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DIRECTIVE 1999/12/EC |
Commission
Directive 1999/12/EC of 8 March 1999 adapting to technical progress for the
second time the Annex to Council Directive 88/320/EEC on the inspection and
verification of good laboratory practice (GLP) (Text with EEA relevance)
Official Journal L 077 ,
COMMISSION DIRECTIVE 1999/12/EC of 8 March 1999
adapting to technical progress for the second time the Annex to Council
Directive 88/320/EEC on the inspection and verification of good laboratory
practice (GLP) (Text with EEA relevance)
THE
COMMISSION OF THE EUROPEAN COMMUNITIES,
Having
regard to the Treaty establishing the European Community,
Having
regard to Council Directive 88/320/EEC of
Whereas,
on 9 March 1995, the OECD Council adopted a Decision amending the Annexes to
the Council Decision-Recommendation on compliance with principles of good
laboratory practice which affects the texts included in the Annex to Directive
88/320/EEC;
Whereas
it is necessary to adapt for a second time the Annex to Directive 88/320/EEC so
as to take account of the OECD Council Decision of 9 March 1995, and, by
publishing the full text of the annexes on the inspection and verification of
good laboratory practice, to facilitate the uniform interpretation thereof;
Whereas
the measures provided for in this Directive are in accordance with the opinion
of the Committee for the adaptation to technical progress of the Directives
concerning the elimination of technical barriers to trade in dangerous
substances and preparations,
HAS
ADOPTED THIS DIRECTIVE:
Article
1
The Annex to Directive 88/320/EEC is replaced
by the Annex hereto.
Article 2
1. Member
States shall adopt the laws, regulations and administrative provisions
necessary in order to comply with this Directive not later than
2. When
Member States adopt these provisions, these shall contain a reference to this
Directive or shall be accompanied by such reference at the time of their
official publication. The procedure for such reference shall be adopted by
Member States.
Article 3
This Directive is addressed to the Member
States.
Done at
For the Commission
Martin BANGEMANN
Member of the Commission
(1) OJ L 145, 11. 6. 1988, p. 35.
(2) OJ L 11, 13. 1. 1990, p. 37.
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 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 2 October 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 GLP 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:
- GLP 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,
- 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 test facilities within its territories, by means of
inspections and study audits,
- (National) GLP 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
- Test facility inspection: an on-site
examination of the test facility's procedures and practices to assess the
degree of compliance with GLP 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) 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 procedures
Administration
A (national)
GLP 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) GLP 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 GLP principles within their territories,
- publish documents providing details of the (national)
GLP 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 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 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 GLP 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)
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) GLP Monitoring
Authorities should:
(a) ensure
that arrangements are made for the appropriate training of GLP inspectors,
having regard to their individual qualifications and experience;
(b)
encourage consultations, including joint training activities where necessary,
with the staff of (national) GLP Monitoring Authorities in other OECD member
countries in order to promote international harmonisation in the interpretation
and application of GLP 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) 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 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) 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 of
assuring that the resulting data are of adequate quality. As indicated above,
Member States should publish the details of their (national) GLP compliance
programmes. 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 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 GLP 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 GLP principles monitored
by the appropriate (national) GLP Monitoring Authority,
-
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-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) GLP Monitoring Authority in such cases
should be defined,
-
describe the test facility inspection
and study audit procedures for verification of GLP compliance.
The
documentation should indicate the procedures which will be used to examine both
the organisational 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 GLP principles are found during
or after a test facility inspection or study audit. The appropriate actions
should be described in documents from the (national) GLP Monitoring Authority.
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
verify that 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 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) GLP 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) GLP Monitoring Authorities will depend on
the particular circumstances of each case and the legal or administrative
provisions under which GLP 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) GLP
compliance programme or from any existing list or register 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 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 GLP
compliance monitoring and/or relating to the action the GLP 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 GLP 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 GLP 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 GLP
principles. Test facility inspections should be conducted on a regular, routine
basis to establish and 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., 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 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. 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 GLP 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 GLP 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 authorised personnel only. Their
responsibilities in this respect will have been established within their
(national) GLP 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,
- 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 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 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 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,
- 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.
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,
- 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 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 (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 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 responsibility for the validity of the study and
confirming that the study was conducted in accordance with GLP principles,
-