89/569/EWG: Beschluß des Rates vom 28. Juli 1989 über die Annahme einer Entscheidung/Empfehlung der OECD durch die Europäische Wirtschaftsgemeinschaft über die Einhaltung der Grundsätze der Guten Laborpraxis

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r : - lists of on-going and completed studies to ascertain the level of work being undertaken by the laboratory; - the identity and qualifications of the study directors, the head of the quality assurance unit and other key personnel; - existence of SOPs for all relevant areas of testing . Quality assurance programme Purpose : to determine whether the mechanisms used to assure management that laboratory 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 QA procedures 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 whether the test facility is of suitable size, construction, 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, e.g ., 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, e.g ., 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 judgement, 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 hazard 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 laboratory has suitably located, operational apparatus in sufficient quantity and of adequate capacity to meet the requirements of the test being conducted in the facility and that the materials, reagents and specimens are properly labelled, used and stored . The inspector should check that : - apparatus are clean and in good working order; - records have been kept of apparatus operation, maintenance, standardization and calibration; - 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 interfere with 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, e.g ., 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 substance were determined and that the reference substances specified in test plans were used; - SOPs exist to cover laboratory activities and that their provisions are observed; - 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 identified; - animals are adequately and, if necessary and appropriate, uniquely identified thoughout the study; - 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 laboratory 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 SOPs for recording the receipt, and for the handling, sampling, usage and storage of test 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 SOPs for the determination of identity, purity, composition, stability, and for the prevention of contamination of test and reference substances, where applicable; - records are kept of the composition, characterization, concentration, and stability 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 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 laboratory has written SOPs relating to all the important aspects of the laboratory's operations, considering that one of the most important management techniques for controlling laboratory operations is the use of written SOPs . These relate directly to the routine elements of tests conducted by the laboratory . The inspector should check that : - each laboratory area has immediately available relevant, authorized copies of SOPs; - procedures exist for revision and updating of SOPs; - any amendments or changes to SOPs have been authorized and dated; - historical files of SOPs are maintained; - SOPs are available for, but not necessarily limited to, the following activities : - ( viii ) ( i ) receipt, identification, labelling, handling, sampling, usage and storage of test and reference substances; ( ii ) maintenance, cleaning and calibration of measuring apparatus 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, characterization, 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; - 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 were signed and dated; - computer-generated or stored data have been identified and that the procedures to protect them against unauthorised amendments or leß are adequate; - the computer software used within the study is reliable, accurate and can be 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 a final report is available, the inspector should check that : - it is signed and dated by the study director and by other principal scientists; - the study director has signed a statement indicating acceptance of responsibility for the validity of the study and confirming that the study was conducted in accordance with GLP principles; - 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 : - the archive facilities for the storage of study plans, raw data, final reports, samples and specimens; - 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 . STUDY AUDITS Laboratory inspections will generally include, inter alia ( limited ), study audits . These may be brief reviews of on-going or completed studies . When specific study audits are requested by regulatory authorities, the conduct and reporting of the study should be subjected to a detailed examination . 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 from the study plan using 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, e.g ., where there is a need to examine tißü sections under the microscope . Whe 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 : - ( iii ) ( i ) the study plan; ( ii ) SOPs in use at the time the study was done; (iii ) log books, laboratory notebooks, files, worksheets, print-outs of computer-stored data, etc .; ( 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 laboratory 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 laboratory inspection or study audit has been completed, the inspector should be prepared to discuß his findings with representatives of the test facility and should prepare a written report, i.e ., the inspection report . A laboratory inspection of any large laboratory is likely to reveal a number of minor deviations from GLP principles but, normally, these will not be sufficiently serious to affect the validity of studies emanating from that laboratory . In such cases, it is reasonable for an inspector to report that the laboratory is operating in compliance with GLP principles according to the criteria established by the ( national ) GLP monitoring authority . Nevertheleß, details of the inadequacies or faults detected should be provided to the laboratory and assurances sought from its senior management that action will be taken to remedy them . The inspector may need to revisit the laboratory after a period of time to verify that necessary action has been taken . If a serious deviation from the GLP principles is identified during a laboratory 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 ) GLP monitoring authority . The action taken by that authority will depend upon the nature and extent of the non-compliance and the legal and/or administrative provisions within the GLP compliance programme . Where a study audit has been conducted at the request of a regulatory authority, a full report of the findings should be prepared and sent via the relevant ( national ) GLP monitoring authority to the regulatory authority concerned . ANNEX III GUIDANCE FOR THE EXCHANGE OF INFORMATION CONCERNING NATIONAL PROCEDURES FOR MONITORING COMPLIANCE Part II, paragraph 2 of the Council Act contains a Decision that Member States exchange information related to their procedures for monitoring compliance with GLP principles . This Annex provides guidance concerning the types of information which should be exchanged . While information concerning all of the aspects covered in the 'guides for compliance monitoring procedures for good laboratory practice' ( Annex I ) are relevant to an understanding of other Member States' procedures for GLP compliance monitoring, certain types of information are of particular importance . These include : - the GLP principles adopted nationally; - the scope of the national programme for monitoring compliance with GLP principles in terms of the types of chemicals and tests covered; - the identity, legal status, and organizational structure of the ( national ) GLP monitoring authority(ies ); - the procedures followed during laboratory inspections and study audits, and the frequency of routine inspections; - the number and qualifications of inspectors; - the actions available to the ( national ) GLP monitoring authority(ies ) in cases of non-compliance, including the ability to inform other Member States, when necessary, of the results of laboratory inspections and study audits; - the arrangements for protecting confidentiality of information; - the procedures for initiating, conducting and reporting on laboratory inspections and study audits at the request of other Member States; - the procedures for obtaining information on laboratories which have been inspected by a ( national ) GLP monitoring authority of another Member State, including such laboratories' compliance status; and - the nature of laboratory certifications that studies were carried out following GLP principles . Recognition of national procedures for monitoring compliance with GLP principles may not be immediately forthcoming from other Member States . Member States should be prepared to meet genuine concerns in a cooperative way . It may be that a Member State is unable to judge the acceptability of the GLP compliance monitoring procedures of another solely on the basis of the exchange of written information . In such cases, Member States may seek the assurance they require through consultation and discussion with relevant ( national ) GLP monitoring authorities . In this context, ÖCD provides a forum for the discussion and solving of problems relating to the international harmonization and acceptance of GLP compliance monitoring procedures . To facilitate international liaison and the continuing exchange of information, the establishment of a single GLP monitoring authority covering all good laboratory practice activities within a Member State has obvious advantages . Where more than one authority exists, a Member State should ensure that they operate in a consistent way, using comparable procedures and having similar GLP compliance programmes . The authority or authorities with responsibilities for international contacts should be identified by Member States . Situations will arise where a national regulatory authority of a Member State will need to request information on the GLP compliance status of a laboratory located in another Member State . On rare occasions, and where good reason exists, a particular study audit may be requested by a regulatory authority of another Member State . Arrangements should be provided whereby these requests may be fulfilled and the results reported back to the requesting regulatory authority . Formal international contact should be established for the exchange of information between GLP monitoring authorities . However, this should not be understood to prevent informal contacts between regulatory authorities and the GLP monitoring authority in another Member State, to the extent that such contacts are accepted by the Member State concerned . National authorities should note that authorities from another Member State, may wish to be present at a laboratory inspection or study audit that they have specifically requested; or they may wish that representative(s ) from the Member State secking a special laboratory inspection or study audit present at that inspection or audit . In these cases, Member States should enable inspectors from another Member State to participate in laboratory inspections and study audits carried out by their GLP monitoring authority .