone and to confirm whether or not the trialreport is an accurate reflection of the studydata.

4.5 QUALITY ASSURANCE OF MULTI-STUDY TRIALS

Multi-study trials can involve independentfacilities which are not formally GLP-compli-

Figure 4: Overview of management for a multi-study validation trial


SponsorFinancesContracts

Quality assuranceInspections to assure

compliance

Trial Management Team(Trial Coordinator)

Trial goalsDesign and trial planApproval of trial plan and overall trial report

Tests/LaboratoriesSelection of testsIdentification of laboratories

Identification of lead laboratories

Approval of Standard Operating Procedures

ChemicalsControl of quality of in vivo data

Selection of chemicalsCodingDistributionSafety

DataPlanning of data structure

Data handlingData analysis



ant, such as facilities for test item analyses.However, the QA monitoring of such facili-ties is advised, to assure compliance with therelevant principles of GLP. Also, this pre-sents the opportunity for QA personnel tomonitor data exchange between facilities.

QA reports should be forwarded to the rele-vant facilities and also to the Trial Coordina-tor. In addition, the production of summaryand periodic QA reports, that would be issuedto the Trial Management Team and sponsorshould be considered. QA review of the trialreport is appropriate, to provide independentassurance that the trial report is an accuratereflection of the study reports and also thetrial data and trial chemical reports.

5 CONCLUSIONS ANDRECOMMENDATIONS

5.1 GOOD LABORATORY PRACTICEPROMOTES CONFIDENCE IN THEDATA

1. The primary GLP reference for thisworkshop, the OECD Principles of

GLP, describes a quality system con-cerned with the organisation and theconditions under which regulatorystudies are planned, performed, moni-tored, recorded, archived and reported.Undertaking studies in compliancewith GLP demonstrates to the regula-tory authorities that studies wereundertaken in a manner which pro-motes confidence in the data andreporting.

5.2 GOOD LABORATORY PRACTICECOMPLIANCE

2. A test facility might only be able to claimformal GLP compliance if it is within acompliance programme run by the rele-vant national GLP monitoring author-ity. The QA monitoring of a facility notwithin a compliance programme, doesnot confer GLP compliance. Studyreports and trial reports must clearlyidentify facilities which did not adhere toformal GLP and address any impact thismight have had on study or trialintegrity.

Figure 5: Preparation of the Trial Report

aSeveral Quality Assurance units might be involved in a multi-study trial.

Dashed lines indicate assurance staff involvement.

Sponsor

Trial CoordinatorOverall trial report

Study DirectorsStudy reports

Chemical SupplierTrial chemical report

StatisticianTrial data report

Quality assurancea

Inspections andaudits

3. If a test facility has designated GLP-compliant areas and non-GLP areas, it isessential that GLP compliance in theGLP areas is not compromised by thenon-GLP areas. Maintenance of GLPand non-GLP areas in the same facilityrequires constant vigilance to ensurecompliance of the GLP areas.

4. A test facility might conduct both �regu-latory studies�, intended for review bythe regulatory authorities, and �non-regulatory� studies, which are notintended for submission to the regula-tory authorities. Where this is the prac-tice in the same GLP area, it will benecessary for the non-regulatory work toalso be conducted in compliance withGLP. Essentially, the main differencesbetween such regulatory and non-regu-latory studies are that the latter may besubject to reduced QA monitoring andhave a reduced amount of specific GLPdocumentation requirements.

5.3 STUDY CONDUCT

5. The management of single-site andmulti-site studies, including the keyroles of Study Director and PrincipalInvestigator, as described in the OECDPrinciples of GLP, are considered rele-vant to the conduct of in vitro studies.

6. To ensure the applicability of GLP to invitro studies, some additions are neces-sary to the OECD Principles of GLP,most notably with respect to: a) defini-tion of test system facilities, with specialreference to handling and storage of testitems; b) characterisation and care oftest systems; c) the required use of posi-tive and negative control items; and d)acceptance criteria.

7. The concept of acceptance criteria is oneof the major additions to the Principlesof GLP proposed by the workshop. Theresponses of a test system to controlitems usually provides the basis fordetermining the acceptability of anassay. The observed control response iscompared to historical values for theassay, to determine whether or not theresponse falls within predefined limitsgiven in the study plan acceptance crite-ria. The performance of the controls alsoallows comparison of the performance of

an assay among laboratories and overtime.

5.4 QUALITY ASSURANCE

8. The principles of GLP include therequirement for QA monitoring by per-sonnel independent of the proceduresbeing inspected. QA is based on organi-sational rather than scientific proce-dures. Therefore, QA does not interferewith the technical and scientific conductof studies.

5.5 VALIDATION AND MULTI-STUDYTRIALS

9. The validation of in vitro tests is under-taken as multi-study trials, consisting ofa number of separate studies, with eachstudy, having its own study plan andStudy Director. Each study within a for-mal validation multi-study trial, is con-ducted and reported without knowledgeof the test item randomisation code.

10. Multi-study trials are overseen by aTrial Management Team which isresponsible for the selection of partici-pating facilities. However, it is the TestFacility Managements of the participat-ing laboratories who have responsibilityfor the GLP compliance of facilities,including the appointment of StudyDirectors.

11. A trial plan serves to outline the multi-study trial and includes trial goals andtime-scales, and identifies participatingfacilities and key personnel. The trialplan becomes a formal document when itis signed by the chairperson of the TrialManagement Team, and the Trial Coor-dinator.

12. The Trial Coordinator undertakes apivotal role in ensuring compliance ofthe multi-study trial with the trial plan,including preparation of the trialreport.

6 ACKNOWLEDGEMENTS

The authors would like to thank Dr MelanieScheiwiller (Novartis, Pharma AG, Switzer-land) and Mr Mike Burrows (Guy�s DrugResearch Unit, Quintiles, London, UK) forcommenting on the draft report.



7 REFERENCES

1. ECVAM (1994). ECVAM News & Views. ATLA22, 7�11.

2. OECD (1998). Organisation for Economic Cooper-ation and Development series on Principles ofGood Laboratory Practice and compliance moni-toring. Number 1. OECD Principles on Good Lab-oratory Practice (as revised in 1997), OECDEnvironmental Health and Safety Publications,Environment Directorate: ENV/MC/CHEM(98)17. Paris, France: OECD.

3. OECD (1992). Environment Monograph No. 50,Series on Principles of Good Laboratory Practiceand Compliance Monitoring: Number 6, TheApplication of the GLP Principles to Field Stud-ies. Paris, France: OECD.

4. Stiles, T. (1997). The revised OECD principles ofGood Laboratory Practice: a reflection upon theimpact of the proposed changes on pre-clinicalsafety testing. Part 1. Scope, definition of terms,responsibilities. The Quality Assurance Journal2, 13�18.

5. Stiles, T. (1997). The revised OECD Principles ofGood Laboratory Practice: a reflection upon theimpact of the proposed changes on pre-clinicalsafety testing. Part 2. Scope, definition of terms,responsibilities. The Quality Assurance Journal2, 49�53.

6. Balls, M., Blaauboer, B.J., Fentem, J.H., Bruner,L., Combes, R.D., Ekwall, B., Fielder, R.J., Guil-louzo, A., Lewis, R.W., Lovell, D.P., Reinhardt,C.A., Repetto, G., Sladowski, D., Speilmann, H. &Zucco, F. (1995). Practical aspects of the valida-tion of toxicity test procedures. ATLA 23,129�147.

7. Harbell, J.W., Southee, J.A. & Curren, R.D.(1997). The path to regulatory acceptance of invitro methods is paved with the strictest scientificstandards. In Animal Alternatives, Welfare andEthics (ed. L.F.M van Zutphen & M. Balls), pp.1177�1181. Amsterdam, The Netherlands: Else-vier.

8. Anon. (1999). Adapting to technical progress forthe second time the Annex to Council Directive

88//320/EEC on the inspection and verification ofGood Laboratory Practice (GLP). CommissionDirective 1999/12/EC. Official Journal of theEuropean Communities 77, 22�33.

9. OECD (1998). Organisation for Economic Co-operation and Development series on Principlesof Good Laboratory Practice and compliance mon-itoring. Number 3 (Revised). Guidance for GLPmonitoring authorities revised guidance for theconduct of laboratory inspections and study audit,Environment Monograph No. 111, OECD Envi-ronmental Health and Safety Publications:OECD/GD(95)67. Paris, France: OECD.

10. Anon. (1999). Adapting to technical progress thePrinciples of Good Laboratory Practice as speci-fied in Council Directive 87/18/EEC on the har-monisation of laws, regulations andadministrative provisions relating to the applica-tion of the principles of good laboratory practiceand the verification of their applications for testson chemical substances. Commission Directive1999/11/EC. Official Journal of the EuropeanCommunities 77, 8�21.

11. Balls, M. & Karcher, W. (1995). The validation ofalternative test methods. ATLA 23, 884�886.

12. Curren, R.D., Southee, J.A., Spielmann, H., Lieb-sch, M., Fentem, J.H. & Balls, M. (1995). The roleof prevalidation in the development, validationand acceptance of alternative methods. ATLA 23,211�217.

13. Fentem, J.H., Archer, G.E.B., Balls, M., Botham,P.A., Curren, R.D., Earl, L.K., Esdaile, D.J.,Holzhütter, H-G. & Liebsch, M. (1998). TheECVAM international validation study on in vitrotests for skin corrosivity. 2. Results and evalua-tion by the Management Team. Toxicology inVitro 12, 483�524.

14. Froud, S.J. & Luker, J. (1994). Good LaboratoryPractice in the cell culture laboratory. In BasicCell Culture: A Practical Approach (ed. J.M.Davis), pp. 273�286. Oxford, UK: Oxford Univer-sity Press.

15. Cooper-Hannan, R. (1997). Good LaboratoryPractice and study management for the valida-tion of in vitro toxicity studies. ATLA 12,527�537.

These terms are based on the terms con-tained in the OECD Principles of Good Lab-oratory Practice. Recommended additionsare in bold and underlined.

Good Laboratory Practice

Good Laboratory Practice (GLP). Aquality system concerned with the organisa-tional process and the conditions underwhich non-clinical health and environmentalsafety studies are planned, performed, moni-tored, recorded, archived and reported.

Terms concerning the organisation of a testfacility

Master Schedule. A compilation of infor-mation to assist in the assessment of work-load and for the tracking of studies at a testfacility.

Principal Investigator. An individualwho, for a multi-site study, acts on behalf ofthe Study Director and has defined responsi-bilities for delegated phases of the study. TheStudy Director�s responsibility for the over-all conduct of the study cannot be delegatedto the Principal Investigator; this includesapproval of the study plan and its amend-ments, approval of the study report, andensuring that all applicable Principles ofGood Laboratory Practice are followed.

Quality Assurance Programme. Adefined system, including personnel, whichis independent of study conduct and isdesigned to assure Test Facility Manage-ment of compliance with these principles ofGood Laboratory Practice.

Sponsor. An entity which commissions,supports and/or submits a non-clinicalhealth and environmental safety study.

Standard Operating Procedures(SOPs). Documented procedures whichdescribe how to perform tests or activitiesnormally not specified in detail in studyplans or test guidelines.

Study Director. The individual responsi-ble for the overall conduct of the non-clin-

ical health and environmental safetystudy.

Test Facility. The persons, premises andoperational unit(s) that are necessary forconducting the non-clinical health andenvironmental safety study. For multi-sitestudies (studies conducted at more thanone site), the test facility comprises the siteat which the Study Director is located andall individual test sites, which individuallyor collectively can be considered to be testfacilities.

Test Facility Management. The personswho have the authority and formal responsi-bility for the organisation and functioning ofthe test facility according to these Principlesof Good Laboratory Practice.

Test Site. A location at which a phase of astudy is conducted.

Test Site Management (if appointed). Theperson responsible for ensuring that thephase of the study, for which he/she isresponsible, are conducted according to thesePrinciples of Good Laboratory Practice.

Terms concerning the study

Acceptance Criteria. The basis fordetermining the acceptability of anassay according to pre-defined perfor-mance parameters.

Experimental Completion Date. The lastdate on which data are collected from thestudy.

Experimental Starting Date. The date onwhich the first study-specific data are col-lected.

Good Laboratory Practice ComplianceStatement. A formal record, signed anddated by the Study Director, to indicateacceptance of responsibility for the validityof the data and to indicate the extent towhich the study complies with Good Labora-tory Practice.

Non-clinical Health and Environmen-tal Safety Study. Henceforth referred to

8 Appendix 1

Terminology


simply as �study�, is an experiment or setof experiments in which a test item(s) isexamined under laboratory conditions or inthe environment, to obtain data on its prop-erties and/or its safety, intended for sub-mission to appropriate regulatoryauthorities.

Quality Assurance Statement. A formalrecord listing the types of inspections madeand their dates, including the phaseinspected, and the dates any inspectionresults were reported to Management, and tothe Study Director and Principal Investiga-tor, if applicable. This statement also servesto confirm that the final report reflects theraw data, as appropriate.

Raw Data. All original test facility recordsand documentation, or verified copiesthereof, which are the result of the originalobservations and activities in a study. Rawdata can also include photographs, micro-film or microfiche copies, computer read-able media, dictated observations, recordeddata from automated instruments, or anyother data storage medium that has beenrecognised as capable of providing securestorage of information for the requiredtime-period.

Short-term Study. A study of short dura-tion with widely used, routine techniques.

Specimen. Any material derived from a testsystem for examination, analysis, or reten-tion.

Study Completion Date. The date onwhich the Study Director signs the studyreport.

Study Initiation Date. The date on whichthe Study Director signs the study plan.

Study Plan. A document which defines theobjectives and experimental design for theconduct of the study, and includes anyamendments.

Study Plan Amendment. An intendedchange to the study plan after the study ini-tiation date.

Study Plan Deviation. An unintendeddeparture from the study plan after thestudy initiation date.

Study Report. A document whichreports the objectives, procedures,results and conclusions of a study.

Test System. Any biological, chemical orphysical system, or combination thereof,used in a study.

Terms concerning the test, reference andcontrol items

Batch. A specific quantity or lot of a test,reference or control item produced dur-ing a defined cycle of manufacture in sucha way that it could be expected to be of auniform character and should be desig-nated as such.

Control Item. An article used to moni-tor the performance of an assay, whichmight not necessarily be used in thesame manner as a reference item.

Reference Item. Any article used to pro-vide a basis for comparison with the testitem.

Test Item. An article that is the subject of astudy.

Vehicle. Any agent which serves as a carrierused to mix, disperse, or solubilise the test,reference or control item to facilitate theadministration/application to the test sys-tem.

Terms covering prevalidation andvalidation

Prevalidation Study. A study carriedout following test development, butprior to the possible inclusion of a testin a formal validation study. This neednot, but usually does, include the blindtesting of coded chemicals.

Validation. The process by which thereliability and relevance of a procedureare established for a specific purpose.The main goal is to conduct multi-sitetrials with coded test items, as a basisfor assessing whether one or moretests, test batteries or testing strategiescan be shown to be relevant and reli-able for one or more specific purposes,according to predefined performancecriteria.

Terms concerning multi-study trials

Multi-study Trial. A set of studies whichcan be used to compare methods and/ortest item(s) and generally refers toprevalidation/validation studies.


Trial Coordinator. The individual whocoordinates the overall conduct andreporting of a multi-study trial.

Trial Management Team. The personswho have responsibility for overseeingthe organisation, conduct and report-ing of a multi-study trial.

Trial Plan. A document which outlinesthe goals, design, participants and pro-posed time-scales of the multi-studytrial.

Trial Report. The document which sum-marises the goals, procedures, resultsand conclusions of a multi-study trial.


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