Meeting of the EU GLP Working Group, February GLP requirements in EU legislation and guidance medical devices

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1 Meeting of the EU GLP Working Group, February 2017 Agenda item: Document title: Action required: Session 2, item 2a GLP requirements in EU legislation and guidance medical devices Requirements of GLP in the conformity assessment of medical devices Document submitted by the member from Austria (AGES) For discussion For discussion at the EU GLP WG meeting on February 2017

2 REQUIREMENTS OF GLP IN THE CONFORMITY ASSESSMENT OF MEDICAL DEVICES 1. CURRENT SITUATION To put a legally compliant medical device on the market, its conformity with essential requirements has to be demonstrated. In order to demonstrate conformity with the essential requirements and to enable conformity to be verified, harmonised European standards may be applied to protect against the risks associated with the design, manufacture and packaging of medical devices. Such harmonised European standards are drawn up by private-law bodies and have the status of non-mandatory texts. If a harmonised standard is followed, conformity with the essential requirements is assumed. The harmonised European standards are listed at this site: Biological safety is one of the essential requirements of a medical device. Biological safety assessment may refer to the harmonized European standard EN ISO This standard requires GLP for certain types of testing: systemic toxicity data should be taken into account for most devices implanted in the body or in contact with the inside of the body. 1 Other toxicity tests (e.g. genotoxicity) are also considered relevant for various devices. For systemic toxicity tests, EN ISO requires GLP. 2 More generally, EN ISO requires in vitro or in vivo tests to be conducted in accordance with the best possible quality standards, notably GLP or ISO (where applicable). 3 As harmonised European standards have the status as non-mandatory texts, GLP is formally not mandatory. However, if the standard is not followed a suitable alternative would have to be justified by the manufacturer. The current texts of the three medical device directives do not explicitly refer to Good Laboratory Practice (GLP). Nevertheless, GLP is already mandatory in the following cases: a. Case 1: The combination of a medicinal product plus a device is a medicinal product. Such product is subject to the licensing procedure for medicinal products according to Directive 2001/83/EC (receiving authority issues a marketing authorisation). b. Case 2: The combination of a medicinal product plus a device is a medical device, a conformity assessment is required. The notified body has to consult a receiving 1 See ISO :2009, Table A.1 2 EN ISO :2009 (Section 4.14): "Die Gute Laborpraxis behandelt die Organisation, den Ablauf und die Bedingungen, unter denen Laboruntersuchungen geplant, durchgeführt, überwacht, aufgezeichnet und berichtet werden. [ ] Untersuchungen zur systemischen Toxizität müssen nach solchen Prinzipien geführt werden." 3 EN ISO :2009 (Section 4.6): "Alle Prüfungen müssen nach anerkannten üblichen/gültigen besten Labor-/qualitätsbezogenen Praktiken, zum Beispiel "Gute Laborpraxis" (GLP) oder ISO/IEC 17025, wenn anwendbar, durchgeführt werden" 2

3 authority or EMA regarding the medicinal product and is bound by the assessment report of the receiving authority or EMA. GLP might apply according to Directive 2001/83/EC. 2. FUTURE SITUATION UNDER THE NEW MEDICAL DEVICE REGULATION The new Regulation on Medical Devices (adoption pending) contains an explicit and legally binding reference to the principles of GLP pursuant to Directive 2004/10/EC: Where applicable, conformity with the provisions of Directive 2004/10/EC of the European Parliament and of the Council of 11 February 2004 on the harmonisation of laws, regulations and administrative provisions relating to the application of the principles of good laboratory practice and the verification of their applications for tests on chemical substances shall be demonstrated. According to the proposed new Regulation requirements for conformity assessment appear to be very similar to the preceding MD legislation (EN ISO remains relevant in biological safety assessment). Interinstitutional File: 2012/0266 (COD): "To recognise the important role of standardisation in the field of medical devices, compliance with harmonised standards as defined in Regulation (EU) No 1025/2012 of the European Parliament and of the Council of 25 October 2012 on European standardisation, amending Council Directives 89/686/EEC and 93/15/EEC and Directives 94/9/EC, 94/25/EC, 95/16/EC, 97/23/EC, 98/34/EC, 2004/22/EC, 2007/23/EC, 2009/23/EC and 2009/105/EC of the European Parliament and of the Council and repealing Council Decision 87/95/EEC and Decision No 1673/2006/EC of the European Parliament and of the Council should be a means for manufacturers to demonstrate conformity with the general safety and performance requirements and other legal requirements, such as quality and risk management." 3. CONCLUSION According to the current legislation, GLP is required for certain types of testing in biological safety assessment pursuant to the harmonised standard. GLP is formally not mandatory, but alternatives have to be justified. Pursuant to the new Regulation, GLP is mandatory for tests on chemical substances. As the requirements for conformity assessment will be very similar to the preceding MD legislation GLP is required for testing in biological safety assessment pursuant to EN ISO The standard foresees the application of GLP to tests on systemic toxicity, genotoxicity, carcinogenicity and reproductive toxicity. GLP covers a wide range of testing in an equivalent way to pharmaceutical substances (please note that this document contains a non-exhaustive overview of the GLP requirements in the EN ISO standard - There could be more). For non-combination products and the device part of medical device combination products, it is the responsibility of the notified body / manufacturer to apply ISO

4 in the conformity assessment, interpret it in combination with the new Regulation and decide what kind of testing and if GLP is required. Notified bodies will have a key role and could be a bottleneck if not sensitive for the issue. If a test facility claims GLP and if it is producing data relevant in the conformity assessment of a medical device such test facility should be GLP certified by the competent GLP monitoring authority. 4. DISCUSSION TOPICS Types of tests, for which GLP is required: Is the list in EN ISO comprehensive? Types of devices, for which GLP toxicity testing is required: Is the table in EN ISO (listing different types of devices, different kinds of exposure, etc.) comprehensive? Is it necessary to have a comprehensive list of tests? Might it be sufficient to have generic rules in order to deduct the kind of testing that requires GLP? Procedural aspects for GLP MA: If the choice of the sponsor, the medical device manufacturer or the GLP test facility is to conduct non-clinical safety studies on a medical device in compliance with GLP, should the test facility be inspected? Procedural aspects for NB: How to ensure that notified bodies (can) verify the GLP status of the test facility? 4

5 Annex: Requirements for systemic toxicity testing for different devices (from EN ISO :2009) 5