Consumer, Environmental and Health Technologies Chemicals. Table of contents

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1 EUROPEAN COMMISSION Directorate-General for Internal Market, Industry, Entrepreneurship and SMEs Consumer, Environmental and Health Technologies Chemicals Ref. Ares(2017) /01/2017 GLP COMPLIANCE MONITORING OF INTERNATIONAL MULTI-SITE STUDIES Table of contents 1. BACKGROUND DEFINITIONS INDEPENDENT AND DEPENDENT TEST SITES MONITORING THE COMPLIANCE OF TEST SITES Monitoring the compliance of independent test sites Monitoring the compliance of dependent test sites... 5 Disclaimer: This document describes GLP compliance monitoring procedures for international test sites. It is the result of discussions within the EU GLP Working Group, which is chaired by the European Commission and comprises representatives from national GLP monitoring authorities and receiving authorities. It is intended to provide guidance to monitoring authorities, regulatory authorities and test facilities. The document was adopted by the EU GLP Working Group on 5 January This document does not constitute any formal commitment on behalf of the Commission. Only the European Court of Justice can give an authoritative interpretation of European Union legislation.

2 1. BACKGROUND Safety studies for the assessment of chemicals and chemical products are increasingly being carried out in multiple sites. The use of multiple test sites enhances the complexity of study design and management tasks, resulting in additional risks to study integrity. The Revised Principles of Good Laboratory Practice, adopted by OECD in 1997, together with OECD GLP Consensus Documents No 6 The application of the GLP Principles to field studies and No 13 The application of the OECD principles of GLP to the organisation and management of multi-site studies", cover various aspects of the organisation of such studies. The EU GLP Working Group identified a need for further guidance on the GLP compliance monitoring of multi-site studies performed at sites in multiple EU Member States. The compliance monitoring of international multi-sites studies can be particularly challenging due to the split responsibilities for different study phases, communication and reporting lines, potential language issues, etc. For such studies, it is necessary to clarify the roles and responsibilities of the monitoring authorities of the Member States, in which the different phases of studies are conducted. The purpose of this document is twofold: on the one hand, it aims to clarify the responsibilities of test facilities and test sites participating in international multi-site studies. On the other hand, it provides guidance to monitoring authorities and receiving authorities that are confronted with multi-site studies performed in multiple EU Member States. 2. DEFINITIONS According to the principles of GLP (Annex I to Directive 2004/10/EC), a test facility and a test site are defined as followed: Test facility means the persons, premises and operational unit(s) that are necessary for conducting the non-clinical health and environmental safety study. For multisite studies, those which are conducted at more than one site, the test facility comprises the site at which the study director is located and all individual test sites, which individually or collectively can be considered to be test facilities Test site means the location(s) at which a phase(s) of a study is conducted. According to OECD GLP Consensus Document Number 13 on the application of the OECD principles of GLP to the organisation and management of multi-site studies (p. 9), multi-site studies and study phases are defined as follows: A multi-site study means any study that has phases conducted at more than one site. Multi-site studies become necessary if there is a need to use sites that are geographically remote, organisationally distinct or otherwise separated. This could include a department of an organisation acting as a test site when another department of the same organisation acts as the test facility. A phase is a defined activity or set of activities in the conduct of a study. 2

3 According to OECD GLP Consensus Document Number 6 on the application of the GLP principles to field studies (p. 9), test sites can include the following: Research laboratory(ies) where test/reference item characterisation (including determination of identity, purity/strength, stability, and other related activities) is conducted. One or more agricultural or other in- or outdoor sites (like greenhouses) where the test or control item is applied to the test system. In some cases, a processing facility where harvested commodities are treated to prepare other items, e.g. the conversion of tomatoes into juice, puree, paste, or sauce. One or more laboratories where collected specimens (including specimens from processing) are analysed for chemical or biological residues, or are otherwise evaluated. According to the principles of GLP (Annex I to Directive 2004/10/EC), a test facility inspection is defined as "an on-site examination of the test facility's procedures and practices". 3. INDEPENDENT AND DEPENDENT TEST SITES The responsibilities of test facility management are listed in Section 1.1 of the principles of GLP. If a phase(s) of a study is conducted at a test site, test site management may be appointed and a principal investigator designated. OECD GLP Consensus Document Number 13 (p. 10) describes the need for designating a principal investigator and appointing test site management: "When the Study Director is unable to perform his/her duties at a test site because of geographical or organisational separation, the need to appoint a Principal Investigator(s) at a test site(s) arises. The performance of duties may be impracticable, for example, because of travel time, time zones, or delays in language interpretation. Geographical separation may relate to distance or to the need for simultaneous attention at more than one location. Test facility management should facilitate good working relationships with test site management to ensure study integrity." In this case, test site management is responsible for ensuring that the phase of the study, for which it is responsible, is conducted according to the principles of GLP. For the purpose of this document, a test site, for which test site management is appointed, is considered as an independent test site. A test site without its own management is considered as a dependent test site. For a dependent test site without any test site management, the test facility management retains all the above-mentioned responsibilities for the test site. This means that the test site does not have its own standard operating procedures. Instead, standard operating procedures from the test facility are directly applicable to the test site and the test facility management is fully responsible for the facilities, equipment and materials at the test site. An example of a dependent test site is a field plot used for field studies without any permanent staff. 3

4 For an independent test site, the responsibilities of the test site management are clearly defined in Section of the principles of GLP: "When a phase(s) of a study is conducted at a test site, test site management (if appointed) will have the responsibilities as defined above with the following exceptions: 1.1.2(g), (i), (j) and (o)." This means that the test site management is fully responsible for ensuring the maintenance of training records, the establishment of appropriate and technically valid standard operating procedures, the functioning of a quality assurance programme with designated personnel, the designation of an appropriately trained, qualified and experienced principal investigator, the maintenance of a historical file of all standard operating procedures, the designation of an individual responsible for the management of the archive(s), the maintenance of a master schedule and the appropriate characterisation of test and reference items. Even if independent test sites choose to use standard operating procedures compiled by the responsible test facility (e.g. a corporate headquarters), the test site management remains fully responsible for the local adoption and implementation of these standard operating procedures in accordance with Section The same applies to the quality assurance (QA) programme: while test site management may contract QA personnel in various ways (own personnel, independent consultants, or QA personnel of other GLP facility in the same country, etc.), it remains responsible for ensuring that the QA programme at the independent test site is functioning in accordance with the principles of GLP. According to the OECD GLP Consensus Document Number 13 (p. 11), "many of the problems associated with the conduct of multi-site studies can be prevented by clear allocation of responsibilities and effective communication among all parties involved in the conduct of the study." Therefore, it is pivotal that the responsibilities of the test site management are clear and in full accordance with Section of the principles of GLP. In consequence, it is not possible for test site management to be only partially responsible for certain activities listed in Section of the principles of GLP. 4. MONITORING THE COMPLIANCE OF TEST SITES 4.1. Monitoring the compliance of independent test sites Independent test sites should be included in the national monitoring programme of the Member State, in which they operate. According to Article 2 of Directive 2004/9/EC, "Member States shall verify the compliance with GLP of any testing laboratory within their territory claiming to use GLP". A testing laboratory is understood as a site that operates independently, hence the independent test site should be inspected by the monitoring authority of the Member State, in which it is located. According to the OECD GLP Consensus Document Number 13, test site management should be aware that it falls within the coverage of its national compliance monitoring programme: "Test facility management should make test site management aware that it may be subject to inspection by the national GLP compliance monitoring authority of the country in which the test site is located." 4

5 As part of its test facility inspection, monitoring authorities should verify whether the responsibilities within the test facility, including its test sites, are clearly defined in accordance with the principles of GLP. If the monitoring authority of the Member State, in which the test facility headquarters is located, discovers that any of its independent test sites are not part of the GLP programme of the Member States, in which they operate, the monitoring authority should inform the test facility management that the test sites are subject to inspection by their national GLP compliance monitoring authority. Furthermore, in such a case, the monitoring authority of the Member State of the test facility headquarters should inform the monitoring authority of the Member State, in which the test site is located. More specifically, in order to verify that the test facility management has fulfilled its specific responsibilities for multi-site studies (e.g. ensuring that clear lines of communication exist between the study director, principal investigator(s), the quality assurance programme(s) and study personnel Section 1.1.2(o) of the principles of GLP), the monitoring authority of the test facility should take relevant information of the inspection of its test sites into account. For this purpose, it may contact the monitoring authority of the test site and request further information in accordance with Article 6(1) of Directive 2004/9/EC. Observed deviations in multi-site studies should be shared with the monitoring authorities in the Member States in which the other phases are carried out. More specifically, if the monitoring authority of the test facility detects any relevant findings related to a phase of the study conducted in another Member State, it should inform the monitoring authority of the test site, responsible for that phase of the study. Conversely, in case the monitoring authority of a test site detects any relevant findings in parts of the study that are under the responsibility of the test facility, it should contact its counterpart in the Member States, in which the test facility management is located. In certain cases, a joint inspection by the monitoring authorities of both the Member State of the test facility management and the Member State of the test site may be warranted. Independent test sites are listed separately in the list of laboratories in the report drawn up by Member States annually in accordance with Article 4(1) of Directive 2004/9/EC Monitoring the compliance of dependent test sites Dependent test sites fall entirely under the responsibility of the test facility management. As they have neither their own test site management, nor the related responsibilities, they cannot undergo a full inspection by themselves. For instance, it is not possible to comprehensively verify GLP compliance of a field plot in the absence of the test site management. During a routine inspection of a test facility, the monitoring authority of the test facility should verify whether or not the test facility also includes (dependent) test sites, especially test sites located in other Member States. Compliance monitoring authorities should be aware of the fact that any conclusion on the compliance status of a test facility can also affect the related dependent test sites. 5

6 As test facility inspections are defined as on-site examinations of the test facility's procedures and practices (see Section 2 above), it may be needed to inspect dependent test sites (e.g. field plots) that are part of a test facility. In such a case, the monitoring authority of the Member State of the test facility will inform the monitoring authority of the Member State of the test site and request a (joint) inspection. Depending on national rules and practices, some Member States may choose to include dependent test sites within their territory in their own monitoring programme. An inspection of such a site should preferably be done in conjunction with an inspection of the responsible test facility. The monitoring authority of the Member State of the test site may request a joint inspection from the monitoring authority of the Member State of the test facility. 6