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ATLA 27, 539–577, 1999 539
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 Michael

Balls,5 Gerard Bowe,5 Miroslav Cervinka,6 Richard Clothier,7 Frauke

Hermann,8 Lynn K. Klahm,9 Jan de Lange,5 Manfred Liebsch10 and
Philippe Vanparys11
3Qualitas, Danworth Lane, Hurstpierpoint, West Sussex BN6 9LN, UK; 4Institute for In
Vitro 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, Hradec
Králové, Czech Republic; 7FRAME Alternatives Laboratory, University of Nottingham
Medical School, Queen’s Medical Centre, Nottingham NG7 2UH, UK; 8RCC Cytotest Cell
Research, In den Leppsteinwiessen 19, 64380 Rossdorf, Germany; 9Human and
Environmental Safety Division, The Procter and Gamble Company, Cincinnati, OH, USA;
10ZEBET, BgVV, Diedersdorfer Weg 1, 12277 Berlin, Germany; 11Genetic and In Vitro
Toxicology, Janssen Pharmaceutica, Turnhoutse Weg 30, 2340 Beerse, Belgium
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 agreed
report of the participants as individual scientists and quality assurance personnel.
540 R. Cooper-Hannan et al.
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 . . . . . . . . . . . . . . . . . 546

3.1.1 Test Facility Management’s responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . 546
3.1.1.1 Study Director . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546
3.1.1.2 Principal Investigator. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547
3.1.1.3 Organisation chart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547
3.1.1.4 Master Schedule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 548
3.1.1.5 Site plans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 548
3.1.1.6 Personnel records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 548
3.1.1.7 Standard Operating Procedures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549
3.1.2 Test Site Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549
3.1.3 Study Director’s responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549
3.1.4 Principal Investigator and study personnel . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551
3.1.4.1 Principal Investigator. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551
3.1.4.2 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

ECVAM Workshop 37: Good Laboratory Practice 541
3.8 PERFORMANCE OF THE STUDY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562

3.8.1 Controls and acceptance criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562
3.8.2 Study preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562
3.8.3 Study plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565
3.8.4 Study plan amendments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566
3.8.5 Notes to file . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566
3.8.6 Raw data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566
3.8.7 Quality control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566
3.8.8 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

PREFACE
This is the report of the thirty-seventh of a series of workshops organised by the European
Centre for the Validation of Alternative Methods (ECVAM). ECVAM’s main goal, as defined
in 1993 by its Scientific Advisory Committee, is to promote the scientific and regulatory
acceptance of alternative methods which are of importance to the biosciences and which
reduce, refine or replace the use of laboratory animals. One of the first priorities set by
ECVAM 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 the
potential for the possible incorporation of alternative tests into regulatory procedures. It was
decided that this would be best achieved by the organisation of ECVAM workshops on specific
topics, at which small groups of invited experts would review the current status of in vitro
tests and their potential uses and make recommendations about the best ways forward (1). In
addition, other topics related to the Three Rs (reduction, refinement, replacement) concept of
alternatives to animal experiments have been considered in several ECVAM workshops.
ECVAM brought together experts in the field of cell culture technology and Good Laboratory
Practice (GLP) to stimulate the use and acceptance of in vitro toxicology data during the human
risk assessment process, at both the European and world levels. The ECVAM workshop on The
Principles of Good Laboratory Practice: Application to In Vitro Toxicology Studies was held in
Angera, 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 assurance
personnel from industry, academia and government. The aim of the workshop was to discuss
and make recommendations on the application of the OECD Principles of GLP to good quality
cell and tissue culture practices. In addition to reviewing the application of GLP to single-site
and multi-site studies, this document pays specific attention to multi-study in vitro toxicology
trials, 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 toxicology
studies should be carried out under GLP, to facilitate the regulatory acceptance of high quality
validated in vitro tests.
1 INTRODUCTION GLP, and outlines the types of studies which

this document addresses (single-site and
The Principles of GLP are intended to iden- multi-site studies and multi-study trials).
tify the GLP requirements for test facilities The OECD Principles of GLP are presented,
(laboratories) which perform studies for reg- in tabular form, with additions and modifica-
ulatory purposes. These principles define a tions applicable to in vitro studies. The
quality system concerned with the organisa- OECD Principles of GLP primarily address
tional process and the conditions under the needs of single-site and multi-site studies
which studies are planned, performed, moni- (2–5). The application of GLP to prevalida-
tored, recorded, reported and archived. GLP tion and validation in multi-study trials
is concerned with the quality of test data and involving blind-coded chemicals is a special
the management of quality studies. The gen- case, for which additional guidelines are nec-
eration of test data according to current sci- essary. Therefore, this report also discusses
entific knowledge and good management the organisation of multi-study trials, includ-
practices has been seen as the best way of ing the terms “trial plan” and “trial report”.
promoting the reliability, and hence the Definitions of terms used in the OECD
international acceptability, of data. GLP Principles of GLP are presented in Appendix
addresses an overall structure intended to 1. Amendments and additional terms, as
promote and maintain quality data. Being a defined by the workshop participants, are
management practice, these principles do presented as bold and underlined text.
not interfere with the use of scientific knowl-
edge or practices, but rather complement it. 1.1 SCOPE OF THE PRINCIPLES OF
The Principles of GLP were originally GOOD LABORATORY PRACTICE
written to address animal-based toxicology.
The OECD Principles of GLP are intended to
However, there has been a growing appreci-
be applied to the non-clinical safety testing of
ation that certain additions/modifications
test items contained in pharmaceuticals, pes-
are required to meet the current state-of-the-
ticides, cosmetics and veterinary drugs, as
art for in vitro studies and to assure the qual-
well as medical devices, food additives, feed
ity of the data they provide. To this end,
additives and industrial chemicals. These
ECVAM and the Institute for In Vitro Sci-
test items are frequently synthetic chemi-
ences (IIVS) convened the workshop on GLP.
cals, but can be of natural or biological origin
It should be emphasised that this workshop
and, in some circumstances, can be living
was not an effort to diminish the Principles
organisms. The purpose of testing these
of GLP, but to enhance them. It drew on suc-
items is to obtain data on their properties
cessful approaches used by industry, quality
and/or their safety with respect to human
assurance professionals and regulatory agen-
health and/or the environment.
cies with in vitro bioassays. The primary
The OECD has stated that “Data gener-
goals were: a) to recommend additions/modi-
ated in the testing of chemicals in an OECD
fications to the OECD Principles of GLP
Member Country in accordance with OECD
needed to address the specific needs of in
Test Guidelines and OECD Principles of
vitro bioassays (for example, test system
Good Laboratory Practice shall be accepted
characterisation, facilities); b) to formalise
in other Member Countries for purposes of
standards of practice to ensure quality data
assessment and other uses relating to the
from in vitro studies (for example, use of con-
protection of man and the environment”.
trols and performance standards); c) to pro-
Therefore, it is relevant to validate the
vide assistance in the implementation of the
increasing numbers of in vitro toxicology
Principles of GLP; and d) to address the spe-
studies in accordance with GLP, in order to
cific needs of prevalidation and validation
facilitate their acceptance by Member Coun-
with respect to in vitro toxicology multi-
tries (6, 7).
study trials.
The current OECD Principles of GLP,
1.2 HISTORY OF THE PRINCIPLES OF
which were adopted by the OECD in 1997
GOOD LABORATORY PRACTICE
(2), were used as the primary GLP reference
for this workshop report. In 1975, the US Food and Drug Administra-
The report commences with a general tion (FDA) raised concerns about the quality
account of GLP, including the history of and integrity of some safety studies submit-
ted to them. This inquiry resulted in the pro- 1.3 CLAIMING GOOD LABORATORY
duction by the FDA of proposals for GLP reg- PRACTICE COMPLIANCE
ulations in 1976, to provide guidance to test
The requirements of national GLP compli-
facilities for promoting the development of
ance programmes can vary among countries.
quality data. A task force of FDA investiga-
It can be the case that a test facility might
tors was set up to conduct a pilot programme
only be able to claim formal GLP compliance
of inspections. Between 1976 and 1978, the if it is within a compliance programme run
inspectors looked at 98 laboratories (mostly by the relevant national GLP Monitoring
in the USA, but some in Europe) to deter- Authority. It is recommended that a test
mine conformity with the proposed GLP reg- facility should clarify this, as appropriate,
ulations. These investigations showed that with the applicable national GLP Monitoring
the integrity of some studies was open to Authority. Test facilities within a national
question, revealing problems so severe that GLP compliance programme are periodically
studies could not be relied upon for regula- visited by government inspectors who under-
tory decision-making. The conclusion of the take a comprehensive assessment and deter-
FDA’s review of laboratories was that there mine the status of GLP compliance (10).
was an obvious need for improving standards The quality assurance (QA) monitoring of
across industry as a whole. a participating test site in a study, which is
In 1978, the FDA issued the regulations not within a national GLP compliance pro-
specifying the principles of GLP for adequate gramme, might not confer formal GLP com-
safety testing. These regulations became law pliance. If work is conducted in a non-GLP
in the USA in 1979. This established the FDA compliant facility, in support of a GLP study,
as the first government agency to assess labo- consideration should be given to informing
ratory compliance with GLP regulations. In the relevant national GLP Monitoring
1987, the FDA regulations on GLP were Authority. Study reports and trial reports
revised. The FDA’s action stimulated much must clearly identify facilities which do not
interest in the US Environmental Protection adhere to formal GLP, and must address any
Agency (EPA), in other countries and in inter- impact that non-compliance could have had
national organisations such as the OECD. on integrity of the study.
The FDA Principles of GLP provided the
basis for the OECD Principles of GLP pub- 1.4 REGULATORY AND NON-
lished in 1981. These OECD Principles of GLP REGULATORY STUDIES
were set out as an integral part of the OECD
Decision on Mutual Acceptance of Data in the A test facility can conduct both “regulatory
Assessment of Chemicals. The OECD identi- studies”, intended for review by the regulatory
fied three essential elements on which the authorities, and “non-regulatory studies”
mutual acceptance of data can be based, (including test development and fundamental
namely: the application of the OECD Princi- research) which are not intended for submis-
ples of GLP; the establishment of harmonised sion to the regulatory authorities. Where this
national GLP compliance programmes and is the practice in the same GLP area, it will be
guidance for national inspectors in the perfor- necessary for the non-regulatory work to also
mance of inspections and audits; and the use be conducted in compliance with GLP. Essen-
of the OECD Test Guidelines. tially, the main differences between such reg-
Since the OECD Principles of GLP were ulatory and non-regulatory studies is that the
adopted by Member Countries, including the latter can be subject to reduced QA monitor-
European Economic Community (notably via ing and can have fewer specific GLP docu-
Directives 87/18/EEC, 88/320/EEC and mentation requirements.
90/18/EEC), the interpretation of GLP is
essentially the same among OECD Member
Countries (8, 9). After a decade and a half of 2 STUDY ORGANISATION
use, the OECD Member Countries consid-
2.1 SINGLE-SITE STUDIES
ered that there was a need to review and
update the Principles of GLP to account for The original OECD Principles of GLP, issued
scientific and technical progress in the area in 1981, were primarily considered for sin-
of safety testing. This led to the revised gle-site studies (Figure 1). A single-site study
OECD Principles of 1997 (2). is one in which the test facility, the Study
Director and all study procedures are based Figure 1: Organisation of a single-site
in one location. The Study Director is the study
individual responsible for the overall conduct
of a study. The role of Study Director is of
central importance in GLP (see section on
Study Director’s responsibilities). Each sin- Sponsor
gle-site study, conducted in accordance with
GLP, has one Study Director, one study plan
and one study report.
2.2 MULTI-SITE STUDIES

Management
Safety studies in a variety of disciplines, most
notably in studies examining the fate of chem-
ical substances in the environment (field Quality
studies) are often undertaken as multi-site assurance
studies. A multi-site study is one study with
one Study Director, but involving several test Study Director
sites, which can be geographically remote
and/or in separate institutions (Figure 2).
Each multi-site study, conducted in accor-
dance with GLP, has one Study Director, one
study plan and one study report (3, 4). Dashed lines indicate quality assurance staff
A multi-site study can present a challenge involvement.
with respect to the need for the Study Direc-
tor to maintain responsibility for the overall
conduct of the study. The OECD recognised
The study reports are forwarded to an
this and introduced the role of Principal
independent facility for data and statistical
Investigator into the revised OECD Princi-
analyses and for preparation of the trial
ples of GLP of 1997 (2). In a multi-site study,
report. Through necessity, the participat-
the Principal Investigator is an individual
ing laboratories will be reporting results on
who acts on behalf of the Study Director and
coded test items, and so cannot address the
who has defined responsibilities for dele-
analytical requirements of GLP compli-
gated phases of the study. Principal Investi-
ance. The management and reporting of
gators prepare contributory reports on their
multistudy trials are further discussed
work for the Study Director. The role and
later.
responsibilities of the Principal Investigator
are discussed in section 3.1.4.
3 THE PRINCIPLES OF GOOD
2.3 MULTI-STUDY TRIALS
LABORATORY PRACTICE AND
A multi-study trial, such as interlaboratory IN VITRO STUDIES
prevalidation/validation blind trials (11–13),
will consist of two or more related studies in This section discusses the Principles of GLP
relation to each test undergoing prevalida- and their application to in vitro studies. The
tion/validation, with each study being inde- text should be read together with the tables
pendent and separate from the other studies. and Appendix 1.
Therefore, each study will have its own Study The OECD Principles of GLP have been
Director, study plan and study report, and presented by the OECD in ten GLP topics.
each study might be conducted as either a sin- The OECD text for these topics is presented
gle-site or a multi-site study (Figure 3). The in Tables 1–10 (the first topic is covered by
blind nature of these trials means that the Tables 1A–1C). The additions and modifica-
Study Director and study personnel are not tions recommended by the workshop partici-
fully aware of details about the test items dur- pants are shown as bold and underlined text,
ing the conduct of the study, or during the and the topics not considered relevant to in
preparation and finalisation of the study vitro studies are shown as italicised and
report. underlined text.
Figure 2: Organisation of a multi-site study
Sponsor
Management
Quality
assurancea
Study Director
Laboratory 1
Principal Principal Principal

Investigator Investigator Investigator Etc.
Laboratory 2 Laboratory 3 Laboratory 4
aQuality assurance staff will also have communication links with each laboratory.
Dashed lines indicate quality assurance staff involvement.
3.1 TEST FACILITY ORGANISATION terms of GLP. In general, it will be the level of
AND PERSONNEL management which has overall responsibility
for ensuring GLP compliance. The roles of
The Principles of GLP relevant to the test
facility are presented in Table 1A–1C. Test Facility Management, Study Director
and QA manager should each be performed by
3.1.1 Test Facility Management’s different persons, so that there are checks and
responsibilities balances in the overall programme. Test Facil-
ity Management is not the same as the Trial
The Principles of GLP related to Test Facil- Management Team, which has responsibilities
ity Management’s responsibilities are for the overall conduct of a multi-study trial,
shown in Table 1A. and is discussed later in this document.
The primary GLP responsibility of Test
Facility Management is to ensure that a suffi- 3.1.1.1 Study Director
cient number of qualified personnel, and
appropriate facilities, equipment and materi- The Study Director is appointed by Test
als, are available for the timely and proper Facility Management. When appointing a
conduct of studies. The test facility includes Study Director to a study, management
the persons, premises and operational units should be aware of that individual’s current
necessary for the conduct of a study. The test or anticipated workload. The Master Sched-
site is the location(s) at which a phase(s) of a ule, as described below, lists the studies
study is conducted in a multi-site study. It is planned, in progress and completed, and
important to document the name of the per- should be used as a reference when appoint-
son who acts as Test Facility Management, in ing a Study Director.
Figure 3: Good Laboratory Practice organisation for a multi-study trial

(including prevalidation and validation studies)
Sponsor
Trial Quality assurancea

management and
co-ordinator
Statistics
Test 1: study 1 Test 1: study 2 Test 2: study 3 Test 2: study 4

Study Director Study Director Study Director Study Director Etc.
Laboratory 1 Laboratory 2 Laboratory 3 Laboratory 4
aSeveral quality assurance units might be involved in a multi-study trial.

In the event that a Study Director has to 3.1.1.2 Principal Investigator

be replaced during a study (for example,
Test Facility Management should ensure in a
because of a career change), it will be neces-
multi-site study, that, if needed, a Principal
sary for Test Facility Management to issue a
Investigator is designated who is appropri-
statement detailing the change and the rea-
ately trained, qualified and experienced, and
son, and naming the replacement Study
whose understanding of GLP is sufficient for
Director. The date on which the change is to
supervision of the delegated phase(s) of the
take effect should also be noted. A study plan
study. The replacement of a Principal Inves-
amendment should be prepared to record
tigator should be done according to proce-
this change, and should be signed by the
dures established by Test Site Management
replacement Study Director, Test Facility
and be similar to those for the replacement
Management and, if applicable, the sponsor.
of a Study Director.
At the time of replacement, it is the
responsibility of the replacement Study
3.1.1.3 Organisation chart
Director to determine whether the study has
been conducted in compliance with GLP. If An organisation chart for the test facility
any GLP deficiencies are noted during this should be available, which should include the
review, it is the responsibility of the replace- identity of the most senior manager who has
ment Study Director to fully document them. overall responsibility for GLP compliance
and should include the lines of reporting and 3.1.1.5 Site plans
communication in the test facility. The chart
Site plans are relevant documents for Test
should identify the main job areas associated
Facility Management, since they can be used
with GLP, and should identify the individu-
to demonstrate that laboratories are well
als who have designated responsibilities with
organised and that there is adequate and
respect to GLP organisation. This includes
the maintenance of lists of individuals who appropriate separation of activities and func-
can be appointed as a Study Director and, tions. Site plans need not be detailed, such as
where appropriate, a list of those individuals in engineering site plans, but they should be
who can be appointed as Principal Investiga- dated and should indicate the main func-
tors. Other positions appropriate for the org- tional areas, such as test item store, formu-
anisation chart are laboratory manager, test lation area and archives. Superseded site
substance controller, Standard Operating plans should be archived.
Procedure (SOP) administrator, archivist
and QA personnel. Superseded organisation 3.1.1.6 Personnel records
charts and superseded lists of designated Test Facility Management must ensure the
Study Directors and Principal Investigators maintenance of a record of the qualifications,
should be retained in the archives. training, experience and job description of
each professional individual with GLP
3.1.1.4 Master Schedule responsibilities. Also, there must be assur-
Reference to the Master Schedule is a useful ance that personnel clearly understand the
means for Test Facility Management to iden- functions they are to perform and, where
tify the allocation of resources. The Master necessary, are provided with training for
Schedule is used to assess the volume of these functions.
work being performed and by which individ- It is usual for the qualifications, together
uals. It also permits an awareness of studies with a brief account of education, employ-
planned, in progress and completed. ment history and experience, to be recorded
The Master Schedule should normally pro- in the form of a curriculum vitae.
vide the following study information: unique Job descriptions will be presented in a
study identification, test system, test item, GLP-compliant manner, if they include job
nature of study, name of Study Director/ title, qualifications and experience necessary
Principal Investigator and start and comple- for the position, reporting relationships and
tion study dates. The inclusion of further an outline of the key objectives of the job
information, such as the date of the issue of position, especially those objectives affecting
the study report and the date of archiving, is GLP. Job descriptions should be signed by
considered appropriate. both employee and manager.
The Master Schedule at the test facility Training is usually documented in the
must show overall dates and the identity of form of an on-going training record listing
the Study Director, whereas a Master Sched- specific tasks which need to be signed off
ule at a test site need only show local dates before an individual can undertake such
and local activities, and the identity of the tasks without direct supervision. Training
relevant Principal Investigator. records are considered to be key GLP docu-
In some test facilities, there is the conduct ments, since they demonstrate those proce-
of both regulatory studies, intended for sub- dures which an individual can undertake.
mission to the regulatory authorities, and One method that can be used by Test Facil-
non-regulatory studies, for example, test ity Management, or the Study Director or
development and fundamental research QA personnel, to determine whether an indi-
studies. Non-regulatory studies can be con- vidual has been trained in a given procedure,
ducted under GLP, but can have a reduced is to check the training record.
amount of QA monitoring and reduced spe- The need for re-training, for example,
cific GLP documentation requirements. after a period of absence or when there have
Where a laboratory has these two types of been procedural and technical revisions,
studies, it is appropriate to identify in the should always be considered.
Master Schedule which are the regulatory Training records should be described in a
studies and which are the non-regulatory Standard Operating Procedure (SOP), which
studies. should address who should have training
records and who can authorise training The role of Study Director is of fundamen-
records. Training records should be consid- tal importance, and it is the Study Director
ered for all grades of professional staff with who is accountable for ensuring the GLP com-
GLP duties, to at least the level of Study pliance in the conduct of the study and in the
Director. The SOP should describe where the study report. The Study Director is the single
training records are to be located, and should critical point of study control and must
identify that a training record should be for- ensure clear lines of communication between
warded to the archives when an individual the Study Director and study personnel.
no longer has GLP responsibilities. The SOP Before any work on a study is undertaken,
should also outline the documentation for the Study Director should ensure that Test
attendance at courses and conferences. Facility Management have committed ade-
In certain cases, especially for personnel quate resources, that study personnel are ade-
with advanced training, self-education and quately trained, and that the equipment to be
self-certification may be possible. Test Facil- used in the study has been appropriately cali-
ity Management should judge whether and brated and maintained. The Study Director
when this is appropriate. should also ensure that appropriate arrange-
ments have been made for the supply of the test
3.1.1.7 Standard Operating Procedures systems, and test, control and reference items,
It is appropriate for Test Facility Manage- which meet the requirements of the study, and
ment to ensure an individual has been that there are appropriate SOPs for the study.
assigned responsibility for the administra- It is the responsibility of the Study Direc-
tion of the SOP system. Such a role serves tor to approve the study plan, and any
to ensure that SOPs are reviewed at appro- amendments to the study plan, by dated sig-
priate time intervals, that new and revised nature. It is also the Study Director’s respon-
SOPs are authorised and issued in a timely sibility to ensure that copies of the study
manner, that SOPs are appropriately dis- plan, any amendments, and relevant SOPs
tributed, and that a historical file of super- are readily available to personnel, that per-
seded SOPs is maintained. In multi-site sonnel are properly briefed, and that any
studies it might be decided to assign an indi- deviations from the study plan or SOPs are
vidual with SOP responsibilities for ensur- documented and acted upon. The Study
ing the administration and control of Director should ensure that QA personnel
certain SOPs across test sites. SOP admin- have a copy of the study plan, and any
istration of this nature would need to be amendments, in a timely manner and com-
clarified in the study plan. municate effectively with them, as required
during the conduct of the study.
3.1.2 Test Site Management Study Director involvement during the
course of a study should include reviewing pro-
In a multi-site study, Test Site Manage- cedures and data, in order to ensure compli-
ment will have the responsibilities defined ance with the study plan and the SOPs. To
in Table 1A, with the following exceptions: demonstrate the monitoring activities of the
a) the appointment of the Study Director, Study Director, the type and frequency of the
and the replacement of the Study Director, reviews should be documented in the study
if applicable; b) ensuring documented records. The impact of any deviations from the
approval of the study plan by the Study study plan on the quality and integrity of the
Director; c) ensuring that the Study Direc- study should be assessed and appropriate cor-
tor has made the approved study plan avail- rective action should be taken, if necessary.
able to the QA personnel; and d) ensuring The Study Director should acknowledge all
that clear lines of communication exist deviations from SOPs during the conduct of
between the Study Director, Principal the study.
Investigator(s), study personnel and QA The Study Director must sign and date the
personnel.
study report to indicate acceptance of
responsibility for the validity of the data and
3.1.3 Study Director’s responsibilities
that the study report accurately reflects the
The Principles of GLP relevant to the Study work conducted and all the results obtained.
Director’s responsibilities are shown in The Study Director should ensure that all
Table 1B. relevant 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 Laboratory
Practice 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 Good
Laboratory 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 job
description for each professional and technical individual;
d) ensure that personnel clearly understand the functions they are to perform and, where
necessary, provide training for these functions;
e) ensure that appropriate and technically valid Standard Operating Procedures are
established and followed, and approve all original and revised Standard Operating Pro-
cedures;
f) ensure that there is a Quality Assurance programme with designated personnel, and
assure that the Quality Assurance responsibility is being performed in accordance with
these Principles of Good Laboratory Practice;
g) ensure that for each study an individual with the appropriate qualifications, training
and experience is designated by the management as the Study Director before the
study 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 is
designated who is appropriately trained, qualified and experienced to supervise the
delegated phase(s) of the study. Replacement of a Principal Investigator should be
done 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 study
personnel;
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 with
these 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 and
2o.
Recommended additions to the test are in bold and underlined.

maintained, to ensure data integrity, and tively carry out the technical phase of the
that upon completion, or termination, of the study in conformance with the study plan,
study, these records are transferred in a applicable SOPs, the Principles of GLP and
timely manner to the archives. the specific technical requirements. It must
be noted that, although a Study Director can
3.1.4 Principal Investigator and study delegate duties to a Principal Investigator,
personnel the Study Director’s responsibilities cannot
be delegated.
3.1.4.1 Principal Investigator
There should not be a need to appoint a
The Principles of GLP related to the Princi- Principal Investigator to work on the study
pal Investigator are shown in Table 1C. at the Study Director’s geographical and
In a multi-site study, it is unreasonable to managerial location.
expect a Study Director to maintain direct The Principal Investigator should indicate
supervision over all test sites. Therefore, it is acceptance of the study plan, and any
appropriate to have a Principal Investigator amendments to the study plan, by dated sig-
appointed at test sites which are remote nature. Management and sponsor dated sig-
from the Study Director. The Principal natures should be provided, as appropriate.
Investigator must be an appropriately quali- In a situation where a Principal Investiga-
fied individual at the test site, who can effec- 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. The
Study 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 are
available to study personnel;
d) ensure that the study plan and the study report for a multi-site study identify and
define the role of any Principal Investigator(s) and any test facilities and test sites
involved 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 of
the study, and take appropriate corrective action if necessary; acknowledge deviations
from 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, the
study report, raw data and supporting material are archived.
Recommended additions to the text are in bold and underlined.

cipal Investigator can prepare, if necessary, enable the Study Director to write the study
an amendment to the study plan, in consul- report. The Principal Investigator should
tation with the Study Director. However, the include a signed GLP compliance statement
Study Director must be responsible for the confirming compliance with GLP, or indicat-
numbering, approval and issue of all study ing clearly where there were any deviations
plan amendments. All study plan amend- from GLP.
ments should be issued to all recipients of If study documents and/or materials are to
the original study plan. be archived locally, the archiving arrange-
The Principal Investigator is responsible for ments should be confirmed in the contribu-
ensuring that QA personnel are kept informed tory report.
about study activities for which the Principal
Investigator is responsible, so that QA person- 3.1.4.2 Study personnel
nel can plan the inspection schedule. It is also All study personnel involved in the conduct
necessary for the Principal Investigator to of the study must be knowledgeable in the
respond, in a timely manner, to QA reports. aspects of the Principles of GLP which are
On completion of a Principal Investigator’s applicable to their involvement in the study,
study activity, the Principal Investigator and should be sure they are undertaking
should sign and date the contributory report, only duties in which they have been ade-
to confirm that it accurately reflects the work quately trained (Table 1C).
conducted and all the results obtained. Suffi- Study personnel should have ready access
cient commentary should be included to to 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 conducted
in 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 parts
of the Principles of Good Laboratory Practice which are applicable to their involvement in
the study.
2. Study personnel will have access to the study plan and appropriate Standard Operating
Procedures 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 instructions
should 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 in
compliance with these Principles of Good Laboratory Practice, and are responsible for the
quality of their data.
4. Study personnel should exercise health precautions to minimise risk to themselves and to
ensure the integrity of the study. They should communicate to the appropriate person any
relevant 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 the compliance programme, but which is partici-
instructions given in these documents. Any pating in a GLP study, increased QA monitor-
deviations from these instructions should be ing of that laboratory should be considered.
documented and communicated directly to Inspections of facilities, procedures and
the Study Director and/or, if appropriate, to study reports result in QA reports, which are
the Principal Investigator. forwarded to relevant study personnel,
All study personnel are responsible for including the Study Director and Test Facil-
recording raw data promptly and accurately ity Management. QA reports should be seen
and in compliance with GLP, and are respon- as a way of promoting awareness of GLP
sible for the quality of their data. issues. There should be an agreed time-
Study personnel should take the necessary frame for recipients to respond to QA
personal and health precautions to avoid any reports, for example, within 2 weeks. Signif-
contamination of test systems and test items, icant findings should be reported, and
and should take adequate safety precautions responses should be made, as quickly as pos-
when handling materials of known, or sible.
unknown, hazard. QA personnel should prepare and sign a
QA statement for inclusion in the study
3.2 QUALITY ASSURANCE report. The QA statement specifies the
inspections undertaken, their dates, and the
The Principles of GLP specific to QA are pre-
dates when the QA findings were reported.
sented in Table 2. The establishment and
This statement also serves to confirm that
effective operation of a QA programme is a
the study report reflects the raw data. The
requirement of GLP and is one of the princi-
QA statement is usually presented as a
pal means by which study personnel, Man-
stand-alone document, within the study
agement, sponsors and ultimately the
report, to confirm the independence of QA.
regulatory authorities are assured of the
GLP compliance status of studies. The QA
3.3 FACILITIES
function is based on organisational, rather
than scientific, procedures. Therefore, QA The Principles of GLP specific to facilities
does not interfere with the technical and sci- are presented in Table 3. The basic require-
entific conduct of studies. ments for facilities will be dictated by the
Test Facility Management has ultimate types of test systems employed and the types
responsibility for compliance with the Prin- of studies to be performed. Facilities include
ciples of GLP. This includes the appointment all of the buildings, individual room(s) and
and effective organisation of a QA function. equipment provided to maintain the speci-
Persons undertaking QA activities must be fied, controlled environment for the test sys-
independent of the studies inspected, and tem(s). Initial quarantine, diagnosis/
should report to a level of management treatment of disease, maintenance before
where the overall responsibility for GLP and after treatment with the test item, and
resides. In small facilities, it might not be isolation from external disturbances, must
feasible to maintain full-time QA personnel. be provided. External disturbances might
However, Management must appoint at least come in the form of contamination from
one individual to have permanent, albeit other studies/test systems (across species),
part-time, coordination of QA. Management dust from the preparation of test or control
can contract out the QA function, so the QA items for dosing (for example, dose feed
function need not be in-house. preparation, treatment or harvest of individ-
QA inspections include reviews of proce- ual test subjects, environmental sources
dures to assure compliance with the study such as noise, light and bioburden). A test
plan, SOPs and the Principles of GLP. They facility appropriate for one type of test sys-
pay attention to the flow of information and tem might be wholly insufficient for another.
the chain of custody of samples and data GLP was originally developed for facili-
across interfaces. This is particularly relevant ties in terms of rooms or areas (portion of
to multi-site studies, where it is necessary to a room), since those units are appropriate
coordinate QA activities across sites, to ensure for most in vivo studies where test systems
that all critical phases and interfaces are sub- are exposed to room air, so environmental
ject to QA monitoring. In the case of a labora- conditions for maintenance and isolation
tory that is not within a national GLP need to be directed at that level. In con-
Table 2: Quality Assurance Programme
2.1 General
1. The test facility should have a documented Quality Assurance programme to assure that
studies 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 test
procedures.
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, the
following 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 that
study plans and Standard Operating Procedures have been made available to study
personnel and are being followed. Inspections can be of three types as specified by
Quality Assurance programme Standard Operating Procedures: i) study-based inspec-
tions; ii) facility-based inspections; and iii) process-based inspections. Records of such
inspections should be retained;
d) inspect the study reports to confirm that the methods, procedures and observations
are accurately and completely described, and that the reported results accurately and
completely reflect the raw data of the studies;
e) promptly report any inspection results in writing to management and to the Study
Director, and to the Principal Investigator(s) and the respective management, when
applicable;
f) prepare and sign a statement, to be included with the study report, which specifies
types of inspections and their dates, including the phase(s) of the study inspected, and
the dates inspection results were reported to management and the Study Director and
Principal Investigator(s), if applicable. This statement would also serve to confirm that
the study report reflects the raw data.
trast, most in vitro (especially cell and the flasks, tubes or plates in which it is
organ culture) systems are manipulated in grown or treated. Therefore, modifications
vertical laminar flow biological safety cabi- are necessary to the wording of the OECD
nets to protect both the test system and Principles of GLP for facilities conducting
the operator. The test system is main- in vitro studies. The addition of the term
tained within an incubator, which provides “or equipment” in the facilities’ require-
the required environmental conditions. It ments is intended to remedy this situation
is further isolated from other cultures by (Table 3).
Table 3: Facilities
3.1 General
1. The test facility should be of suitable size, construction and location to meet the
requirements of the study and to minimise disturbance that would interfere with the
validity of the study.
2. The design of the test facility should provide an adequate degree of separation of the
different 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 appropriate
equipment (for example, biological safety cabinets) to assure the isolation of test
systems and the isolation of individual projects, involving substances or organisms
known 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. Storage
rooms, areas or equipment should be separated from rooms, areas or equipment
housing the test systems and should provide adequate protection against infestation,
contamination, and/or deterioration
4. The facilities should provide adequate equipment (for example, biohazard

hoods, 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. Mixing
of the test, reference and control items with a vehicle should be performed
so as to preclude contamination and mix-up.
2. Storage rooms, areas or storage cabinets for the test, reference and control items
should 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.

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 archive
conditions 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 jeopardise
the integrity of studies. This includes provision for appropriate collection, storage and dis-
posal facilities, and decontamination and transportation procedures.
The handling of test, reference and control in order to introduce a general GLP working
items (7) for an in vitro study is generally practice among all laboratory personnel (for
performed in containment equipment to pro- example, for weighing, labelling and calibra-
tect the items and the operator. The volumes tion).
of sample being prepared are quite small Personnel should not undertake activities
compared to those used in many in vivo stud- within a GLP area unless they have been
ies. Changes to Table 3 focus on the need for trained in the appropriate GLP require-
the absence of contamination and mix-up, ments. The presence of both GLP and non-
and reflect the facilities used for in vitro GLP activities within the same facility
studies and the volumes of material to be requires constant vigilance on the part of
manipulated. Test Facility Management, Study Directors,
There should be adequate storage facilities supervisors and QA personnel, to ensure
for supplies and equipment (for example, continual GLP compliance.
refrigerators, freezers, cryopreservators, The GLP practices in the non-regulatory
ventilated cabinets, storage rooms). Storage studies must not run counter to those for the
facilities should be adequately separated regulatory studies. For example, cell cultures
from the test system and should provide ade- associated with a non-regulatory study
quate protection against infestation, contam- placed in a GLP-compliant incubator must
ination, and/or deterioration. have the same labelling and freedom from
Some facilities work with dedicated GLP adventitious agents as those used for the
and non-GLP areas, while others will con- GLP studies.
duct both regulatory and non-regulatory
studies within a single GLP-compliant area. 3.4 APPARATUS, MATERIAL AND
If a test facility carries out both regulatory REAGENTS
and non-regulatory studies, it is essential The Principles of GLP specific to this area
that the GLP compliance of the regulatory are presented in Table 4. Procedures on how
studies is not compromised by the non-regu- apparatus is inspected, cleaned, maintained
latory studies. and calibrated must conform to the needs of
Management must clearly establish poli- the study plan and SOPs. This conformity
cies and procedures which preclude compro- must be documented as raw data.
mising the GLP compliance of regulatory The apparatus used to maintain test sys-
studies by non-regulatory studies. If a test tem isolation and environment is particu-
facility does have dedicated GLP and non- larly critical for in vitro studies. For
GLP areas, a base level of GLP compliance example, a study plan should specify an
for the complete facility could be established, acceptable temperature range for the incuba-
tor. The incubator must be able to conform for maintaining and controlling the system.
to that range, and a record of the monitoring The raw data for each computer system
must be maintained. There will usually be should be defined, and the system design
several parameters that should be main- should always provide for the retention of
tained and documented daily (temperature, audit trails, to show all changes to data,
humidity, CO2 concentrations), and others without obscuring the original data. Respon-
which can be assessed and documented peri- sibilities for computer systems must be
odically (cleaning and bioburden). clearly defined before a study begins.
Clearly, the quality of the apparatus must The focus of the acceptance testing effort
meet the expected and established levels of should be on the application(s) being used,
accuracy and precision. The specific require- rather than on the computer system itself.
ments for a certain piece of apparatus (for That is, do the hardware and software
example, frequency of cleaning or calibra- together produce the desired result when
tion) might not be the same in all laborato- challenged by rigorous testing with known
ries or for all assay systems. Management data sets? For example, a spreadsheet might
and the Study Director should establish be prepared to manipulate data in a study.
appropriate requirements. As a minimum The performance of that spreadsheet, for its
requirement, the manufacturer’s specifica- intended purpose, would be tested and docu-
tions should be met. The implementation of mented, rather than an attempt to evaluate
a monitoring/calibration programme is rec- an entire commercial spreadsheet program.
ommended. Any data transfer steps between platforms
The acceptance testing of new, or changed, and any direct data capture functions from
computer systems for data capture, manipu- instrumentation would be included in the
lation and storage is complex, involving both evaluation. In such cases, it will be essential
hardware and software components, and to define precisely the form of the raw data.
should be conducted and documented in a If the raw data are in the form of an elec-
GLP-compliant manner. Before a computer tronic file, electronic signatures and date
system is used for GLP studies, it must be stamps must meet GLP standards, as
demonstrated that it is suitable for its defined by the appropriate regulatory
intended use and that there are procedures authorities.
Table 4: Apparatus, Materials and Reagents
1. Apparatus, including validated computerised systems, used for the generation, storage
and 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 concerning
source, preparation date and stability should be available. The expiry date may be
extended on the basis of documented evaluation or analysis.

The requirement that the apparatus and This requirement is similar to documenta-
materials used in a study do not interfere tion of the origin and basic health of an in
with a test system is also critical for in vitro vivo test system.
studies. As study plans, and equipment In vitro test systems are often propagated
maintenance, cleaning and decontamination within test facilities. Both prokaryotic and
procedures (i.e. SOPs) are developed, consid- eukaryotic systems can be expanded and
eration must be given to avoidance of the banked to provide a continuous source of
introduction of chemical residues, tempera- material. Since the study plan will have been
ture fluctuations or other environmental fac- prepared with certain expectations of the
tors which will affect the test system. For test system and specific performance criteria
example, consideration must be given to the for the assay (see section 3.8), the test sys-
effects of bright sunlight on culture media, tem must be maintained in such a way as to
or of incubator vibration on cell culture uni- promote stability over time. Test system
formity. maintenance and propagation should be
The labelling of chemicals, reagents and addressed in the planning of a study (or
solutions, including commercially prepared study type) and documented in sufficient
media and reagent solutions, should be con- detail for the critical elements required to
ducted in such a way as to ensure compliance maintain stability to be included. Records of
with GLP requirements. Revised labelling test system maintenance should also include
should be prepared when appropriate; for all critical elements.
example, supplementation of a medium with Characterisation of the in vitro test system
a labile component could change the expiry is of the utmost importance. The handling of
date. in vitro systems is perhaps more critical than
that of in vivo systems. The following points
3.5 TEST SYSTEMS should be considered.
The Principles of GLP in relation to test sys- 1. Proper conditions should be established
tems are presented in Table 5. Several addi- and maintained for the storage, handling
tions to this table have been made, which are and care of test systems, in order to
directed toward cell/tissue culture systems. ensure the quality of the data. High qual-
These address the needs to authenticate the ity cell and tissue culture practices and
origin of the test system, its freedom from good aseptic techniques, which are an
adventitious agents and its condition upon essential part of in vitro work, should be
arrival. Also, within the facility, the test sys- enforced.
tem must be propagated and maintained in
2. Characterisation of the test system is
order to preserve its biological integrity for
necessary, to ensure that it is what it
its intended application.
claims to be, and any significant changes
Many in vitro test systems are not directly
in the test system should be evaluated.
isolated by the facility from the original
species and tissue of origin, but are cell lines 3. Newly received test systems should be
obtained from other sources. In some cases, controlled for their purity, lack of contam-
the primary isolation might have occurred ination, suitability and identity. Until the
several decades earlier. In other cases, par- test system has met these pre-defined cri-
ticularly with human cells and tissues, the teria, it should not be used in GLP-com-
donor records are not available to the end- pliant studies and should be appropriately
user of the test system. Thus, the agency treated or destroyed. Any future contami-
(cell repository or commercial source) pro- nation or defects which could affect the
viding the test system might be the primary quality of the data should be investigated,
source of data on the species and tissue of and the test system returned to quaran-
origin. It might also provide data on any tine until it is “cleared”. When beginning
tests performed to demonstrate the absence the experimental work in a study, the test
of adventitious agents and the purity system should be free of any contamina-
(species and tissue type) of the test system. It tion or defects, or any conditions which
is essential that the test facility is able to might interfere with the purpose or con-
trace the lineage of the test system to its duct of the study. Test systems that do not
immediate source and to document the han- conform (for example, those with contam-
dling of that system within the test facility. 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 located
and 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, handling
and 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 lot
should not be used in studies and should be appropriately destroyed. At the
experimental starting date of a study, test systems should be free of any disease
or condition that might interfere with the purpose or conduct of the study. Test
systems that become contaminated or damaged during the course of a study
should be appropriately destroyed, if necessary, to maintain the integrity of the
study.
3. The origin (for example, species and tissue), source, arrival condition and
maintenance requirements of the in vitro test system should be documented.
4. Biological test systems should be acclimatised to the test environment for an adequate
period 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 or
containers 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 at
appropriate intervals. Any material that comes into contact with the test system should
be free of contaminants at levels that would interfere with the study. Bedding for animals
should be changed as required by sound husbandry practice. Use of pest control agents
should be documented.
7. Test systems used in field studies should be located so as to avoid interference in the study
from spray drift and from past usage of pesticides.
Recommended additions to the text are in bold and underlined. Recommended deletions are in
italics and underlined.
study should be appropriately treated, if Procedures must be established that are

possible, or destroyed, if necessary, to designed to prevent errors in the identifica-
maintain the integrity of the study. Any tion and cross-contamination of test, control,
diagnosis and treatment of non-confor- and reference items and their preparations.
mity before, or during, a study should be These procedures might include, for exam-
recorded. ple, the separation of storage and handling
4. Records of origin (for example, species, areas for control and reference items from
tissue), maintenance requirements, iden- storage and handling areas for test items.
tity, source, date of arrival, and arrival There might also be separation of storage
condition of in vitro test systems should and handling areas for negative control
be maintained. items and for test and positive control sub-
stances. In addition, other procedures might
5. Test systems should be acclimatised (if be used to limit the risk of contamination or
necessary) to the test environment for an degradation; for example, limitations on the
adequate period before the first adminis- number of materials which might be manip-
tration or application of the test, control ulated at any one time and the strict colour
or reference item. The propagation of the coding of samples and receiving vessels.
in vitro test system after receipt by the Test, reference and control item account-
test facility should be consistent with the ability and supervision begin with receipt of
study plan and/or SOPs. the materials and continue throughout the
6. All information needed to properly iden- life of the study until the final disposition
tify the in vitro test system should be ade- (archiving, return and/or disposal) of the
quately recorded throughout the course material. Test, reference and control item
of the study. Individual test materials accounting encompasses the systems for
(for example, flasks, plates) that are pre- receipt, storage, issue and use (by date and
pared and used during the course of the study), and final disposition. Once the study
study, should bear appropriate identifica- is completed, these records are archived.
tion, wherever possible. Individual test Good test substance control is demonstrated
system containers (i.e. transwells) too by a well documented audit trail, supple-
small to be individually labelled, should mented by checks of operations at critical
be contained in a properly labelled outer points.
container. Demonstration of the concentration, sta-
bility and homogeneity of the test, control
7. Any material that comes into contact or reference item in the vehicle might not
with the test system should be free of be possible or practical in short-term stud-
contaminants. Sterile equipment and ies. Unlike many studies where large
good culture techniques should be used batches of material must be prepared and
where appropriate (14). held for some time (for example, feeding
studies), most in vitro studies involve dilu-
3.6 TEST, REFERENCE AND CONTROL tion of the items immediately before use
ITEMS and in relatively small volumes. The study
The Principles of GLP specific to these mat- plan must carefully address the preparation
ters are presented in Table 6. The category of and handling requirements of test, control
control items has been added to the table, and reference items in the vehicles used to
since control items do not meet the definition present the substance to the test system. If
of reference items. Control items serve in analysis is not to be performed, its exclu-
monitoring the performance of the test sys- sion should be clearly stated in the study
tem(s), but might not necessarily be compared plan and study report. It might be appro-
with the test item(s) in the same way as a ref- priate to state this exclusion as part of the
erence item (bench mark material). In many GLP compliance statement (see section 3.9)
situations, only the positive control items are in the study report.
classed as separate item(s), since the negative In many situations (including prevalida-
control items might just be the tion and validation studies), the laboratory
diluent/medium used to prepare the test might be testing test, reference and control
items, the positive controls and/or the refer- items which are provided under code from
ence items. the sponsor. In this case, the sponsor would
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 are
precluded.
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, concentrations
or 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, there
should 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 conditions
should 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 may
be determined through separate laboratory experiments.
6. A sample from each batch should be retained for analytical purposes for all studies except
short-term studies.
be responsible for characterisation and for provide some information directly to the
providing the laboratory with sufficient laboratory if there is a particular hazard
information to handle the test and refer- which must be addressed. Safety instruc-
ence items appropriately. Laboratory safety tions (for example, material safety data
is also an issue when testing coded materi- sheets) may be sent to the laboratory safety
als. It is common practice for the sponsor to officer or another appropriate agency (for
example, a poisons control centre) in a SOPs which are the primary reference for
sealed envelope which is opened only in the the study. In multi-site studies, it may be
case of an emergency (spill or exposure). It helpful for the lead laboratory to provide
is important that the supplier of the blind study SOPs to the other laboratories. This
coded materials takes on these responsibil- reduces the workload and helps to assure
ities and provides sufficient information to greater uniformity in procedures among the
help ensure that the handling of the test participating laboratories.
items under code does not affect the out-
come of the study. 3.8 PERFORMANCE OF THE STUDY
This section includes discussion on the study
3.7 STANDARD OPERATING
plan and performance of a study. The Princi-
PROCEDURES
ples of GLP specific to this area are pre-
The Principles of GLP specific to SOPs are sented in Table 8.
presented in Table 7. SOPs are the written
body of procedures that govern the proce- 3.8.1 Controls and acceptance criteria
dural aspects of the GLP-compliant labora-
One of the major additions to the Principles
tory. They should address all the categories
of GLP proposed by the workshop is the con-
listed in Table 7. Collectively, they should set
cept of assay acceptance criteria for end-
the standards by which the test facility oper-
points (Table 8).
ates, reflecting the expectations of Test
The responses of a test system to control
Facility Management, the Study Director,
items usually provides the basis for deter-
and QA.
mining the acceptability of an assay. In
The procedure for preparing, distributing
some assays, both negative and positive
and maintaining SOPs should be addressed
control items are used to determine accep-
in an SOP. This SOP should describe SOP
tance. In other assays, only positive control
format, including section headings and sec-
responses are used. The observed positive
tion numbering, in order to promote consis-
control response is compared to historical
tency. SOPs can be written by a variety of
values for the assay to determine whether
authors, reflecting the expertise of many
or not the response falls within the prede-
individuals within the organisation. In
fined limits given in the study plan’s accep-
turn, the SOPs should be reviewed and ulti-
tance criteria. The range of acceptable
mately approved by the appropriate signa-
values is generally derived as a function of
tory.
the historical mean and standard deviation
SOPs are controlled to ensure that only
for the controls. They must also address
current authorised SOPs are available.
the required precision of the assay. Ideally,
Given that they are controlled documents, it
each endpoint in an assay should be
is appropriate for every SOP page to have the
addressed by a positive control and have an
SOP identifier and version number. Manage-
acceptable range of values. The perfor-
ment should ensure that a responsible indi-
mance of the controls also allows compari-
vidual has been assigned, such as an SOP
son of an assay’s performance in different
administrator, who is accountable for ensur-
laboratories and over time.
ing that SOPs are current, authorised,
appropriately distributed, and reviewed on a
3.8.2 Study preparation
regular basis.
A copy of each superseded or withdrawn Before the commencement of a study, it can
SOP should be maintained in a designated be useful for the Study Director to have a
archive. In this manner, when reconstruct- pre-study meeting to discuss the proposed
ing studies, the SOPs which were current at study plan. Such a meeting should clarify
the time of a study can be referenced. communications throughout the study. The
If common SOPs are to be issued to all lab- establishment of open, two-way communica-
oratories in a multi-site study, it is necessary tion between the Study Director and study
to establish, before beginning the study, how personnel is essential to the proper control of
SOPs are to be authorised, issued and even- a study. In addition to a discussion of the
tually archived. Where there are differences study plan, such a meeting can include prac-
between a study plan and SOPs, it should be tical demonstrations of applicable tech-
clarified whether it is the study plan or the 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 generated
by that test facility. Revisions to Standard Operating Procedures should be approved by
Test Facility Management.
7.2 Each separate test facility unit or area should have immediately available current Standard
Operating Procedures relevant to the activities being performed therein. Published text
books, 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 following
categories of test facility activities. The details given under each heading are to be consid-
ered as illustrative examples.
1. Test, Reference and Control Items

Receipt, identification, labelling, handling, sampling and storage.
2. Apparatus, Materials and Reagents

a) 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 Retrieval

Coding 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 Procedures

Operation of Quality Assurance personnel in planning, scheduling, performing, documenting
and 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 study
plan 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 also
be 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 signature
of 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 supplement

may 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 if
required by national regulation or legislation in the country where the study is being
performed;
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.

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 determinations
within 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 positive
and negative controls, type and frequency of analysis, measurements, observations
and 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 study
should carry this identification. Specimens from the study should be identified to confirm
their 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 signed
or initialled and dated.
4. Any change in the raw data should be made so as not to obscure the previous entry, should
indicate 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 input
by the individual(s) responsible for direct data entries. Computerised system design
should always provide for the retention of full audit trails to show all changes to the data
without obscuring the original data. It should be possible to associate all changes to data
with the persons having made those changes, for example, by use of timed and dated (elec-
tronic) signatures. Reason for changes should be given.
3.8.3 Study plan of the study as possible. It would be hard to

over-emphasise the need for careful, detailed
Sufficient information should be available to preparation of the study plan. The study
prepare a detailed study plan which elimi- plan includes the conceptual design of the
nates as much uncertainty in the execution study (what is tested and how it is tested),
the raw data to be obtained, the manipula- bered, indicate the reason for the change,
tions of the raw data to produce the study and include the dated signature of the Study
endpoint values, the interpretation scheme Director and, if applicable, those of the Prin-
for endpoints, and the acceptance criteria for cipal Investigators and Test Facility Man-
the study. The study plan must be written in agement. All amendments should be
such a way as to preclude misinterpretation distributed to all recipients of the original
by the study personnel. This requirement is study plan.
particularly important when more than one
laboratory will use the same study plan. 3.8.5 Notes to file
In a multi-site study, the study plan
A note to file provides a means of recording
should include the name and address of the
study information, such as a study plan devi-
Principal Investigator, the location of the
ation. Notes to file can be initiated by any
test site(s), the study-part(s) performed, the
study personnel, but should be acknowl-
methods and statistical parameters used, the
edged by the Study Director, who should
location where the documentation relating to
approve any corrective action and decide
the part for which the Principal Investigator
upon the recipients of notes to file. Sequen-
is responsible is archived, the GLP regula-
tial numbering of notes to file assists study
tions followed (according to national require-
control. Significant deviations from the
ments), and any time schedules necessary for
study plan might be best documented as
the conduct of the study. A study plan
study plan amendments.
amendment will be necessary if a new Prin-
cipal Investigator and new test site become
3.8.6 Raw data
involved in the study. The study plan should
include procedures for the recording of study Study personnel must have a clear under-
data to ensure consistency of data recording standing of what constitutes raw data. The
at all of the sites in a multi-site study, and to definition of raw data (see Appendix 1) must
meet the requirements of data management. be documented.
In addition to the study plan which identi- Raw data records should enable the recon-
fies the records to be retained or archived, it struction of the study. They should also be
is also appropriate to address at which loca- able to explain who did what, when, by what
tions archived records will be kept. means, why and where. To do so, data must
The study plan becomes an authorised be generated completely, accurately, legibly
document when it is signed by the Study and promptly. Entries should be signed or
Director, Test Facility Management and the initialled and dated. Corrections should be
sponsor, if applicable. The study plan should made without obscuring the original entry.
be distributed to study personnel and QA Corrections should also be dated and signed,
personnel, who need to be informed of stud- and the reason for the correction should be
ies so that QA inspections can be planned. given. Raw data not only involve study-spe-
Obtaining signatures in a multi-site study cific documentation (performance of a
can be a lengthy process. It might be accept- study), but also the more general records
able, subject to written procedures, for fac- concerning apparatus, material and
similied signatures to be used in order to reagents, and handling of test, control and
allow the study plan and amendments to be reference items and of test systems. During a
issued in a timely manner. study, raw data should be maintained in safe
A study plan is distinct from the trial plan, storage areas prior to transfer to archives for
which is specific to multi-study trials and is long-term secure retention.
discussed later.
3.8.7 Quality control
3.8.4 Study plan amendments
The conduct of the study should include
If a change to the original study plan is pro- quality control (QC) steps, undertaken by
posed, a study plan amendment should be study personnel, as described in SOPs. QC
issued before the change occurs. An amend- steps should be undertaken when there is a
ment may also be issued as a result of unex- need for verification, especially at a data
pected occurrences during a study, which interface. For example, manual entry of raw
will require significant action. Study plan data should be checked by another study
amendments should be sequentially num- member. If the data being checked are criti-
cal, i.e. one error in the data could affect sented in the study report, which is a distinct
study integrity, all such data should be con- and separate record of QA study monitoring.
sidered for checking. If the data being The Study Director should authorise and
checked are non-critical, consideration can sign any subsequent corrections and/or addi-
be given to checking samples of data (for tions to the study report.
example, a sample from each analytical
batch). 3.10 STORAGE AND RETENTION OF
RECORDS AND MATERIALS
3.8.8 Confidentiality issues
The principles of GLP specific to records are
In multi-site studies, it should be ensured presented in Table 10.
in advance that confidentiality issues will On completion of a study, the Study Direc-
not impede the flow of information between tor is responsible for ensuring that all study
institutions. It may be appropriate for data are transferred in a timely manner to
study personnel to sign confidentiality the archives, as described in the study
statements. report. If study data are archived at several
locations, it should be remembered that, if
3.9 REPORTING OF STUDY RESULTS the study is subject to regulatory audit, it
could be necessary, at short notice, for all
The Principles of GLP specific to the report-
study data to be transferred to one location
ing of study results are presented in Table 9.
for the audit.
The OECD Principles of GLP employ the
Once archived, the responsibility for the
term “final report”. In the current docu-
safe keeping of study data passes from the
ment, “study report” is used instead of final
Study Director to Test Facility Manage-
report, in order to keep study report distinct
ment, which has responsibility for ensuring
from the trial report, i.e. the report of a
that there are designated personnel respon-
multi-study prevalidation and validation
sible for the archives, and that the archives
trial (see section 4.4).
are secure areas with the contents indexed
Study reports should be prepared in a
in an orderly manner. The duration of
timely manner. The Study Director should
archiving should be in accordance with reg-
sign and date the study report to indicate
ulatory requirements or as specified by
acceptance of responsibility for the validity
Test Facility Management.
of the data and that the study report accu-
rately reflects work conducted and all the
results obtained. The study report for a
4 MULTI-STUDY TRIALS
multi-site study should identify and define
the role of any Principal Investigators and
4.1 TRIAL MANAGEMENT TEAM
test sites involved in the conduct of the
study. The sponsor of a multi-study trial appoints
The study report should include a GLP a Trial Management Team to have respon-
compliance statement, which is a formal sibility for overseeing the organisation,
record to confirm that the study was con- conduct and reporting of the trial (6, 15).
ducted and reported in accordance with The Trial Management Team does not have
GLP, clearly identifying, as appropriate, immediate responsibility for ensuring GLP
where the study deviated from GLP. The compliance, since it is Test Facility Man-
GLP compliance statement is signed and agement which has direct GLP responsibil-
dated by the Study Director and should ity. However, there are some Principles of
address, in particular, the GLP status of any GLP which can be usefully applied to the
test sites not within a national GLP compli- Trial Management Team. For example, the
ance programme. trial plan should identify the key responsi-
In a multi-site study, it might be appropri- bilities of specific members of the Trial
ate for the Principal Investigator to include a Management Team, including that of the
signed GLP compliance statement in the chairperson and Trial Coordinator. It
contributory report that is forwarded to the might be appropriate to designate an indi-
Study Director. vidual in the Trial Management Team to
The GLP compliance statement should not coordinate GLP compliance issues; how-
be confused with the QA statement, also pre- 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, a
standardised 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 and
dated by them.
3. The study report should be signed and dated by the Study Director to indicate acceptance
of 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 should
be signed and dated by the Study Director.
5. Reformatting of the study report to comply with the submission requirements of a

national registration or regulatory authority does not constitute a correction, addition or
amendment 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 inspections

made and their dates, including the phase(s) inspected, and the dates any inspection
results 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 report
reflects the raw data.

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 control
items, specimens, raw data and the study report are to be stored.
facility remains with Test Facility Manage- on a need-to-know basis. Any changes to the
ment. Some of the required responsibilities trial plan should result in a trial plan amend-
of the Trial Management Team are illus- ment, in the same manner that any changes
trated in Figure 4 (6, 13). The Trial Man- to a study plan result in a study plan amend-
agement Team is responsible for the ment. Trial plan amendments must be num-
selection of participating laboratories, but bered, sequentially, and should be issued to
not for the appointment of Study Directors, all the original recipients of the trial plan.
who are appointed by Test Facility Man-
agement. 4.3 TRIAL COORDINATOR’S
RESPONSIBILITIES
4.2 TRIAL PLAN
The name and location of the Trial Coordi-
The trial plan outlines the trial goals and nator should be identified in each of the indi-
proposed time-scales, and identifies the stud- vidual study plans as the person responsible
ies, all the participating facilities and the for coordinating the supply and analysis of
names of Test Facility Management, Study test, reference and control items and the
Directors and Principal Investigators. Where coordination and preparation of the trial
there is no formal Study Director or Princi- report. It should be clarified whether the
pal Investigator, as might be the case for Trial Coordinator has direct access to the
facilities undertaking test item supply, data test item coding.
management and statistics, the person
The Trial Coordinator’s responsibilities
responsible for the technical conduct of the
include:
work should be identified.
The trial plan should include: a) the iden- 1. Responsibility for the coordination and
tity of the Trial Coordinator; b) SOP admin- communication network for test, refer-
istration, if common SOPs are to be used ence and control item supply and analy-
across studies; c) arrangements for QA mon- sis, data management and statistics for
itoring of study activities, including any pre- all the studies in a multi-study trial.
trial inspections; and d) the identity of
2. Ensuring that document and data flow
archiving locations.
between facilities are recorded.
The trial plan must be signed by at least
the chairperson of the Trial Management 3. Ensuring that QA monitoring is being
Team. The final trial plan should be identi- undertaken in accordance with the trial
fied as final, be fully authorised, and issued plan.
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 materials
should be documented. When samples of test, reference and control items and specimens are
disposed of before the expiry of the required retention period for any reason, this should be
justified and documented. Samples of test, reference and control items and specimens
should 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 storage
and 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 legal
successor, the archive should be transferred to the archives of the sponsor(s) of the
study(s).
4. Assessing and documenting the impact of 8. Ensuring that the trial documentation is
any amendments and/or deviations from properly archived.
the trial plan and study plans on the qual-
ity and integrity of the multi-study trial. 4.4 TRIAL REPORT
5. Ensuring that the individual study The trial report summarises the trial goals,
reports are forwarded, in a timely man- procedures, results and conclusions of a multi-
ner, for data and statistical analysis. study trial. This represents the whole multi-
study trial, including archiving and, as such,
6. Preparing the trial report, which can be
will cover several study reports, as well as
allocated to a Study Director or an inde-
reports for test item supply, data management
pendent person.
and statistics. The preparation of the trial
7. Ensuring that the trial report is an accu- report is outlined in Figure 5. The Trial Coor-
rate reflection of the overall multi-study dinator oversees the preparation of the trial
trial. The Trial Coordinator signs and report. The Trial Coordinator might also be
dates the final trial report to confirm that responsible for preparation of the scientific
the trial report is an accurate account of conclusions. Signatories to the trial report
the multi-study trial. include the Trial Coordinator, the chairperson
Figure 4: Overview of management for a multi-study validation trial
Sponsor
Finances
Contracts
Trial Management Team

(Trial Coordinator)
Quality assurance
Trial goals
Inspections to assure
Design and trial plan
compliance
Approval of trial plan and
overall trial report
Tests/Laboratories Chemicals
Selection of tests Control of quality of in Data
Identification of vivo data Planning of data
laboratories Selection of chemicals structure
Identification of lead Coding Data handling
laboratories
Distribution Data analysis
Approval of Standard
Operating Procedures Safety
of the Trial Management Team, the statisti- ing matters of GLP compliance. A QA state-
cian, and the Study Directors. Although the ment could be included in the trial report, in
Study Directors may not be involved with the order to identify what QA monitoring was
preparation of the trial report, their signa- done and to confirm whether or not the trial
tures confirm that the trial report is an accu- report is an accurate reflection of the study
rate reflection of study events. The trial report data.
should contain a statement, signed by the
Trial Coordinator, commenting on the accu- 4.5 QUALITY ASSURANCE OF MULTI-
racy and completeness of the trial report and STUDY TRIALS
identifying any significant issues which could Multi-study trials can involve independent
have affected the integrity of the trial, includ- facilities which are not formally GLP-compli-
Figure 5: Preparation of the Trial Report
Sponsor
Quality assurancea
Trial Coordinator
Inspections and Overall trial report
audits
Study Directors Chemical Supplier Statistician

Study reports Trial chemical report Trial data report
aSeveral Quality Assurance units might be involved in a multi-study trial.

Dashed lines indicate assurance staff involvement.
ant, such as facilities for test item analyses. GLP, describes a quality system con-
However, the QA monitoring of such facili- cerned with the organisation and the
ties is advised, to assure compliance with the conditions under which regulatory
relevant principles of GLP. Also, this pre- studies are planned, performed, moni-
sents the opportunity for QA personnel to tored, recorded, archived and reported.
monitor data exchange between facilities. Undertaking studies in compliance
QA reports should be forwarded to the rele- with GLP demonstrates to the regula-
vant facilities and also to the Trial Coordina- tory authorities that studies were
tor. In addition, the production of summary undertaken in a manner which pro-
and periodic QA reports, that would be issued motes confidence in the data and
to the Trial Management Team and sponsor reporting.
should be considered. QA review of the trial
report is appropriate, to provide independent 5.2 GOOD LABORATORY PRACTICE
assurance that the trial report is an accurate COMPLIANCE
reflection of the study reports and also the
2. A test facility might only be able to claim
trial data and trial chemical reports.
formal GLP compliance if it is within a
compliance programme run by the rele-
vant national GLP monitoring author-
5 CONCLUSIONS AND
ity. The QA monitoring of a facility not
RECOMMENDATIONS
within a compliance programme, does
not confer GLP compliance. Study
5.1 GOOD LABORATORY PRACTICE
reports and trial reports must clearly
PROMOTES CONFIDENCE IN THE
identify facilities which did not adhere to
DATA
formal GLP and address any impact this
1. The primary GLP reference for this might have had on study or trial
workshop, the OECD Principles of integrity.
3. If a test facility has designated GLP- an assay among laboratories and over
compliant areas and non-GLP areas, it is time.
essential that GLP compliance in the
GLP areas is not compromised by the 5.4 QUALITY ASSURANCE
non-GLP areas. Maintenance of GLP
8. The principles of GLP include the
and non-GLP areas in the same facility
requirement for QA monitoring by per-
requires constant vigilance to ensure
sonnel independent of the procedures
compliance of the GLP areas. being inspected. QA is based on organi-
4. A test facility might conduct both “regu- sational rather than scientific proce-
latory studies”, intended for review by dures. Therefore, QA does not interfere
the regulatory authorities, and “non- with the technical and scientific conduct
regulatory” studies, which are not of studies.
intended for submission to the regula-
tory authorities. Where this is the prac- 5.5 VALIDATION AND MULTI-STUDY
tice in the same GLP area, it will be TRIALS
necessary for the non-regulatory work to 9. The validation of in vitro tests is under-
also be conducted in compliance with taken as multi-study trials, consisting of
GLP. Essentially, the main differences a number of separate studies, with each
between such regulatory and non-regu- study, having its own study plan and
latory studies are that the latter may be Study Director. Each study within a for-
subject to reduced QA monitoring and mal validation multi-study trial, is con-
have a reduced amount of specific GLP ducted and reported without knowledge
documentation requirements. of the test item randomisation code.
5.3 STUDY CONDUCT 10. Multi-study trials are overseen by a
Trial Management Team which is
5. The management of single-site and responsible for the selection of partici-
multi-site studies, including the key pating facilities. However, it is the Test
roles of Study Director and Principal Facility Managements of the participat-
Investigator, as described in the OECD ing laboratories who have responsibility
Principles of GLP, are considered rele- for the GLP compliance of facilities,
vant to the conduct of in vitro studies. including the appointment of Study
6. To ensure the applicability of GLP to in Directors.
vitro studies, some additions are neces- 11. A trial plan serves to outline the multi-
sary to the OECD Principles of GLP, study trial and includes trial goals and
most notably with respect to: a) defini- time-scales, and identifies participating
tion of test system facilities, with special facilities and key personnel. The trial
reference to handling and storage of test plan becomes a formal document when it
items; b) characterisation and care of is signed by the chairperson of the Trial
test systems; c) the required use of posi- Management Team, and the Trial Coor-
tive and negative control items; and d) dinator.
acceptance criteria.
12. The Trial Coordinator undertakes a
7. The concept of acceptance criteria is one pivotal role in ensuring compliance of
of the major additions to the Principles the multi-study trial with the trial plan,
of GLP proposed by the workshop. The including preparation of the trial
responses of a test system to control report.
items usually provides the basis for
determining the acceptability of an
assay. The observed control response is 6 ACKNOWLEDGEMENTS
compared to historical values for the
assay, to determine whether or not the The authors would like to thank Dr Melanie
response falls within predefined limits Scheiwiller (Novartis, Pharma AG, Switzer-
given in the study plan acceptance crite- land) and Mr Mike Burrows (Guy’s Drug
ria. The performance of the controls also Research Unit, Quintiles, London, UK) for
allows comparison of the performance of commenting on the draft report.
7 REFERENCES 88//320/EEC on the inspection and verification of

Good Laboratory Practice (GLP). Commission
1. ECVAM (1994). ECVAM News & Views. ATLA Directive 1999/12/EC. Official Journal of the
22, 7–11. European Communities 77, 22–33.
2. OECD (1998). Organisation for Economic Cooper- 9. OECD (1998). Organisation for Economic Co-
ation and Development series on Principles of operation and Development series on Principles
of Good Laboratory Practice and compliance mon-
Good Laboratory Practice and compliance moni-
itoring. Number 3 (Revised). Guidance for GLP
toring. Number 1. OECD Principles on Good Lab-
monitoring authorities revised guidance for the
oratory Practice (as revised in 1997), OECD
conduct of laboratory inspections and study audit,
Environmental Health and Safety Publications,
Environment Monograph No. 111, OECD Envi-
Environment Directorate: ENV/MC/CHEM(98) ronmental Health and Safety Publications:
17. Paris, France: OECD. OECD/GD(95)67. Paris, France: OECD.
3. OECD (1992). Environment Monograph No. 50, 10. Anon. (1999). Adapting to technical progress the
Series on Principles of Good Laboratory Practice Principles of Good Laboratory Practice as speci-
and Compliance Monitoring: Number 6, The fied in Council Directive 87/18/EEC on the har-
Application of the GLP Principles to Field Stud- monisation of laws, regulations and
ies. Paris, France: OECD. administrative provisions relating to the applica-
4. Stiles, T. (1997). The revised OECD principles of tion of the principles of good laboratory practice
Good Laboratory Practice: a reflection upon the and the verification of their applications for tests
impact of the proposed changes on pre-clinical on chemical substances. Commission Directive
safety testing. Part 1. Scope, definition of terms, 1999/11/EC. Official Journal of the European
responsibilities. The Quality Assurance Journal Communities 77, 8–21.
2, 13–18. 11. Balls, M. & Karcher, W. (1995). The validation of
5. Stiles, T. (1997). The revised OECD Principles of alternative test methods. ATLA 23, 884–886.
Good Laboratory Practice: a reflection upon the 12. Curren, R.D., Southee, J.A., Spielmann, H., Lieb-
impact of the proposed changes on pre-clinical sch, M., Fentem, J.H. & Balls, M. (1995). The role
safety testing. Part 2. Scope, definition of terms, of prevalidation in the development, validation
responsibilities. The Quality Assurance Journal and acceptance of alternative methods. ATLA 23,
2, 49–53. 211–217.
6. Balls, M., Blaauboer, B.J., Fentem, J.H., Bruner, 13. Fentem, J.H., Archer, G.E.B., Balls, M., Botham,
L., Combes, R.D., Ekwall, B., Fielder, R.J., Guil- P.A., Curren, R.D., Earl, L.K., Esdaile, D.J.,
louzo, A., Lewis, R.W., Lovell, D.P., Reinhardt, Holzhütter, H-G. & Liebsch, M. (1998). The
C.A., Repetto, G., Sladowski, D., Speilmann, H. & ECVAM international validation study on in vitro
Zucco, F. (1995). Practical aspects of the valida- tests for skin corrosivity. 2. Results and evalua-
tion of toxicity test procedures. ATLA 23, tion by the Management Team. Toxicology in
129–147. Vitro 12, 483–524.
7. Harbell, J.W., Southee, J.A. & Curren, R.D. 14. Froud, S.J. & Luker, J. (1994). Good Laboratory
(1997). The path to regulatory acceptance of in Practice in the cell culture laboratory. In Basic
vitro methods is paved with the strictest scientific Cell Culture: A Practical Approach (ed. J.M.
standards. In Animal Alternatives, Welfare and Davis), pp. 273–286. Oxford, UK: Oxford Univer-
Ethics (ed. L.F.M van Zutphen & M. Balls), pp. sity Press.
1177–1181. Amsterdam, The Netherlands: Else- 15. Cooper-Hannan, R. (1997). Good Laboratory
vier. Practice and study management for the valida-
8. Anon. (1999). Adapting to technical progress for tion of in vitro toxicity studies. ATLA 12,
the second time the Annex to Council Directive 527–537.
8 Appendix 1
Terminology
These terms are based on the terms con- ical health and environmental safety
tained in the OECD Principles of Good Lab- study.
oratory Practice. Recommended additions
Test Facility. The persons, premises and
are in bold and underlined.
operational unit(s) that are necessary for
conducting the non-clinical health and
Good Laboratory Practice
environmental safety study. For multi-site
Good Laboratory Practice (GLP). A studies (studies conducted at more than
quality system concerned with the organisa- one site), the test facility comprises the site
tional process and the conditions under at which the Study Director is located and
which non-clinical health and environmental all individual test sites, which individually
safety studies are planned, performed, moni- or collectively can be considered to be test
tored, recorded, archived and reported. facilities.
Test Facility Management. The persons
Terms concerning the organisation of a test
who have the authority and formal responsi-
facility
bility for the organisation and functioning of
Master Schedule. A compilation of infor- the test facility according to these Principles
mation to assist in the assessment of work- of Good Laboratory Practice.
load and for the tracking of studies at a test
Test Site. A location at which a phase of a
facility.
study is conducted.
Principal Investigator. An individual
Test Site Management (if appointed). The
who, for a multi-site study, acts on behalf of
person responsible for ensuring that the
the Study Director and has defined responsi-
phase of the study, for which he/she is
bilities for delegated phases of the study. The
responsible, are conducted according to these
Study Director’s responsibility for the over-
Principles of Good Laboratory Practice.
all conduct of the study cannot be delegated
to the Principal Investigator; this includes
Terms concerning the study
approval of the study plan and its amend-
ments, approval of the study report, and Acceptance Criteria. The basis for
ensuring that all applicable Principles of determining the acceptability of an
Good Laboratory Practice are followed. assay according to pre-defined perfor-
mance parameters.
Quality Assurance Programme. A
defined system, including personnel, which Experimental Completion Date. The last
is independent of study conduct and is date on which data are collected from the
designed to assure Test Facility Manage- study.
ment of compliance with these principles of
Experimental Starting Date. The date on
Good Laboratory Practice.
which the first study-specific data are col-
Sponsor. An entity which commissions, lected.
supports and/or submits a non-clinical
Good Laboratory Practice Compliance
health and environmental safety study.
Statement. A formal record, signed and
Standard Operating Procedures dated by the Study Director, to indicate
(SOPs). Documented procedures which acceptance of responsibility for the validity
describe how to perform tests or activities of the data and to indicate the extent to
normally not specified in detail in study which the study complies with Good Labora-
plans or test guidelines. tory Practice.
Study Director. The individual responsi- Non-clinical Health and Environmen-
ble for the overall conduct of the non-clin- tal Safety Study. Henceforth referred to
simply as “study”, is an experiment or set Test System. Any biological, chemical or

of experiments in which a test item(s) is physical system, or combination thereof,
examined under laboratory conditions or in used in a study.
the environment, to obtain data on its prop-
erties and/or its safety, intended for sub- Terms concerning the test, reference and
mission to appropriate regulatory control items
authorities.
Batch. A specific quantity or lot of a test,
Quality Assurance Statement. A formal reference or control item produced dur-
record listing the types of inspections made ing a defined cycle of manufacture in such
and their dates, including the phase a way that it could be expected to be of a
inspected, and the dates any inspection uniform character and should be desig-
results were reported to Management, and to nated as such.
the Study Director and Principal Investiga-
Control Item. An article used to moni-
tor, if applicable. This statement also serves
tor the performance of an assay, which
to confirm that the final report reflects the
might not necessarily be used in the
raw data, as appropriate.
same manner as a reference item.
Raw Data. All original test facility records
Reference Item. Any article used to pro-
and documentation, or verified copies
vide a basis for comparison with the test
thereof, which are the result of the original
item.
observations and activities in a study. Raw
data can also include photographs, micro- Test Item. An article that is the subject of a
film or microfiche copies, computer read- study.
able media, dictated observations, recorded
Vehicle. Any agent which serves as a carrier
data from automated instruments, or any
used to mix, disperse, or solubilise the test,
other data storage medium that has been
reference or control item to facilitate the
recognised as capable of providing secure
administration/application to the test sys-
storage of information for the required
tem.
time-period.
Short-term Study. A study of short dura- Terms covering prevalidation and
tion with widely used, routine techniques. validation
Specimen. Any material derived from a test Prevalidation Study. A study carried
system for examination, analysis, or reten- out following test development, but
tion. prior to the possible inclusion of a test
in a formal validation study. This need
Study Completion Date. The date on
not, but usually does, include the blind
which the Study Director signs the study
testing of coded chemicals.
report.
Validation. The process by which the
Study Initiation Date. The date on which
reliability and relevance of a procedure
the Study Director signs the study plan.
are established for a specific purpose.
Study Plan. A document which defines the The main goal is to conduct multi-site
objectives and experimental design for the trials with coded test items, as a basis
conduct of the study, and includes any for assessing whether one or more
amendments. tests, test batteries or testing strategies
can be shown to be relevant and reli-
Study Plan Amendment. An intended
able for one or more specific purposes,
change to the study plan after the study ini-
according to predefined performance
tiation date.
criteria.
Study Plan Deviation. An unintended
departure from the study plan after the Terms concerning multi-study trials
study initiation date.
Multi-study Trial. A set of studies which
Study Report. A document which can be used to compare methods and/or
reports the objectives, procedures, test item(s) and generally refers to
results and conclusions of a study. prevalidation/validation studies.
Trial Coordinator. The individual who Trial Plan. A document which outlines
coordinates the overall conduct and the goals, design, participants and pro-
reporting of a multi-study trial. posed time-scales of the multi-study
trial.
Trial Management Team. The persons
who have responsibility for overseeing Trial Report. The document which sum-
the organisation, conduct and report- marises the goals, procedures, results
ing of a multi-study trial. and conclusions of a multi-study trial.
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The Principles of Good Laboratory Practice: Application to In Vitro Toxicology

Article in Alternatives to laboratory animals: ATLA · July 1999

John Harbell Sandra Coecke

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Michael Balls Miroslav Cervinka

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The Principles of Good Laboratory Practice:

The Report and Recommendations of ECVAM Workshop 371,2

Robin Cooper-Hannan,3 John W. Harbell,4 Sandra Coecke,5 Michael

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

3.1 TEST FACILITY ORGANISATION AND PERSONNEL . . . . . . . . . . . . . . . . . 546

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

3.8 PERFORMANCE OF THE STUDY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562

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

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

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

1 INTRODUCTION GLP, and outlines the types of studies which

2.2 MULTI-SITE STUDIES

Figure 2: Organisation of a multi-site study

Principal Principal Principal

Figure 3: Good Laboratory Practice organisation for a multi-study trial

Trial Quality assurancea

Test 1: study 1 Test 1: study 2 Test 2: study 3 Test 2: study 4

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

In the event that a Study Director has to 3.1.1.2 Principal Investigator

Table 1A: Test Facility Organisation and Personnel

1.1 Test Facility Management’s Responsibilities

Recommended additions to the test are in bold and underlined.

Table 1B: Test Facility Organisation and Personnel

1.2 Study Director’s Responsibilities