MT
The Good Laboratory Practice Regulations, 2004
Table of Provisions (15)
Statutory Text (15 Articles)
Suppliment tal-Gazzetta tal-Gvern ta’ Malta, Nru. 17,633, 30 ta’ Lulju, 2004
L.N. 371 of 2004
PRODUCT SAFETY ACT
(ACT NO. V OF 2001)
The Good Laboratory Practice Regulations, 2004
IN exercise of the powers conferred by article 39 of the Product
Safety Act, the Minister for Competitiveness and Communications has,
on the advice of the Malta Standards Authority, made the following
regulations
The title of these regulations is the Good Laboratory Practice Citation.
Regulations, 2004.
THE OECD PRINCIPLES OF GOOD LABORATORY PRACTICE (GLP)
Contents
Section I
INTRODUCTION
Preface
1. Scope
2. Definitions of terms
2.1.
Good laboratory practice
2.2.
Terms concerning the organisation of a test facility
2.3.
Terms concerning the non-clinical health and environmental safety study
2.4.
Terms concerning the test item
Section II
GOOD LABORATORY PRACTICE PRINCIPLES
1. Test facility organisation and personnel
1.1.
Test facility management's responsibilities
1.2.
Study director's responsibilities
1.3.
Principal investigator's responsibilities
1.4.
Study personnel's responsibilities
2. Quality assurance programme
2.1.
General
2.2.
Responsibilities of the quality assurance personnel
3. Facilities
3.1.
General
3.2.
Test system facilities
3.3.
Facilities for handling test and reference items
3.4.
Archive facilities
3.5.
Waste disposal
4. Apparatus, material, and reagents
5. Test systems
5.1.
Physical/chemical
5.2.
Biological
6. Test and reference items
6.1.
Receipt, handling, sampling and storage
6.2.
Characterisation
7. Standard operating procedures
(1) Laboratories carrying out tests on chemical products, in General provisions.
accordance with the Dangerous Substances (Notification) Regulations,
2001, (L.N. 318 of 2001) shall comply with the principles of Good
Laboratory Practice as laid down in the First Schedule to these
regulations.
(2) Regulation 2(1) shall apply also where other provisions
provide for the application of the principles of Good Laboratory Practice
in respect of tests on chemical products to evaluate their safety for man
and, or the environment.
(3) These regulations implement the provisions of Directive
2004/9/EC of the European Parliament and of the Council and of
Directive 2004/10/EC of the European Parliament and of the Council.
The provisions for the inspection and verification of Good Laboratory Practice which are contained
in parts A and B are those contained in Annexes I (Guides for compliance monitoring procedures
for Good Laboratory Practice) and II (Guidance for the conduct of test facility inspections and study
audits) respectively of the OECD Council Decision-Recommendation on compliance with principles
of Good Laboratory Practice [C(89)87(Final)] of 2October 1989 as revised by the OECD Council
Decision amending the Annexes to the Council Decision-Recommendation 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 the procedures adopted to monitor Good
Laboratory Practice compliance, as well as comparability of their quality and rigour, are essential.
The aim of this part of the Annex is to provide detailed practical guidance to the Member States on
the structure, mechanisms and procedures they should adopt when establishing national Good
Laboratory Practice compliance monitoring programmes so that these programmes may be
internationally acceptable.
It is recognised that Member States will adopt Good Laboratory Practice principles and establish
compliance monitoring procedures according to national legal and administrative practices, and
according to priorities they give to, for example the scope of initial and subsequent coverage
concerning categories of chemicals and types of testing. Since Member States may establish more
than one Good Laboratory Practice Monitoring Authority due to their legal framework for chemicals
control, more than one Good Laboratory Practice compliance programme may be established. The
guidance set forth in the following paragraphs concerns each of these Authorities 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
– Good Laboratory Practice principles
principles of Good Laboratory Practice that are
consistent with the OECD principles of Good Laboratory Practice as
adopted in Article 1 of Directive 87/18/EEC,
(1) OJ L 15, 17. 1. 1987, p. 29.
– Good Laboratory Practice compliance monitoring
the periodic inspection of test
facilities and/or auditing of studies for the purpose of
verifying adherence to Good Laboratory Practice principles,
– (National) Good Laboratory Practice compliance programme: the
particular
scheme
established by a Member State to monitor Good
Laboratory Practice compliance by test facilities
within its territories, by means of inspections and
study audits,
– (National) Good Laboratory Practice Monitoring Authority
a body established within a
Member State with responsibility for monitoring the
Good Laboratory Practice compliance of test
facilities within its territories and for discharging
other such functions related to Good Laboratory
Practice as may be nationally determined. It is
understood that more than one such body may be
established in a Member State,
an on-site examination of the test facility's procedures and practices
to assess the degree of compliance with Good Laboratory Practice
principles. During inspections, the management structures and
operational procedures of the test facility are examined, key
technical personnel are interviewed, and the quality and integrity of
data generated by the facility are assessed and reported,
– 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 been accurately reported, to
determine whether testing was carried out in accordance with the study plan and
standard operating procedures, to obtain additional information not provided in the
report, and to establish whether practices were employed in the development of
data that would impair their validity, – Inspector: a person who performs the test
facility inspections and study audits on behalf of the (national) Good Laboratory
Practice Monitoring Authority,
– Good Laboratory Practice compliance status
the level of adherence of a test facility to the
Good Laboratory Practice principles as assessed by the (national)
Good Laboratory Practice Monitoring Authority,
a national body with legal responsibility for aspects of the control of
chemicals.
Components of Good Laboratory Practice compliance monitoring procedures
A (national) Good Laboratory Practice compliance programme should be the responsibility of a
properly constituted, legally identifiable body adequately staffed and working within a defined
administrative framework.
Member States should
ensure that the (national) Good Laboratory Practice Monitoring Authority is directly
responsible for an adequate `team’ of inspectors having the necessary technical/scientific
expertise or is ultimately responsible for such a team,
publish documents relating to the adoption of Good Laboratory Practice principles within
their territories,
publish documents providing details of the (national) Good Laboratory Practice compliance
programme, including information on the legal or administrative framework within which the
programme operates and references to published acts, normative documents (e.g.,
regulations, codes of practice), inspection manuals, guidance notes, periodicity of
inspections and/or criteria for inspection schedules, etc.,
maintain records of test facilities inspected (and their Good Laboratory Practice compliance
status) and of studies audited for both national and international purposes.
Confidentiality
(National) Good Laboratory Practice Monitoring Authorities will have access to commercially
valuable information and, on occasion, may even need to remove commercially sensitive 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 as a result of Good Laboratory
Practice compliance monitoring activities,
ensure that, unless all commercially sensitive and confidential information has been excised,
reports of test facility inspections and study audits are made available only to Regulatory
Authorities and, where appropriate, to the test facilities inspected or concerned with study
audits and/or to study sponsors.
Personnel and training
(National) Good Laboratory Practice Monitoring Authorities should
ensure that an adequate number of inspectors is available.
The number of inspectors required will depend on
B
(a)
the number of test facilities involved in the (national) Good Laboratory Practice compliance
programme;
(b)
the frequency with which the Good Laboratory Practice 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) Good Laboratory Practice Monitoring Authorities
should
(a)
ensure that arrangements are made for the appropriate training of Good Laboratory Practice
inspectors, having regard to their individual qualifications and experience;
(b)
encourage consultations, including joint training activities where necessary, with the staff of
(national) Good Laboratory Practice Monitoring Authorities in other OECD member
countries in order to promote international harmonisation in the interpretation and application
of Good Laboratory Practice principles, and in the monitoring 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 audited or 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) Good Laboratory Practice Monitoring Authority,
on the permanent staff of a body separate from the (national) Good Laboratory Practice
Monitoring Authority, or
employed on contract, or in another way, by the (national) Good Laboratory Practice
Monitoring Authority to perform test facility inspections or study audits.
In the latter two cases, the (national) Good Laboratory Practice Monitoring Authority should have
ultimate responsibility for determining the Good Laboratory Practice compliance status of test
facilities and the quality/acceptability of a study audit, and for taking any action based on the results
of test facility inspections or study audits which may be necessary.
(National) Good Laboratory Practice compliance programmes
Good Laboratory Practice compliance monitoring is intended to ascertain whether test facilities have
implemented Good Laboratory Practice principles for the conduct of studies and are capable of
assuring that the resulting data are of adequate quality. As indicated above, Member States should
publish the details of their (national) Good Laboratory Practice compliance programmes.
Such information should, inter alia
–
define the scope and extent of the programme.
A (national) Good Laboratory Practice 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 compliance should be defined, both with respect to the
categories of chemicals and to the types of tests subject to it, for example, physical, chemical,
toxicological and/or ecotoxicological,
–
provide an indication as to the mechanism whereby test facilities enter the programme.
The application of Good Laboratory Practice principles to health and environmental safety data
generated for regulatory purposes may be mandatory. A mechanism should be available whereby
test facilities may have their compliance with Good Laboratory Practice principles monitored by the
appropriate (national) Good Laboratory Practice Monitoring Authority,
–
provide information on categories of test facility inspections/study audits.
A (national) Good Laboratory Practice 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-going or completed studies;
(b)
provisions for special test facility inspections/study audits at the request of a Regulatory
Authority, for example, prompted by a query arising from the submission of data to a
Regulatory Authority,
–
define the powers of inspectors for entry into test facilities and their access to data held by
test facilities (including specimens, SOPs (standard operating procedures) 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 facility entry and access to data are essential to
protect public health or the environment. The powers available to the (national) Good Laboratory
Practice Monitoring Authority in such cases should be defined,
–
describe the test facility inspection and study audit procedures for verification of Good
Laboratory Practice compliance.
B
The documentation should indicate the procedures which will be used to examine both the
organizational processes and the conditions under which studies are planned, performed, monitored
and recorded.
Guidance for such procedures is available in part B of this Annex,
–
describe actions that may be taken as follow-up test facility inspections and study audits.
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 Good Laboratory Practice principles are
found during or after a test facility inspection or study audit. The appropriate actions should be
described in documents from the (national) Good Laboratory Practice Monitoring Authority.
If a test facility inspection or study audit reveals only minor deviations from Good Laboratory
Practice 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 verify that corrections have been
introduced.
Where no, or where only minor deviations have been found, the (national) Good Laboratory
Practice Monitoring Authority may
–
issue a statement that the test facility has been inspected and found to be operating in
compliance with Good Laboratory Practice principles. The date of the inspections and, if
appropriate, the categories of test inspected in the test facility at that time should be
included. Such statements may be used to provide information to (national) Good
Laboratory Practice Monitoring Authorities in other OECD member countries, 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) Good Laboratory Practice
Monitoring Authorities will depend on the particular circumstances of each case and the legal or
administrative provisions under which Good Laboratory Practice compliance monitoring has been
established within their countries. Actions which may be taken 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 facility from the (national) Good
Laboratory Practice compliance programme or from any existing list or register of test
facilities subject to Good Laboratory Practice 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 management will normally
be resolved during the course of a test facility inspection or study audit. However, it may not always
be possible for agreement to be reached. A procedure should exist whereby a test facility may make
representations relating to the outcome of a test facility inspection or study audit for Good
Laboratory Practice compliance monitoring and/or relating to the action the Good Laboratory
Practice Monitoring Authority proposes to take thereon.
PART B
REVISED GUIDANCE FOR THE CONDUCT OF TEST FACILITY INSPECTIONS 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 to OECD member countries. It is
principally concerned with test facility inspections, an activity which occupies much of the time of
Good Laboratory Practice inspectors. A test facility inspection will usually include a study audit or
review as a part of the inspection, but study audits will also have to be conducted from time to time
at 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 Good Laboratory Practice principles and to determine the integrity of data to assure
that resulting data are of adequate quality for assessment and decision-making by national
Regulatory Authorities. They result in reports which describe the degree of adherence of a test
facility to the Good Laboratory Practice principles. Test facility inspections should be conducted on
a regular, routine basis to establish and maintain records of the Good Laboratory Practice
compliance status of test facilities.
B
Further clarification of many of the points in this part of the Annex may be obtained by referring to
the OECD consensus documents on Good Laboratory Practice (on, e.g., the role 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 this Directive are applicable to this part of the
Annex.
Test facility inspections
Inspections for compliance with Good Laboratory Practice 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. In some 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 and extent of compliance with Good Laboratory Practice
principles. Nevertheless, inspectors should strive for a consistent approach in evaluating whether, in
the case of a particular test facility or study, an adequate level of compliance with each Good
Laboratory Practice principle has been 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 be examined by inspectors. In each section, there
is a statement of purpose, as well as an illustrative list of specific items which could be considered
during the course of a test facility inspection. These lists are not meant to be comprehensive and
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 human health or the environment. These aspects
are the responsibility of those Regulatory 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 planned way and, so far as practicable, respect
the wishes of the management of the test facility 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 they ensure that such information is
seen by authorized personnel only. Their responsibilities in this respect will have been established
within their (national) Good Laboratory Practice compliance 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 and range 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 existing information on the facility should be reviewed.
This may include previous inspection reports, the layout of the facility, organisation charts, study
reports, protocols and curricula vitae (CVs) of personnel. Such documents would provide
information on
–
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, a pre-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 and documentation are available. In cases where particular
documents or records are to be examined, it may be useful to identify these to the test facility in
advance of the visit so that they will be immediately available during the test facility inspection.
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 identify the facility areas,
study(ies) selected for audit, documents and personnel likely to be 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 inspection, such as lists
of on-going and completed studies, study plans, standard operating procedures, study
reports, etc. Access to and, if necessary, arrangements for the copying of relevant
documents should be agreed on at this time,
B
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 Good Laboratory Practice
principles in the areas of the test facility where Good Laboratory Practice 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 a general rule, when inspecting a facility, 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 studies undertaken; the
organisational structure is appropriate, and management has established a policy
regarding training and staff health surveillance appropriate to the 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 test substance and name of
study director,
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 Good Laboratory Practice 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 the system for recording observations
made during QA monitoring.
Inspectors should 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 identified critical
phases in a study, and what resources are available for QA inspections 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,
B
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 cannot be confused with those of
another,
environmental control and monitoring procedures exist and function adequately in critical
areas, for example, animal and other biological test systems 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 for their care, housing
and containment, adequate to prevent stress and other problems 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. The type of test systems being used will
determine the aspects relating to care, 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 of disease,
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 equipment, 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 such as test substances, pest
control chemicals or disinfectants, and that they are separate from areas in which animals are
housed or other biological test systems are kept,
stored feed and bedding are protected from deterioration by adverse environmental
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 requirements of the tests
being conducted in the facility and that the materials, reagents and 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 computerised systems),
materials and chemical reagents are properly labelled and stored at appropriate
temperatures and that expiry dates are not being ignored. Labels for reagents should indicate
their source, identity and concentration and/or other pertinent 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.
B
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 the facility, for example,
chemical and physical systems, cellular and microbic systems, 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 were used,
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
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 the test 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 different substances,
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 other similar 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
reference substances are in accordance with their specifications, and
(ii)
to properly receive and 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 and reference 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, composition, stability, and
for the prevention of contamination of test and reference substances, 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 of their 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 and that they have been
retained for an appropriate time,
procedures for mixing substances are designed to prevent errors in identification 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 important management
techniques for controlling facility operations is the use of written SOPs. These relate
directly to the routine elements of tests conducted by the test facility.
The inspector should check that
each test facility area has immediately available relevant, authorised copies of SOPs,
B
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 reference substances;
(ii)
use, maintenance, cleaning, calibration and validation of measuring apparatus,
computerised systems and environmental control equipment;
(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 Good Laboratory Practice 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 (or initialled) 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 identified the person responsible for the
change and the date it was made,
computer-generated or stored data have been identified and that the procedures 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 consistent 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 Good
Laboratory Practice principles.
When examining a final report, the inspector should check that
it is signed and dated by the study director to indicate acceptance of responsibility for the
validity of the study and confirming that the study was conducted in accordance with Good
Laboratory Practice 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,
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 and retention 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
Good Laboratory Practice studies), final reports, samples and specimens and records 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,
B
that records and materials are retained for the required or appropriate period of time and
are protected from loss or damage by fire, adverse environmental conditions, 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 often requested by Regulatory Authorities, and can
be conducted independently of test facility inspections. Because of the wide variation in the types of
studies which might be audited, only general guidance is appropriate, and inspectors and others
taking part in study audits will always need to exercise judgment as to the nature and extent of their
examinations. The objective should be to reconstruct the study by comparing the final report with the
study plan, relevant SOPs, raw data and other 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 examine tissue sections under the microscope.
When conducting a study audit, 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 and principal 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 equipment,
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 if these individuals had the time to
accomplish the tasks specified in the study plan 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 their arrival at the test facility to autopsy. They should
pay particular attention to the records relating to
–
animal body weight, food/water intake, dose formulation and administration, etc.,
–
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 facility at a closing conference and should
prepare a written report, i.e., the inspection report.
A test facility inspection of any large facility is likely to reveal a number of minor deviations from
Good Laboratory Practice principles but, normally, these will not be sufficiently 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 is operating in compliance with Good Laboratory Practice principles
according to the criteria established by the (national) Good Laboratory Practice Monitoring
Authority. Nevertheless, details of the inadequacies or faults detected should be provided to the test
facility and assurances sought 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 a serious deviation from the Good Laboratory Practice principles is identified during a test facility
inspection or study audit which, in the opinion of the inspector, may have affected the validity of that
study, or of other studies performed at the facility, the inspector should report back to the (national)
Good Laboratory Practice Monitoring Authority. The action 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/or administrative provisions within the Good Laboratory Practice 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) Good Laboratory Practice
Monitoring Authority.
(1) The National Accreditation Body-Malta Standards Duties of the
Competent
Authority (NAB-MSA), hereinafter referred to as the competent Authority.
authority, shall be responsible for verifying compliance with the
principles of Good Laboratory Practice of any testing laboratory in Malta
claiming to use Good Laboratory Practice, as referred to in regulation
2(1), in the conduct of tests on chemicals.
(2) Should it be established on the basis of detailed evidence
that the application of the principles of Good Laboratory Practice and
the verification of their application for tests on chemical substances
show that, although a chemical substance has been examined in
accordance with the requirements of these regulations, it presents a
danger to man and, or the environment, the Director responsible for
Consumer Affairs may, on the advice of the Head of the Directorate
responsible for chemicals within the Malta Standards Authority,
provisionally prohibit or make subject to special conditions the
marketing of that substance in Malta.
(3) On a yearly basis, the competent authority shall draw
up a report relating to the implementation of Good Laboratory Practice
in Malta. The report shall contain a list of laboratories inspected, the
date on which such inspection was carried out and a brief summary of
the conclusions of the inspections. The report shall be forwarded to the
European Commission each year, not later than 31 st March.
Where a laboratory has carried out a test in accordance with
sub-regulation 2(1) of these regulations, it shall give a notice in writing
to the person who commissioned the test and to the competent authority,
stating that the test has been carried out in conformity with the principles
of Good Laboratory Practice.
(1) This regulation shall apply to the inspection and
verification of Good
verification of the organizational processes and the conditions under
which laboratory studies are planned, performed, recorded and reported
for the non-clinical testing, carried out in accordance with the rules and
regulations, of all chemicals (e.g. cosmetics, industrial chemicals,
medicinal products, food additives, animal feed additives, pesticides)
in order to assess the effect of such products on man, animals and the
environment.
(2) This regulation is not concerned with the interpretation
and evaluation of test results.
(3) The compliance with Good Laboratory Practice of any
testing laboratory claiming to use Good Laboratory Practice in the
conduct of tests on chemicals shall be verified using the procedure laid
down in this regulation.
(4) Where the provisions of sub-regulation 5(3) hereof have
been complied with, and the results of the inspection and verification
are satisfactory, the competent authority may provide endorsement of a
claim by a laboratory that it and the tests that it carries out comply with
Good Laboratory Practice, using the formula ‘Assessment of conformity
with Good Laboratory Practice according to Directive 2004/9/EC on
……………….. (date)’.
(5) The competent authority shall inspect the laboratory and
audit the studies in accordance with the provisions laid down in the
Second Schedule to these regulations.
(6) The competent authority shall ensure that commercially
sensitive and other confidential information to which it gains access as
a result of Good Laboratory Practice compliance monitoring activities
is made available only to those national and international bodies which
the Minister may, from time to time, designate, and to a laboratory or
study sponsor directly concerned with a particular inspection or study
audit.
(7) The names of the laboratories subject to inspection by
the competent authority, their Good Laboratory Practice compliance
status and the dates upon which laboratory inspections or study audits
have been conducted shall not be considered to be confidential.
(1) Without prejudice to sub-regulation 6(2) hereof, the Recognition of
Good Laboratory
competent authority shall accept the results of laboratory inspections Practice compliance
and study audits on Good Laboratory Practice compliance carried out status in other
States.
by Member States of the European Community.
(2)
Where the competent authority has sufficient reason
to believe that a laboratory in another Member State claiming Good
Laboratory Practice compliance has not carried out a test according to
Good Laboratory Practice, it may request further information from the
competent authority of that Member State prior to taking a decision on
whether to accept the test results.
(1) The Good Laboratory Practice Regulations, 2003 (L.N. Repeal
regulations.
234 of 2003) are hereby repealed.
(2) References in other regulations to the Good Laboratory
Practice Regulations, 2003 shall henceforth be construed as references
to these regulations.
Performance of the study
8.1.
Study plan
8.2.
Content of the study plan
8.3.
Conduct of the study
Reporting of study results
9.1.
General
9.2.
Content of the final report
Storage and retention of records and materials
Section I
INTRODUCTION
Preface
Government and industry are concerned about the quality of non-clinical health and environmental
safety studies upon which hazard assessments are based. As a consequence, OECD Member
countries have established criteria for the performance of these studies.
To avoid different schemes of implementation that could impede international trade in chemicals,
OECD Member countries have pursued international harmonisation of test methods and Good
Laboratory Practice. In 1979 and 1980 an international group of experts, established under the
special programme on the control of chemicals, developed the ‘OECD principles of Good
Laboratory Practice’ (Good Laboratory Practice), utilising common managerial and scientific
practices and experience from various national and international sources. These principles of Good
Laboratory Practice were adopted by the OECD Council in 1981, as an Annex to the Council
Decision on the mutual acceptance of data in the assessment of chemicals. [C(81)30(Final)].
In 1995 and 1996, a new group of experts was formed to revise and update the principles. The
current document is the result of the consensus reached by that group. It cancels and replaces the
original principles adopted in 1981.
The purpose of these principles of Good Laboratory Practice is to promote the development of
quality test data. Comparable quality of test data forms the basis for the mutual acceptance of data
among countries. If individual countries can confidently rely on test data developed in other
countries, duplicative testing can be avoided, thereby saving time and resources. The application of
these principles should help to avoid the creation of technical barriers to trade, and further improve
the protection of human health and the environment.
1. Scope
These principles of Good Laboratory Practice should be applied to the non-clinical safety testing of
test items contained in pharmaceutical products, pesticide products, cosmetic products, veterinary
drugs as well as food additives, feed additives, and industrial chemicals. These test items are
frequently synthetic chemicals, but may be of natural or biological origin and, in some circumstances,
may be living organisms. The purpose of testing these test items is to obtain data on their properties
and/or their safety with respect to human health and/or the environment.
Non-clinical health and environmental safety studies covered by the principles of Good Laboratory
Practice include work conducted in the laboratory, in greenhouses, and in the field.
Unless specifically exempted by national legislation, these principles of Good Laboratory Practice
apply to all non-clinical health and environmental safety studies required by regulation for the
purpose of registering or licensing pharmaceuticals, pesticides, food and feed additives, cosmetic
products, veterinary drug products and similar products, and for the regulation of industrial
2. Definition of terms
Good laboratory practice
Good laboratory practice (GLP) is a quality system concerned with the organisational process and
the conditions under which non-clinical health and environmental safety studies are planned,
performed, monitored, recorded, archived and reported.
Terms concerning the organisation of a test facility
1. Test facility means the persons, premises and operational unit(s) that are necessary
for conducting the non-clinical health and environmental safety study. For multisite
studies, those which are conducted at more than one site, the test facility comprises
the site at which the study director is located and all individual test sites, which
individually or collectively can be considered to be test facilities.
2. Test site means the location(s) at which a phase(s) of a study is conducted.
3. Test facility management means the person(s) who has the authority and formal
responsibility for the organisation and functioning of the test facility according to
these principles of Good Laboratory Practice.
4. Test site management (if appointed) means the person(s) responsible for ensuring
that the phase(s) of the study, for which he is responsible, are conducted according
to these principles of Good Laboratory Practice.
5. Sponsor means an entity which commissions, supports and/or submits a non-clinical
health and environmental safety study.
6. Study director means the individual responsible for the overall conduct of the non-
clinical health and environmental safety study.
7. Principal investigator means an individual who, for a multisite study, acts on behalf
of the study director and has defined responsibility for delegated phases of the
study. The study director's responsibility for the overall conduct of the study cannot
be delegated to the principal investigator(s); this includes approval of the study plan
and its amendments, approval of the final report, and ensuring that all applicable
principles of Good Laboratory Practice are followed.
8. Quality assurance programme: means a defined system, including personnel,
which is independent of study conduct and is designed to assure test facility
management of compliance with these principles of Good Laboratory Practice.
9. Standard operating procedures (SOPs) means documented procedures which
describe how to perform tests or activities normally not specified in detail in study
plans or test guidelines.
10. Master schedule means a compilation of information to assist in the assessment of
workload and for the tracking of studies at a test facility.
Terms concerning the non-clinical health and environmental safety study
1. Non-clinical health and environmental safety study, henceforth referred to
simply as `study’, means an experiment or set of experiments in which a test item is
examined under laboratory conditions or in the environment to obtain data on its
properties and/or its safety, intended for submission to appropriate regulatory
authorities.
2. Short-term study means a study of short duration with widely used, routine
techniques.
3. Study plan means a document which defines the objectives and experimental design
for the conduct of the study, and includes any amendments.
4. Study plan amendment means an intended change to the study plan after the study
initiation date.
5. Study plan deviation means an unintended departure from the study plan after the
study initiation date.
6. Test system means any biological, chemical or physical system or a combination
thereof used in a study.
7. Raw data means all original test facility records and documentation, or verified
copies thereof, which are the result of the original observations and activities in a
study. Raw data also may include, for example, photographs, microfilm or
microfiche copies, computer readable media, dictated observations, recorded data
from automated instruments, or any other data storage medium that has been
recognised as capable of providing secure storage of information for a time period
as stated in section 10 below.
8. Specimen means any material derived from a test system for examination, analysis,
or retention.
9. Experimental starting date means the date on which the first study specific data
are collected.
10. Experimental completion date means the last date on which data are collected
from the study.
Study initiation date means the date the study director signs the study plan.
Study completion date means the date the study director signs the final report.
Terms concerning the test item
1. Test item means an article that is the subject of a study.
2. Reference item (`control item’) means any article used to provide a basis for
comparison with the test item.
3. Batch means a specific quantity or lot of a test item or reference item produced
during a defined cycle of manufacture in such a way that it could be expected to be
of a uniform character and should be designated as such.
4. Vehicle means any agent which serves as a carrier used to mix, disperse, or
solubilise the test item or reference item to facilitate the administration/application to
the test system.
Section II
GOOD LABORATORY PRACTICE PRINCIPLES
1. Test facility organisation and personnel
Test facility management's responsibilities
1. Each test facility management should ensure that these 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 fulfil the responsibilities of management as defined by these
principles of Good Laboratory Practice;
(b)
ensure that a sufficient number of qualified personnel, appropriate facilities,
equipment, 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 procedures;
(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 established procedures, and should be documented;
(h)
ensure, in the event of a multisite 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 approval 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 multisite 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 and reference 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: 1.1.2(g), (i), (j) and (o).
Study director's responsibilites
1. The study director is the single point of study control and has the responsibility for
the overall conduct of the study and for its final 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 assurance 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 final report for a multisite 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 document 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 final report to indicate acceptance of responsibility for the
validity of the data and to indicate the extent to which the study complies
with these principles of Good Laboratory Practice;
(i)
ensure that after completion (including termination) of the study, the study
plan, the final report, raw data and supporting material are archived.
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.
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 comply 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 appropriate, 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 operations that may affect the study.
2. Quality assurance programme
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
individuals designated by and directly responsible to management and who are
familiar with the test procedures.
3. This individual(s) should not be involved in the conduct of the study being assured.
Responsibilities of the quality assurance personnel
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 if 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
– study-based inspections,
– facility-based inspections,
– process-based inspections.
Records of such inspections should be retained;
(d)
inspect the final 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 final 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 final report reflects the raw data.
3. Facilities
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.
Test system facilities
1. The test facility should have a sufficient number of rooms or areas 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 or areas should be available for the diagnosis, treatment and control
of diseases, in order to ensure that there is no unacceptable degree of deterioration
of test systems.
3. There should be storage rooms or areas as needed for supplies and equipment.
Storage rooms or areas should be separated from rooms or areas housing the test
systems and should provide adequate protection against infestation, contamination,
and/or deterioration.
Facilities for handling test and reference items
1. To prevent contamination or mix-ups, there should be separate rooms or areas for
receipt and storage of the test and reference items, and mixing of the test items with
a vehicle.
2. Storage rooms or areas for the test items should be separate from rooms or areas
containing the test systems. They should be adequate to preserve identity,
concentration, purity, and stability, and ensure safe storage for hazardous
substances.
Archive facilities
Archive facilities should be provided for the secure storage and retrieval of study plans, raw
data, final reports, samples of test items and specimens. Archive design and archive
conditions should protect contents from untimely deterioration.
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 disposal
facilities, and decontamination and transportation procedures.
4. Apparatus, material, 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, 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 systems.
4. Chemicals, reagents, and solutions should be labelled to indicate identity (with concentration
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.
5. Test systems
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.
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. Newly received animal and plant test systems should be isolated until their health
status has been evaluated. If any unusual mortality or morbidity occurs, this lot
should not be used in studies and, when appropriate, should be humanely 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 diseased or injured during the course of a study should be
isolated and treated, if necessary to maintain the integrity of the study. Any diagnosis
and treatment of any disease before or during a study should be recorded.
3. Records of source, date of arrival, and arrival condition of test systems should be
maintained.
4. Biological test systems should be acclimatised to the test environment for an
adequate period before the first administration/application of the test or reference
item.
5. All information needed to properly identify the test systems should appear on their
housing 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, wherever 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.
6. Test and reference items
Receipt, handling, sampling and storage
1. Records including test item and reference item characterisation, date of receipt,
expiry date, quantities received and used in studies should be maintained.
2. Handling, sampling, and storage procedures should be identified in order that the
homogeneity and stability are assured to the degree possible and contamination or
mix-up are precluded.
3. Storage container(s) should carry identification information, expiry date, and specific
storage instructions.
Characterisation
1. Each test and reference item should be appropriately identified (e.g. code, chemical
abstracts service registry number (CAS number), name, biological parameters).
2. For each study, the identity, including batch number, purity, composition,
concentrations, or other characteristics to appropriately define each batch of the test
or reference items should be known.
3. In cases where the test item is supplied by the sponsor, there should be a
mechanism, developed in cooperation between the sponsor and the test facility, to
verify the identity of the test item subject to the study.
4. The stability of test and reference items under storage and test conditions should be
known for all studies.
5. If the test item is administered or applied in a vehicle, the homogeneity,
concentration and stability of the test item in that vehicle should be determined. For
test items used in field studies (e.g. tank mixes), these may be determined through
separate laboratory experiments.
6. A sample for analytical purposes from each batch of test item should be retained for
all studies except short-term studies.
7. Standard operating procedures
1. A test facility should have written standard operating procedures approved by test facility
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.
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
standard operating procedures.
3. Deviations from standard operating procedures related to the study should be documented
and should be acknowledged by the study director and the principal investigator(s), as
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
considered as illustrative examples.
1. Test and reference items
Receipt, identification, labelling, handling, sampling and storage.
2. Apparatus, materials and reagents
(a)
Apparatus
use, maintenance, cleaning 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 preparation and environmental room 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 conclusion of the study.
(d)
Handling of test system individuals 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.
8. Performance of the study
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 Good Laboratory Practice compliance by quality assurance personnel as
specified in 2.2(b) of Section II. The study plan should also be appproved by the
test facility management and the sponsor, if required by national regulation 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.
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 and reference item
(a)
a descriptive title;
(b)
a statement which reveals the nature and purpose of the study;
(c)
identification of the test item by code or name (IUPAC; CAS number,
biological parameters, etc.);
(d)
the reference item to be used.
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 delegated 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.
5. Issues (where applicable)
(a)
the justification for selection of the test system;
(b)
characterisation of the test system, such as the species, strain, substrain,
source of supply, number, body weight range, sex, age and other pertinent
information;
(c)
the method of administration and the reason for its choice;
(d)
the dose levels and/or concentration(s), frequency, and duration of
administration/application;
(e)
detailed information on the experimental design, including a description of
the chronological procedure of the study, all methods, materials and
conditions, type and frequency of analysis, measurements, observations and
examinations to be performed, and statistical methods to be used (if any).
6. Records
a list of records to be retained.
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 specimen 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 individual 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 (electronic) signatures. Reason for changes should be given.
9. Reporting of study results
General
1. A final report should be prepared for each study. In the case of short-term studies, a
standardized final 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 final 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 principles of Good Laboratory Practice should be indicated.
4. Corrections and additions to a final report should be in the form of amendments.
Amendments should clearly specify the reason for the corrections or additons and
should be signed and dated by the study director.
5. Reformatting of the final report to comply with the submission requirements of a
national registration or regulatory authority does not constitute a correction, addition
or amendment to the final report.
Content of the final report
The final report should include, but not be limited to, the following information
1. Identification of the study, the test item and reference item
(a)
a descriptive title;
(b)
identification of the test item by code or name (IUPAC, CAS number,
biological parameters, etc.);
(c)
identification of the reference item 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 delegated, if applicable;
(e)
name and address of scientists having contributed reports to the final 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 investigator(s),
if applicable. This statement would also serve to confirm that the final report reflects
the raw data.
5. Description of materials and test methods
B
(a)
description of methods and materials 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 and determinations of
statistical significance;
(d)
an evaluation and discussion of the results and, where appropriate,
conclusions.
7. Storage
the location(s) where the study plan, samples of test and reference items, specimens,
raw data and the final report are to be stored.
10. Storage and retention of records and materials
The following should be retained in the archives for the period specified by the appropriate
authorities
(a)
the study plan, raw data, samples of test and reference items, specimens, and the
final 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 and reference 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 and reference items and specimens should be
retained only as long as the quality of the preparation permits evaluation.
Material retained in the archives should be indexed so as to facilitate orderly storage and
retrieval.
Only personnel authorised by management should have access to the archives. Movement of
material in and out of the archives should be properly recorded.
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).