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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e 'guides for compliance monitoring procedures for good laboratory practice' and the 'guidance for the conduct of laboratory inspections and study audits' set out in Annexes I and II are updates and expanded, as necessary, in light of developments and experience of Member States and relevant work in other international organizations . 2 . INSTRUCTS the Environment Committee and the Management Committee of the special programme on the control of chemicals to pursü a programme of work designed to facilitate the implementation of this decision/recommendation, and to ensure continuing exchange of information experience on technical and administrative matters related to the application of GLP principles and the implementation of procedures for monitoring compliance with good laboratory practice . 3 . INSTRUCTS the Environment Committee and the Management Committee of the special programme on the control of chemicals to review actions taken by Member States in pursuance of this decision/recommendation . ANNEX I GUIDES FOR COMPLIANCE MONITORING PROCEDURES FOR GOOD LABORATORY PRACTICE To facilitate the mutual acceptance of test data generated for submission to regulatory authorities of ÖCD Member States, harmonization 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 Annex is to provide detailed practical guidance to ÖCD 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 recognized 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, e.g ., 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 dü 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 'ÖCD principles of good laboratory practice' ( Annex 2 to Council Decision C(81)30 ( final )) are applicable to this document. In addition, the following definitions apply : GLP principles : principles of good laboratory practice, that are consistent with the ÖCD principles of good laboratory practice as set out in Annex 2 of Council Decision C(81)30 ( final ). GLP compliance monitoring : the periodic inspection of laboratories 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 laboratories within its territories, by means of inspections and study audits . ( National ) GLP monitoring authority : a management body established within a Member State with responsibility for monitoring the good laboratory practice compliance of laboratories 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 . Laboratory 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 laboratory 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 laboratory inspections on behalf of the ( national ) GLP monitoring authority . GLP compliance status : the level of adherence of a laboratory 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 management 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, etc .; - maintain records of laboratories inspected ( and their GLP compliance status ) and of studies audited . To foster international understanding and liaison, Member States should inform the ÖCD and other Member States ( e.g ., through the ÖCD complementary information exchange procedure ) of the nature and availability of the documentation on GLP which has been produced, together with the addresses and telephone numbers of the ( national ) GLP monitoring authorities . 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 laboratory 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 laboratory inspections and study audits are made available only to regulatory authorities and, where appropriate, to the laboratories inspected or concerned with study audits and/or to study sponsors . The names of laboratories subject to laboratory inspections within a ( national ) GLP compliance programme, their levels of compliance with the national GLP principles and the date(s ) the inspections were conducted should be made available to ( national ) GLP monitoring authorities in other Member States upon request . Personnel and training ( National) GLP monitoring authorities should : - ensure that an adequate number of inspectors is available The number of inspectors required will depend upon : ii(i ) the number of laboratories involved in the ( national ) GLP compliance programme; i(ii ) the frequency with which the GLP compliance status of the laboratories is to be assessed; ( iii ) the number and complexity of the studies undertaken by those laboratories; ( iv ) 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 : i(i ) ensure that arrangements are made for the appropriate training of inspectors, having regard to their individual qualifications and experience; ( ii ) encourage consultations, including joint training activities where necessary, with the staff of ( national ) GLP monitoring authorities in other Member States in order to promote international harmonization in the interpretation and application of GLP principles, and in the monitoring of compliance with such principles . - ensure that inspectorate personnel have no financial or other interests in the laboratories 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 by another way, by the ( national ) GLP monitoring authority to perform laboratory 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 laboratories and the quality/acceptability of a study audit, and for taking any action based on the results of laboratory inspections or study audits which may be necessary . ( National ) GLP compliance programmes GLP compliance monitoring is intended to ascertain whether laboratories 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, e.g ., 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, e.g ., physical, chemical, toxicological and/or ecotoxicological . - provide an indication as to the mechanism whereby laboratories 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 laboratories may have their compliance with GLP principles monitored by the appropriate ( national ) GLP monitoring authority . - provide information on categories of laboratory inspections/study audits A ( national ) GLP compliance programme should include : i(i ) routine laboratory inspections, i.e ., the regular monitoring of laboratories, in principle on a two-year cycle . These inspections include both a general laboratory inspection and a ( limited ) study audit of an on-going or completed study; ( ii ) special laboratory inspections/study audits at the request of a regulatory authority, e.g ., prompted by a query arising from the submission of data to a regulatory authority . - define the powers of inspectors for entry into laboratories and their acceß to data held by laboratories While inspectors will not normally wish to enter laboratories against the will of the laboratory management, circumstances may arise where laboratory 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 laboratory inspection and study audit procedures for verification of GLP compliance The documentation should indicate the procedures which will be used to examine both the organizational processes and the conditions under which laboratory studies are planned, performed, monitored and recorded . Guidance for such procedures is available in Annex II to this decision/recommendation . - describe actions that may be taken as follow-up to laboratory inspections and study audits . Follow-up to laboratory inspections and study audits When a laboratory 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 laboratory inspection or study audit . The appropriate actions should be described in documents from the ( national ) GLP monitoring authority . If a laboratory inspection or study audit reveals only minor deviations from GLP principles, the laboratory 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 : - ißü a statement that the laboratory has been inspected and found to be operating in compliance with GLP principles . The date of inspection and, if appropriate, the categories of tests inspected in the laboratory at that time should be included . Such statements may be used to provide information to ( national ) GLP monitoring authorities in other Member States; 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 upon 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 laboratory; - suspension of laboratory inspections or study audits of a laboratory and, for example and where administratively possible, removal of the laboratory from the ( national ) GLP compliance programme or from any existing list or register of laboratories subject to GLP laboratory inspections; - the requirement that a statement detailing the deviations be attached to specific studyreports; - action through the courts, where warranted by circumstances and where legal/administrative procedures so permit . Where serious deviations are found which may have affected specific studies, the ( national ) GLP monitoring authority should consider the need to inform relevant regulatory authorities or ( national ) GLP monitoring authorities in other Member States of their findings . Appeals procedures Problems, or differences of opinion, between inspectors and laboratory management will normally be resolved during the course of a laboratory inspection or study audit . However, it may not always be possible for agreement to be reached . A procedure should exist whereby a laboratory may make representations relating to the outcome of a laboratory inspection or study audit for GLP compliance monitoring and/or relating to the action the GLP monitoring authority proposes to take thereon . ANNEX II GUIDANCE FOR THE CONDUCT OF LABORATORY INSPECTIONS AND STUDY AUDITS INTRODUCTION The purpose of this Annex is to provide guidance for the conduct of Laboratory inspections and study audits which would be mutually acceptable to ÖCD Member States . Is is principally concerned with laboratory inspections, an activity which occupies much of the time of GLP inspectors . A laboratory inspection will usually include a limited study audit or 'review' as a part of the inspection, but study audits will also have to be concerned 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 . Laboratory inspections are conducted to determine the degree of conformity of test facilities and laboratory 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 . Laboratory inspections should be conducted on a regular, routine basis to establish and maintain a record of the GLP compliance status of a test facility . DEFINITIONS OF TERMS The definitions of terms in the 'ÖCD principles of good laboratory practice' [Annex 2 to the Council Decision C(81)30 ( Final )] and in Annex I to this decision recommendation are applicable to this Annex . LABORATORY 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 judgement 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 laboratory 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 laboratory inspection . These lists are not meant to be comprehensive and should not be taken as such . Inspectors should not concern themselves with the need for, or objectives 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 . Laboratory inspections and study audits inevitably disturb the normal work in a laboratory . 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 laboratory as to the timing of visits to certain sections of the facility. Inspectors will, while conducting laboratory 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 ) GLP compliance monitoring programme . INSPECTION PROCEDURES Pre-inspection Purpose : to familiarize 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 laboratory inspection or study audit, inspectors should familiarize 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, organization charts, study reports, protocols and curricula vitä ( CVs ) of key 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 laboratory inspections . Where no previous laboratory inspections have been conducted, a pre-inspection visit can be made to obtain relevant information . Laboratories should be informed of the date and time of inspectors' arrival, the objective of their visit and the length of time they expect to be on the premises . This will allow the laboratory 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 laboratory in advance of the visit so that they will be immediately available during the laboratory inspection . Starting conference Purpose : to inform the management and staff of the facility of the reason for the laboratory inspection or study audit that is about to take place, and to identify the laboratory areas, study(ies ) selected for audit, documents and personnel likely to be involved . The administrative and practical details of a laboratory 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 laboratory 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 upon at this time; - clarify or request information as to the management structure ( organization ) and personnel of the facility; - request information as to the conduct, side-by-side, of studies subject to GLP principles with others for which they are not applied; - make an initial determination as to the parts of the facility to be covered during the laboratory inspection; - describe the documents and specimens that will be needed for on-going or completed study(ies ) selected for study audit . Before proceeding further with a laboratory inspection, it is advisable for the inspector to establish contact with the laboratory'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 . Organization 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 organizational 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, for example : - floor plans; - facility management and scientific organization charts; - CVs of key 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, route of administration and name of study director; - staff training and health surveillance policies, where such policies have been established; - staff training records where available; - 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 associated with the study(ies ) being audited . The inspector should check, in particula