Directive 2004/9/EC of the European Parliament and of the Council of 11 February 2004 on the inspection and verification of good laboratory practice (GLP) (Codified version) (Text with EEA relevance)
Modified by
- Regulation (EC) No 219/2009 of the European Parliament and of the Councilof 11 March 2009adapting a number of instruments subject to the procedure referred to in Article 251 of the Treaty to Council Decision 1999/468/EC with regard to the regulatory procedure with scrutinyAdaptation to the regulatory procedure with scrutiny — Part Two, 32009R0219, March 31, 2009
- Regulation (EU) 2019/1243 of the European Parliament and of the Councilof 20 June 2019adapting a number of legal acts providing for the use of the regulatory procedure with scrutiny to Articles 290 and 291 of the Treaty on the Functioning of the European Union(Text with EEA relevance), 32019R1243, July 25, 2019
cooperation between the authorities designated by the Member States in technical and administrative matters arising from the implementation of GLP, and the exchange of information on the training of inspectors.
(a) the formula in Article 2(2); (b) Annex I, to take account of technical progress.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 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.
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.
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.
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.
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.
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.
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, 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.
that a person has been identified as responsible for the archive, the archive facilities for the storage of study plans, raw data (including that from discontinued GLP studies), final reports, samples and specimens 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, 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.
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.
animal body weight, food/water intake, dose formulation and administration, etc., clinical observations and autopsy findings, clinical chemistry, pathology.
| Council Directive 88/320/EEC | ( |
| Commission Directive 90/18/EEC | |
| Commission Directive 1999/12/EC | ( |
| Regulation (EC) No 1882/2003 of the European Parliament and of the Council, Annex III, point 8 only | ( |
| Directive | Deadline for transposition |
|---|---|
| 88/320/EEC | 1.1.1989 |
| 90/18/EEC | 1.7.1990 |
| 1999/12/EC | 30.9.1999 |
| Directive 88/320/EEC | This Directive |
|---|---|
| Articles 1 to 6 | Articles 1 to 6 |
| Article 7 | Article 8 |
| Article 8 | Article 7 |
| Article 9 | — |
| — | Article 9 |
| — | Article 10 |
| Article 10 | Article 11 |
| Annex | Annex I |
| — | Annex II |
| — | Annex III |
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