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This document is meant purely as a documentation tool and the institutions do not assume any liability for its contents
►B COUNCIL DIRECTIVE
►C1 of 7June 1988 ◄
on the inspection and verification of Good Laboratory Practice (GLP)
(88/320/EEC)
(OJ L 145, 11.6.1988, p. 35)
Amended by:
Official Journal
No page date
►M1Commission Directive 90/18/EEC of 18 December 1989 L 11 37 13.1.1990
►M2Commission Directive 1999/12/EC of 8 March 1999 L 77 22 23.3.1999
Corrected by:
►C1Corrigendum, OJ L 174, 6.7.1988, p. 55 (88/320)
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▼B
COUNCIL DIRECTIVE
▼C1
of 7June 1988
▼B
on the inspection and verification of Good Laboratory Practice
(GLP)
(88/320/EEC)
THE COUNCIL OF THE EUROPEAN COMMUNITIES,
Having regard to the Treaty establishing the European Economic
Community, and in particular Article 100A thereof,
Having regard to the proposal from the Commission (1),
In cooperation with the European Parliament (2),
Having regard to the opinion of the Economic and Social Committee (3),
Whereas the application of standardized organizational processes and
conditions under which laboratory studies are planned, performed,recorded and reported for the non-clinical testing of chemicals for theprotection of man, animals and the environment, hereinafter referred toas ‘Good Laboratory Practice'(GLP), contributes to the reassurance ofMember States as to the quality of the test data generated;
Whereas, in Annex 2 to its Decision on 12 May 1981 on the mutual
acceptance of data in the assessment of chemicals, the council of theOrganization for Economic Cooperation and Development (OECD)adopted principles of good laboratory practice which are acceptedwithin the Community and are specified in Council Directive 87/18/EEC of 18 December 1986 on the harmonization of laws, regulationsand administrative provisions relating to the application of the princi-ples of good laboratory practice and the verification of their applicationsfor tests on chemical substances (
4);
Whereas, in the conduct of tests on chemicals, it is desirable that
specialist manpower and testing laboratory resources should not bewasted owing to the need to duplicate tests because of differences inlaboratory practices from one Member State to another; whereas thisapplies especially for animal protection which requires that the numberof experiments on animals be restricted in accordance with CouncilDirective 86/609/EEC of 24 November 1986 on the approximation oflaws, regulations and administrative provisions of the Member Statesregarding the protection of animals used for experimental and otherscientific purposes (
5); whereas mutual recognition of the results of tests
obtained using standard and recognized methods is an essential condi-tion for reducing the number of experiments in this area;
Whereas, however, in order to ensure that test data generated by labora-
tories in one Member State are also recognized by other Member States,it is necessary to provide for a harmonized system for study audit andinspection of laboratories to ensure that they are working under GLPconditions;
Whereas Member States designate the authorities responsible for
carrying out monitoring on compliance with GLP;
Whereas a committee, the members of which will be appointed by the
Member States, would be of assistance to the Commission in thetechnical application of this Directive and would cooperate in its effortsto encourage the free movement of goods by the mutual recognition byMember States of procedures for monitoring compliance with GLP;
(1) OJ No C 13, 17. 1. 1987, p. 5.
(2) OJ No C 156; 15. 6. 1987, p. 190 and OJ No C 122, 9. 5. 1988.
(3) OJ No C 232, 31. 8. 1987, p. 1.
(4) OJ No L 15, 17. 1. 1987, p. 29.
(5) OJ No L 358, 18. 12. 1986, p. 1.
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whereas the committee set up by Council Directive 67/548/EEC of 27
June 1967 on the approximation of laws, regulations and administrativeprovisions relating to the classification, packaging and labelling ofdangerous substances (
1), as last amended by Directive 87/432/EEC (2),
may be used for this purpose;
Whereas this committee may assist the Commission not only in the
application of this Directive but also in contributing to the exchange ofinformation and experience in this field,
HAS ADOPTED THIS DIRECTIVE:
Article 1
1. This Directive applies to the inspection and verification of the
organizational processes and the conditions under which laboratorystudies are planned, performed, recorded and reported for the non-clin-ical testing, carried out in accordance with the rules and regulations, ofall chemicals (e. g. cosmetics, industrial chemicals, medicinal products,food additives, animal feed additives, pesticides) in order to assess theeffect of such products on man, animals and the environment.
2. For the purposes of this Directive, the GLP, is described in
Directive 87/18/EEC.
3. This Directive is not concerned with the interpretation and evalu-
ation of test results.
Article 2
1. Using the procedure laid down in Article 3, Member States shall
verify the compliance with GLP of any testing laboratory within theirterritory claiming to use GLP in the conduct of tests on chemicals.
2. Where the provisions of paragraph 1 have been complied with,
and the results of the inspection and verification are satisfactory, theMember State in question may provide endorsement of a claim by alaboratory that it and the tests that it carries out comply with GLP, usingthe formula‘Assessment of conformity with GLP a ccording toDirective 88/320/EEC on … (date)'.
Article 3
1. Member States shall designate the authorities responsible for the
inspection of laboratories within their territories and for the audit ofstudies carried out by laboratories to assess compliance with GLP.
2. The authorities referred to in paragraph 1 shall inspect the labora-
tory and audit the studies in accordance with the provisions laid downin the Annex.
Article 4
1. Each year, Member States shall draw up a report relating to the
implementation of GLP within their territory.
This report shall contain a list of laboratories inspected, the date on
which such inspection was carried out and a brief summary of theconclusions of the inspections.
2. The reports shall be forwarded to the Commission each year, not
later than 31 March. The Commission shall communicate them to thecommittee referred to in Article 7. The committee may request informa-tion in addition to those elements mentioned in paragraph 1.
3. Member States shall ensure that commercially sensitive and other
confidential information to which they gain access as a result of GLPcompliance monitoring activities is made available only to the Commis-
(1) OJ No 196, 16. 8. 1967, p. 1/67.
(2) OJ No L 239, 21. 8. 1987, p. 1.
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sion, to national regulatory and designated authorities and to a labora-
tory or study sponsor directly concerned with a particular inspection orstudy audit.
4. The names of laboratories subject to inspection by a designated
authority, their GLP compliance status and the dates upon which labora-tory inspections or study audits have been conducted shall not beconsidered to be confidential.
Article 5
1. Without prejudice to Article 6, the results of laboratory inspec-
tions and study audits on GLP compliance carried out by a MemberState shall be binding on the other Member States.
2. Where a Member State considers that a laboratory within its
territory claiming GLP compliance does not in fact comply with GLP tothe extent that the integrity or authenticity of the studies it performsmight be compromised, it shall forthwith inform the Commission. TheCommission shall inform the other Member States.
Article 6
1. Where a Member State has sufficient reason to believe that a
laboratory in another Member State claiming GLP compliance has notcarried out a test according to GLP, it may request further informationfrom that Member State and in particular may request a study audit,possibly in conjunction with anew inspection.
Should it not be possible for the Member States concerned to reach
agreement, the Member States in question shall immediately inform theother Member States and the Commission, giving reasons for theirdecision.
2. The Commission shall examine as soon as possible the reasons put
forward by the Member States within the Committee; it shall then takethe appropriate measures in accordance with procedure laid down inArticle 8. It may in this connection ask for expert opinions from thedesignated authorities in the Member States.
3. If the Commission considers that amendments to this Directive are
necessary in order to resolve the matters to in paragraph 1, it shallinitiate the procedure laid down in Article 8 with a view to adoptingthose amendments.
Article 7
1. The committee set up by Article 20 of Directive 67/548/EEC,
hereinafter called ‘the Committee',may examine any question which isreferred to it by its chairman either on his own initiative or at therequest of arepresenta tive of aMember Sta te, concerning the imple-mentation of this Directive and in particular regarding:
— cooperation between the authorities designated by the Member
States in technical and administrative matters arising from theimplementation of GLP, and
— the exchange of information on the training of inspectors.
2. The amendments necessary for the adaptation of the formula
referred to in Article 2 (2) and of the Annex to this Directive to takeaccount of technical progress shall be adopted in accordance with theprocedure set out in Article 8.
Article 8
1. The representative of the Commission shall submit to the
Committee a draft of the measures to be adopted. The Committee shalldeliver its opinion on the draft within a time limit which the chairmanmay lay down according to the urgency of the matter. The opinion shallbe delivered by the majority laid down in Article 148 (2) of the Treatyin the case of decisions which the Council is required to adopt on aproposal from the Commission. The votes of the representatives of the
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Member States within the Committee shall be weighted in the mannerset out in that Article. The chairman shall not vote.
2. The Commission shall adopt the measures envisaged if they are in
accordance with the opinion of the Committee.
If the measures envisaged are not in accordance with the opinion of the
Committee, or if no opinion is delivered, the Commission shall, withoutdelay, submit to the Council a proposal relating to the measures to betaken. The Council shall act by a qualified majority.
3. If within three months of submission of the proposal the Council
has not acted, the proposed measures shall be adopted by the Commis-sion.
Article 9
Member States shall bring into force the laws, regulations or adminis-
trative provisions necessary to comply with this Directive not later than1 January 1989. They shall forthwith inform the Commission thereof.
Article 10
This Directive is addressed to the Member States.
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ANNEX
The provisions for the inspection and verification of GLP which are contained in
parts A and B are those contained in Annexes I (Guides for compliancemonitoring procedures for good laboratory practice) and II (Guidance for theconduct of test facility inspections and study audits) respectively of the OECDCouncil Decision-Recommendation on compliance with principles of good labo-ratory practice [C(89)87(Final)] of 2 October 1989 as revised by the OECDCouncil Decision amending the Annexes to the Council Decision-Recommenda-tion on compliance with principles of good laboratory practice of 9 March 1995[C(95)8(Final)].
PART A
REVISED GUIDES FOR COMPLIANCE MONITORING PROCEDURES FOR
GOOD LABORATORY PRACTICE
To facilitate the mutual acceptance of test data generated for submission to
Regulatory Authorities of the OECD member countries, harmonisation of theprocedures adopted to monitor good laboratory practice compliance, as well ascomparability of their quality and rigour, are essential. The aim of this part of theAnnex is to provide detailed practical guidance to the Member States on thestructure, mechanisms and procedures they should adopt when establishingnational good laboratory practice compliance monitoring programmes so thatthese programmes may be internationally acceptable.
It is recognised that Member States will adopt GLP principles and establish
compliance monitoring procedures according to national legal and administrativepractices, and according to priorities they give to, for example the scope of initialand subsequent coverage concerning categories of chemicals and types of testing.Since Member States may establish more than one Good Laboratory PracticeMonitoring Authority due to their legal framework for chemicals control, morethan one good laboratory practice compliance programme may be established.The guidance set forth in the following paragraphs concerns each of theseAuthorities and compliance programmes, as appropriate.
Definitions of terms
The definitions of terms in the OECD principles of good laboratory practice
adopted in Article 1 of Council Directive 87/18/EEC (
1) are applicable to this
part of the Annex. In addition, the following definitions apply:
—GLP principles: principles of good laboratory practice that are consistent
with the OECD principles of good laboratory practice as adopted in Article 1of Directive 87/18/EEC,
—GLP compliance monitoring: the periodic inspection of test facilities and/or
auditing of studies for the purpose of verifying adherence to GLP principles,
—(National) GLP compliance programme: the particular scheme established
by a Member State to monitor good laboratory practice compliance by testfacilities within its territories, by means of inspections and study audits,
—(National) GLP Monitoring Authority: abody esta blished within aMember
State with responsibility for monitoring the good laboratory practice compli-ance of test facilities within its territories and for discharging other suchfunctions related to good laboratory practice as may be nationally deter-mined. It is understood that more than one such body may be established in aMember State,
—Test facility inspection: an on-site examination of the test facility’s proced-
ures and practices to assess the degree of compliance with GLP principles.During inspections, the management structures and operational procedures ofthe test facility are examined, key technical personnel are interviewed, andthe quality and integrity of data generated by the facility are assessed andreported,
—Study audit: a comparison of raw data and associated records with the
interim or final report in order to determine whether the raw data have beenaccurately reported, to determine whether testing was carried out in accord-ance with the study plan and standard operating procedures, to obtain addi-tional information not provided in the report, and to establish whether prac-tices were employed in the development of data that would impair theirvalidity,
(1) OJ L 15, 17. 1. 1987, p. 29
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—Inspector: a person who performs the test facility inspections and study
audits on behalf of the (national) GLP Monitoring Authority,
—GLP compliance status: the level of adherence of a test facility to the GLP
principles as assessed by the (national) GLP Monitoring Authority,
—Regulatory Authority: a national body with legal responsibility for aspects of
the control of chemicals.
Components of good laboratory practice compliance monitoring proced-
ures
Administration
A (national) GLP compliance programme should be the responsibility of a
properly constituted, legally identifiable body adequately staffed and workingwithin a defined administrative framework.
Member States should:
— ensure that the (national) GLP Monitoring Authority is directly responsible
for an adequate ‘team'of inspectors having the necessary technical/scientificexpertise or is ultimately responsible for such a team,
— publish documents relating to the adoption of GLP principles within their
territories,
— publish documents providing details of the (national) GLP compliance
programme, including information on the legal or administrative frameworkwithin which the programme operates and references to published acts,normative documents (e.g., regulations, codes of practice), inspectionmanuals, guidance notes, periodicity of inspections and/or criteria for inspec-tion schedules, etc.,
— maintain records of test facilities inspected (and their GLP compliance status)
and of studies audited for both national and international purposes.
Confidentiality
(National) GLP Monitoring Authorities will have access to commercially
valuable information and, on occasion, may even need to remove commerciallysensitive documents from a test facility or refer to them in detail in their reports.
Member States should:
— make provision for the maintenance of confidentiality, not only by Inspectors
but also by any other persons who gain access to confidential information asa result of GLP compliance monitoring activities,
— ensure that, unless all commercially sensitive and confidential information
has been excised, reports of test facility inspections and study audits aremade available only to Regulatory Authorities and, where appropriate, to thetest facilities inspected or concerned with study audits and/or to study spon-sors.
Personnel and training
(National) GLP Monitoring Authorities should:
— ensure that an adequate number of inspectors is available.
The number of inspectors required will depend on:
(a) the number of test facilities involved in the (national) GLP compliance
programme;
(b) the frequency with which the GLP compliance status of the test facilities
is to be assessed;
(c) the number and complexity of the studies undertaken by those test
facilities;
(d) the number of special inspections or audits requested by Regulatory
Authorities,
— ensure that inspectors are adequately qualified and trained.
Inspectors should have qualifications and practical experience in the range of
scientific disciplines relevant to the testing of chemicals. (National) GLPMonitoring Authorities should:
(a) ensure that arrangements are made for the appropriate training of GLP
inspectors, having regard to their individual qualifications and experi-ence;
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(b) encourage consultations, including joint training activities where neces-
sary, with the staff of (national) GLP Monitoring Authorities in otherOECD member countries in order to promote international harmonisationin the interpretation and application of GLP principles, and in themonitoring of compliance with such principles,
— ensure that inspectorate personnel, including experts under contract, have no
financial or other interests in the test facilities inspected, the studies auditedor the firms sponsoring such studies,
— provide inspectors with a suitable means of identification (e.g., an identity
card).
Inspectors may be:
— on the permanent staff of the (national) GLP Monitoring Authority,
— on the permanent staff of a body separate from the (national) GLP
Monitoring Authority, or
— employed on contract, or in another way, by the (national) GLP Monitoring
Authority to perform test facility inspections or study audits.
In the latter two cases, the (national) GLP Monitoring Authority should have
ultimate responsibility for determining the GLP compliance status of test facili-ties and the quality/acceptability of a study audit, and for taking any action basedon the results of test facility inspections or study audits which may be necessary.
(National) GLP compliance programmes
GLP compliance monitoring is intended to ascertain whether test facilities have
implemented GLP principles for the conduct of studies and are capable ofassuring that the resulting data are of adequate quality. As indicated above,Member States should publish the details of their (national) GLP complianceprogrammes. Such information should, inter alia :
— define the scope and extent of the programme.
A (national) GLP compliance programme may cover only a limited range of
chemicals, for example, industrial chemicals, pesticides, pharmaceuticals,etc., or may include all chemicals. The scope of the monitoring for compli-ance should be defined, both with respect to the categories of chemicals andto the types of tests subject to it, for example, physical, chemical, toxicolog-ical and/or ecotoxicological,
— provide an indication as to the mechanism whereby test facilities enter the
programme.
The application of GLP principles to health and environmental safety data
generated for regulatory purposes may be mandatory. A mechanism shouldbe available whereby test facilities may have their compliance with GLPprinciples monitored by the appropriate (national) GLP MonitoringAuthority,
— provide information on categories of test facility inspections/study audits.
A (national) GLP compliance programme should include:
(a) provision for test facility inspections. These inspections include both a
general test facility inspection and a study audit of one or more on-goingor completed studies;
(b) provisions for special test facility inspections/study audits at the request
of a Regulatory Authority, for example, prompted by a query arisingfrom the submission of da tato aRegula tory Authority,
— define the powers of inspectors for entry into test facilities and their access to
data held by test facilities (including specimens, SOPs (standard operatingprocedures) other documentation, etc.).
While inspectors will not normally wish to enter test facilities against the will
of the facility’s management, circumstances may arise where test facilityentry and access to data are essential to protect public health or the environ-ment. The powers available to the (national) GLP Monitoring Authority insuch cases should be defined,
— describe the test facility inspection and study audit procedures for verifica-
tion of GLP compliance.
The documentation should indicate the procedures which will be used to
examine both the organisational processes and the conditions under whichstudies are planned, performed, monitored and recorded. Guidance for suchprocedures is available in part B of this Annex,
— describe actions that may be taken as follow-up test facility inspections and
study audits.
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Follow-up to test facility inspections and study audits
When a test facility inspection or study audit has been completed, the inspector
should prepare a written report of the findings.
Member States should take action where deviations from GLP principles are
found during or after a test facility inspection or study audit. The appropriateactions should be described in documents from the (national) GLP MonitoringAuthority.
If a test facility inspection or study audit reveals only minor deviations from
GLP principles, the facility should be required to correct such minor deviations.The inspector may need, at an appropriate time, to return to the facility to verifythat corrections have been introduced.
Where no, or where only minor deviations have been found, the (national) GLP
Monitoring Authority may:
— issue a statement that the test facility has been inspected and found to be
operating in compliance with GLP principles. The date of the inspectionsand, if appropriate, the categories of test inspected in the test facility at thattime should be included. Such statements may be used to provide informa-tion to (national) GLP Monitoring Authorities in other OECD member coun-tries,
and/or
— provide the Regulatory Authority which requested a study audit with a
detailed report of the findings.
Where serious deviations are found, the action taken by (national) GLP
Monitoring Authorities will depend on the particular circumstances of each caseand the legal or administrative provisions under which GLP compliancemonitoring has been established within their countries. Actions which may betaken include, but are not limited to, the following:
— issuance of a statement, giving details of the inadequacies or faults found
which might affect the validity of studies conducted in the test facility,
— issuance of a recommendation to a Regulatory Authority that a study be
rejected,
— suspension of test facility inspections or study audits of a test facility and, for
example and where administratively possible, removal of the test facilityfrom the (national) GLP compliance programme or from any existing list orregister of test facilities subject to GLP test facility inspections,
— requiring that a statement detailing the deviations be attached to specific
study reports,
— action through the courts, where warranted by circumstances and where
legal/administrative procedures so permit.
Appeals procedures
Problems, or differences of opinion, between inspectors and test facility manage-
ment will normally be resolved during the course of a test facility inspection orstudy audit. However, it may not always be possible for agreement to be reached.A procedure should exist whereby a test facility may make representationsrelating to the outcome of a test facility inspection or study audit for GLPcompliance monitoring and/or relating to the action the GLP MonitoringAuthority proposes to take thereon.
PART B
REVISED GUIDANCE FOR THE CONDUCT OF TEST FACILITY INSPEC-
TIONS AND STUDY AUDITS
Introduction
The purpose of this part of the Annex is to provide guidance for the conduct of
test facility inspections and study audits which would be mutually acceptable toOECD member countries. It is principally concerned with test facility inspec-tions, an activity which occupies much of the time of GLP inspectors. A testfacility inspection will usually include a study audit or review as a part of theinspection, but study audits will also have to be conducted from time to time at
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the request, for example, of a Regulatory Authority. General guidance for the
conduct of study audits will be found at the end of this Annex.
Test facility inspections are conducted to determine the degree of conformity of
test facilities and studies with GLP principles and to determine the integrity ofdata to assure that resulting data are of adequate quality for assessment anddecision-making by national Regulatory Authorities. They result in reports whichdescribe the degree of adherence of a test facility to the GLP principles. Testfacility inspections should be conducted on a regular, routine basis to establishand maintain records of the GLP compliance status of test facilities.
Further clarification of many of the points in this part of the Annex may be
obtained by referring to the OECD consensus documents on GLP (on, e.g., therole and responsibilities of the study director).
Definitions of terms
The definitions of terms in the OECD principles of good laboratory practice
adopted in Article 1 of Directive 87/18/EEC and in part A of the Annex to thisDirective are applicable to this part of the Annex.
Test facility inspections
Inspections for compliance with GLP principles may take place in any test
facility generating health or environmental safety data for regulatory purposes.Inspectors may be required to audit data relating to the physical, chemical,toxicological or ecotoxicological properties of a substance or preparation. Insome cases, inspectors may need assistance from experts in particular disciplines.
The wide diversity of facilities (in terms both of physical layout and management
structure), together with the variety of types of studies encountered by inspectors,means that the inspectors must use their own judgment to assess the degree andextent of compliance with GLP principles. Nevertheless, inspectors should strivefor a consistent approach in evaluating whether, in the case of a particular testfacility or study, an adequate level of compliance with each GLP principle hasbeen achieved.
In the following sections, guidance is provided on the various aspects of the
testing facility, including its personnel and procedures, which are likely to beexamined by inspectors. In each section, there is a statement of purpose, as wellas an illustrative list of specific items which could be considered during thecourse of a test facility inspection. These lists are not meant to be comprehensiveand should not be taken as such.
Inspectors should not concern themselves with the scientific design of the study
or the interpretation of the findings of studies with respect to risks for humanhealth or the environment. These aspects are the responsibility of those Regula-tory Authorities to which the data are submitted for regulatory purposes.
Test facility inspections and study audits inevitably disturb the normal work in a
facility. Inspectors should therefore carry out their work in a carefully plannedway and, so far as practicable, respect the wishes of the management of the testfacility as to the timing of visits to certain sections of the facility.
Inspectors will, while conducting test facility inspections and study audits, have
access to confidential, commercially valuable information. It is essential that theyensure that such information is seen by authorised personnel only. Their respon-sibilities in this respect will have been established within their (national) GLPcompliance monitoring programme.
Inspection procedures
Pre-inspection
Purpose : to familiarise the inspector with the facility which is about to be
inspected in respect of management structure, physical layout of buildings andrange of studies.
Prior to conducting a test facility inspection or study audit, inspectors should
familiarise themselves with the facility which is to be visited. Any existinginformation on the facility should be reviewed. This may include previousinspection reports, the layout of the facility, organisation charts, study reports,protocols and curricula vitae (CVs) of personnel. Such documents would provideinformation on:
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— the type, size and layout of the facility,
— the range of studies likely to be encountered during the inspection,— the management structure of the facility.
Inspectors should note, in particular, any deficiencies from previous test facility
inspections. Where no previous test facility inspections have been conducted, apre-inspection visit can be made to obtain relevant information.
Test facilities may be informed of the date and time of inspector’s arrival, the
objective of their visit and the length of time they expect to be on the premises.This could allow the test facility to ensure that the appropriate personnel anddocumentation are available. In cases where particular documents or records areto be examined, it may be useful to identify these to the test facility in advanceof the visit so that they will be immediately available during the test facilityinspection.
Starting conference
Purpose : to inform the management and staff of the facility of the reason for the
test facility inspection or study audit that is about to take place, and to identifythe facility areas, study(ies) selected for audit, documents and personnel likely tobe involved.
The administrative and practical details of a test facility inspection or study audit
should be discussed with the management of the facility at the start of the visit.At the starting conference, inspectors should:
— outline the purpose and scope of the visit,
— describe the documentation which will be required for the test facility inspec-
tion, such as lists of on-going and completed studies, study plans, standardoperating procedures, study reports, etc. Access to and, if necessary, arrange-ments for the copying of relevant documents should be agreed on at thistime,
— clarify or request information as to the management structure (organisation)
and personnel of the facility,
— request information as to the conduct of studies not subject to GLP principles
in the areas of the test facility where GLP studies are being conducted,
— make an initial determination as to the parts of the facility to be covered
during the test facility inspection,
— describe the documents and specimens that will be needed for on-going or
completed study(ies) selected for study audit,
— indicate that a closing conference will be held at the completion of the
inspection.
Before proceeding further with a test facility inspection, it is advisable for the
inspector(s) to establish contact with the facility’s quality assurance (QA) unit.
As agenera l rule, when inspecting afa cility, inspectors will find it helpful to be
accompanied by a member of the QA unit.
Inspectors may wish to request that a room be set aside for examination of
documents and other activities.
Organisation and personnel
Purpose : to determine whether the test facility has sufficient qualified personnel,
staff resources and support services for the variety and number of studiesundertaken; the organisational structure is appropriate, and management hasestablished a policy regarding training and staff health surveillance appropriate tothe studies undertaken in the facility.
The management should be asked to produce certain documents, such as:
— floor plans,
— facility management and scientific organisation charts,— CVs of personnel involved in the type(s) of studies selected for the study
audit,
— list(s) of on-going and completed studies with information on the type of
study, initiation/completion dates, test system, method of application of testsubstance and name of study director,
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— staff health surveillance policies,
— staff job descriptions and staff training programmes and records,— an index to the facility’s standard operating procedures (SOPs),— specific SOPs as related to the studies or procedures being inspected or
audited,
— list(s) of the study directors and sponsors associated with the study(ies) being
audited.
The inspector should check, in particular:
— lists of on-going and completed studies to ascertain the level of work being
undertaken by the test facility,
— the identity and qualifications of the study director(s), the head of the quality
assurance unit and other personnel,
— existence of SOPs for all relevant areas of testing.
Quality assurance programme
Purpose : to determine whether the mechanisms used to assure management that
studies are conducted in accordance with GLP principles are adequate.
The head of the quality assurance (QA) unit should be asked to demonstrate the
systems and methods for QA inspection and monitoring of studies, and thesystem for recording observations made during QA monitoring. Inspectorsshould check:
— the qualifications of the head of QA, and of all QA staff,
— that the QA unit functions independently from the staff involved in the
studies,
— how the QA unit schedules and conducts inspections, how it monitors identi-
fied critical phases in a study, and what resources are available for QAinspections and monitoring activities,
— that where studies are of such short duration that monitoring of each study is
impracticable, arrangements exist for monitoring on a sample basis,
— the extent and depth of QA monitoring during the practical phases of the
study,
— the extent and depth of QA monitoring of routine test facility operation,— the QA procedure for checking the final report to ensure its agreement with
the raw data,
— that management receives reports from QA concerning problems likely to
affect the quality or integrity of a study,
— the actions taken by QA when deviations are found,— the QA role, if any, if studies or parts of studies are done in contract
laboratories,
— the part played, if any, by QA in the review, revision and updating of SOPs.
Facilities
Purpose : to determine if the test facility, whether indoor or outdoor, is of suitable
size, design and location to meet the demands of the studies being undertaken.
The inspector should check that:
— the design enables an adequate degree of separation so that, for example, test
substances, animals, diets, pathological specimens, etc. of one study cannotbe confused with those of another,
— environmental control and monitoring procedures exist and function
adequately in critical areas, for example, animal and other biological testsystems rooms, test substance storage areas, laboratory areas,
— the general housekeeping is adequate for the various facilities and that there
are, if necessary, pest control procedures.
Care, housing and containment of biological test systems
Purpose : to determine whether the test facility, if engaged in studies using
animals or other biological test systems, has support facilities and conditions fortheir care, housing and containment, adequate to prevent stress and other prob-lems which could affect the test system and hence the quality of data.
A test facility may be carrying out studies which require a diversity of animal or
plant species as well as microbial or other cellular or sub-cellular systems. Thetype of test systems being used will determine the aspects relating to care,
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housing or containment that the inspector will monitor. Using his judgment, the
inspector will check, according to the test systems, that:
— there are facilities adequate for the test systems used and for testing needs,
— there are arrangements to quarantine animals and plants being introduced into
the facility and that these arrangements are working satisfactorily,
— there are arrangements to isolate animals (or other elements of a test system,
if necessary) known to be, or suspected of being, diseased or carriers ofdisease,
— there is adequate monitoring and record-keeping of health, behaviour or other
aspects, as appropriate to the test system,
— the equipment for maintaining the environmental conditions required for each
test system is adequate, well maintained, and effective,
— animal cages, racks, tanks and other containers, as well as accessory equip-
ment, are kept sufficiently clean,
— analyses to check environmental conditions and support systems are carried
out as required,
— facilities exist for removal and disposal of animal waste and refuse from the
test systems and that these are operated so as to minimise vermin infestation,odours, disease hazards and environmental contamination,
— storage areas are provided for animal feed or equivalent materials for all test
systems; that these areas are not used for the storage of other materials suchas test substances, pest control chemicals or disinfectants, and that they areseparate from areas in which animals are housed or other biological testsystems are kept,
— stored feed and bedding are protected from deterioration by adverse environ-
mental conditions, infestation or contamination.
Apparatus, materials, reagents and specimens
Purpose : to determine whether the test facility has suitably located, operational
apparatus in sufficient quantity and of adequate capacity to meet the require-ments of the tests being conducted in the facility and that the materials, reagentsand specimens are properly labelled, used and stored.
The inspector should check that:
— apparatus is clean and in good working order,
— records have been kept of operation, maintenance, verification, calibration
and validation of measuring equipment and apparatus (including computer-ised systems),
— materials and chemical reagents are properly labelled and stored at appro-
priate temperatures and that expiry dates are not being ignored. Labels forreagents should indicate their source, identity and concentration and/or otherpertinent information,
— specimens are well identified by test system, study, nature and date of
collection,
— apparatus and materials used do not alter to any appreciable extent the test
systems.
Test systems
Purpose : to determine whether adequate procedures exist for the handling and
control of the variety of test systems required by the studies undertaken in thefacility, for example, chemical and physical systems, cellular and microbicsystems, plants or animals.
Physical and chemical systems
The inspector should check that:
— where required by study plans, the stability of test and reference substances
was determined and that the reference substances specified in test plans wereused,
— in automated systems, data generated as graphs, recorder traces or computer
print-outs are documented as raw data and archived.
Biological test systems
Taking account of the relevant aspects referred to above relating to care, housing
or containment of biological test systems, the inspector should check that:
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— test systems are as specified in study plans,
— test systems are adequately and, if necessary and appropriate, uniquely
identified throughout the study, and that records exist regarding receipt of thetest systems and document fully the number of test systems received, used,replaced or discarded,
— housing or containers of test systems are properly identified with all the
necessary information,
— there is an adequate separation of studies being conducted on the same
animal species (or the same biological test systems) but with differentsubstances,
— there is an adequate separation of animal species (and other biological test
systems) either in space or in time,
— the biological test system environment is as specified in the study plan or in
SOPs for aspects such as temperature, or light/dark cycles,
— the recording of the receipt, handling, housing or containment, care and
health evaluation is appropriate to the test systems,
— written records are kept of examination, quarantine, morbidity, mortality,
behaviour, diagnosis and treatment of animal and plant test systems or othersimilar aspects as appropriate to each biological test system,
— there are provisions for the appropriate disposal of test systems at the end of
tests.
Test and reference substances
Purpose : to determine whether the test facility has procedures designed (i) to
ensure that the identity, potency, quantity and composition of test and referencesubstances are in accordance with their specifications, and (ii) to properly receiveand store test and reference substances.
The inspector should check that:
— there are written records on the receipt (including identification of the person
responsible), and for the handling, sampling, usage and storage of tests andreference substances,
— test and reference substances containers are properly labelled,— storage conditions are appropriate to preserve the concentration, purity and
stability of the test and reference substances,
— there are written records on the determination of identity, purity, composi-
tion, stability, and for the prevention of contamination of test and referencesubstances, where applicable,
— there are procedures for the determination of the homogeneity and stability of
mixtures containing test and reference substances, where applicable,
— containers holding mixtures (or dilutions) of the test and reference substances
are labelled and that records are kept of the homogeneity and stability oftheir contents, where applicable,
— when the test is of longer than four weeks duration, samples from each batch
of test and reference substances have been taken for analytical purposes andthat they have been retained for an appropriate time,
— procedures for mixing substances are designed to prevent errors in identifica-
tion or cross-contamination.
Standard operating procedures
Purpose : to determine whether the test facility has written SOPs relating to all
the important aspects of its operations, considering that one of the most impor-tant management techniques for controlling facility operations is the use ofwritten SOPs. These relate directly to the routine elements of tests conducted bythe test facility.
The inspector should check that:
— each test facility area has immediately available relevant, authorised copies
of SOPs,
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— procedures exist for revision and updating of SOPs,
— any amendments or changes to SOPs have been authorised and dated,— historical files of SOPs are maintained,— SOPs are available for, but not necessarily limited to, the following activities:
(i) receipt; determination of identity, purity, composition and stability;
labelling; handling; sampling; usage; and storage of test and referencesubstances;
(ii) use, maintenance, cleaning, calibration and validation of measuring
apparatus, computerised systems and environmental control equip-ment;
(iii) preparation of reagents and dosing formulations;
(iv) record-keeping, reporting, storage and retrieval of records and reports;
(v) preparation and environmental control of areas containing the test
systems;
(vi) receipt, transfer, location, characterisation, identification and care of
test systems;
(vii) handling of the test systems before, during and at the termination of
the study;
(viii) disposal of test systems;
(ix) use of pest control and cleaning agents;
(x) quality assurance programme operations.
Performance of the study
Purpose : to verify that written study plans exist and that the plans and the
conduct of the study are in accordance with GLP principles.
The inspector should check that:
— the study plan was signed by the study director,
— any amendments to the study plan were signed and dated by the study
director,
— the date of the agreement to the study plan by the sponsor was recorded
(where applicable),
— measurements, observations and examinations were in accordance with the
study plan and relevant SOPs,
— the results of these measurements, observations and examinations were
recorded directly, promptly, accurately and legibly and were signed (orinitialled) and dated,
— any changes in the raw data, including data stored in computers, did not
obscure previous entries, included the reason for the change and identifiedthe person responsible for the change and the date it was made,
— computer-generated or stored data have been identified and that the proced-
ures to protect them against unauthorised amendments or loss are adequate,
— the computerised systems used within the study are reliable, accurate and
have been validated,
— any unforeseen events recorded in the raw data have been investigated and
evaluated,
— the results presented in the reports of the study (interim or final) are consis-
tent and complete and that they correctly reflect the raw data.
Reporting of study results
Purpose : to determine whether final reports are prepared in accordance with GLP
principles.
When examining a final report, the inspector should check that:
— it is signed and dated by the study director to indicate acceptance of responsi-
bility for the validity of the study and confirming that the study wasconducted in accordance with GLP principles,
— it is signed and dated by other principal scientists, if reports from cooperating
disciplines are included,
— a quality assurance statement is included in the report and that it is signed
and dated,
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— any amendments were made by the responsible personnel,
— it lists the archive location of all samples, specimens and raw data.
Storage and retention of records
Purpose : to determine whether the facility has generated adequate records and
reports and whether adequate provision has been made for the safe storage andretention of records and materials;
The inspector should check:
— that a person has been identified as responsible for the archive,
— the archive facilities for the storage of study plans, raw data (including that
from discontinued GLP studies), final reports, samples and specimens andrecords of education and training of personnel,
— the procedures for retrieval of archived materials,— the procedures whereby access to the archives is limited to authorised
personnel and records are kept of personnel given access to raw data, slides,etc.,
— that an inventory is maintained of materials removed from, and returned to,
the archives,
— that records and materials are retained for the required or appropriate period
of time and are protected from loss or damage by fire, adverse environmentalconditions, etc.
Study audits
Test facility inspections will generally include, inter alia , study audits, which
review on-going or completed studies. Specific study audits are also oftenrequested by Regulatory Authorities, and can be conducted independently of testfacility inspections. Because of the wide variation in the types of studies whichmight be audited, only general guidance is appropriate, and inspectors and otherstaking part in study audits will always need to exercise judgment as to the natureand extent of their examinations. The objective should be to reconstruct the studyby comparing the final report with the study plan, relevant SOPs, raw data andother archived material.
In some cases, inspectors may need assistance from other experts in order to
conduct an effective study audit, for example, where there is a need to examinetissue sections under the microscope.
When conducting astudy a udit, the inspector should:
— obtain names, job descriptions and summaries of training and experience for
selected personnel engaged in the study(ies) such as the study director andprincipal scientists,
— check that there is sufficient staff trained in relevant areas for the study(ies)
undertaken,
— identify individual items of apparatus or special equipment used in the study
and examine the calibration, maintenance and service records for the equip-ment,
— review the records relating to the stability of the test substances, analyses of
test substance and formulations, analyses of feed, etc.,
— attempt to determine, through the interview process if possible, the work
assignments of selected individuals participating in the study to ascertain ifthese individuals had the time to accomplish the tasks specified in the studyplan or report,
— obtain copies of all documentation concerning control procedures or forming
integral parts of the study, including:
(i) the study plan;
(ii) SOPs in use at the time the study was done;
(iii) logbooks, laboratory notebooks, files, worksheets, print-outs of
computer-stored data, etc.; checking of calculations, where appropriate;
(iv) the final report.
In studies in which animals (i.e., rodents and other mammals) are used, the
inspectors should follow a certain percentage of individual animals from theirarrival at the test facility to autopsy. They should pay particular attention to therecords relating to:
— animal body weight, food/water intake, dose formulation and administration,
etc.,
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— clinical observations and autopsy findings,
— clinical chemistry,— pathology.
Completion of inspection or study audit
When a test facility inspection or study audit has been completed, the inspector
should be prepared to discuss his findings with representatives of the test facilityat a closing conference and should prepare a written report, i.e., the inspectionreport.
A test facility inspection of any large facility is likely to reveal a number of
minor deviations from GLP principles but, normally, these will not be suffi-ciently serious to affect the validity of studies emanating from that test facility.In such cases, it is reasonable for an inspector to report that the facility isoperating in compliance with GLP principles according to the criteria establishedby the (national) GLP Monitoring Authority. Nevertheless, details of the inade-quacies or faults detected should be provided to the test facility and assurancessought from its senior management that action will be taken to remedy them.
The inspector may need to revisit the facility after a period of time to verify that
necessary action has been taken.
If aserious devia tion from the GLP principles is identified during atest fa cility
inspection or study audit which, in the opinion of the inspector, may haveaffected the validity of that study, or of other studies performed at the facility,the inspector should report back to the (national) GLP Monitoring Authority. Theaction taken by that Authority and/or the Regulatory Authority, as appropriate,will depend on the nature and extent of the non-compliance and the legal and/oradministrative provisions within the GLP compliance programme.
Where a study audit has been conducted at the request of a Regulatory Authority,
a full report of the findings should be prepared and sent via the relevant(national) GLP Monitoring Authority.