1、BSI Standards PublicationBS EN ISO 10993-3:2014Biological evaluation ofmedical devicesPart 3: Tests for genotoxicity, carcinogenicityand reproductive toxicityBS EN ISO 10993-3:2014 BRITISH STANDARDNational forewordThis British Standard is the UK implementation of EN ISO10993-3:2014. It supersedes BS
2、 EN ISO 10993-3:2009 which iswithdrawn.The UK participation in its preparation was entrusted to TechnicalCommittee CH/194, Biological evaluation of medical devices.A list of organizations represented on this committee can beobtained on request to its secretary.This publication does not purport to in
3、clude all the necessaryprovisions of a contract. Users are responsible for its correctapplication. The British Standards Institution 2014. Published by BSI StandardsLimited 2014ISBN 978 0 580 69691 6ICS 11.100.20Compliance with a British Standard cannot confer immunity fromlegal obligations.This Bri
4、tish Standard was published under the authority of theStandards Policy and Strategy Committee on 31 October 2014.Amendments issued since publicationDate Text affectedEUROPEAN STANDARD NORME EUROPENNE EUROPISCHE NORM EN ISO 10993-3 October 2014 ICS 11.100.20 Supersedes EN ISO 10993-3:2009English Vers
5、ion Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity (ISO 10993-3:2014) valuation biologique des dispositifs mdicaux - Partie 3: Essais concernant la gnotoxicit, la cancrognicit et la toxicit sur la reproduction (ISO 10993-3:2014) B
6、iologische Beurteilung von Medizinprodukten - Teil 3: Prfungen auf Gentoxizitt, Karzinogenitt und Reproduktionstoxizitt (ISO 10993-3:2014) This European Standard was approved by CEN on 6 September 2014. CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the con
7、ditions for giving this European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references concerning such national standards may be obtained on application to the CEN-CENELEC Management Centre or to any CEN member. This European Standard exis
8、ts in three official versions (English, French, German). A version in any other language made by translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management Centre has the same status as the official versions. CEN members are the national sta
9、ndards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, Former Yugoslav Republic of Macedonia, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, S
10、lovenia, Spain, Sweden, Switzerland, Turkey and United Kingdom. EUROPEAN COMMITTEE FOR STANDARDIZATION COMIT EUROPEN DE NORMALISATION EUROPISCHES KOMITEE FR NORMUNG CEN-CENELEC Management Centre: Avenue Marnix 17, B-1000 Brussels 2014 CEN All rights of exploitation in any form and by any means reser
11、ved worldwide for CEN national Members. Ref. No. EN ISO 10993-3:2014 EBS EN ISO 10993-3:2014EN ISO 10993-3:2014 (E) 3 Foreword This document (EN ISO 10993-3:2014) has been prepared by Technical Committee ISO/TC 194 “Biological and clinical evaluation of medical devices“ in collaboration with Technic
12、al Committee CEN/TC 206 “Biological evaluation of medical devices” the secretariat of which is held by NEN. This European Standard shall be given the status of a national standard, either by publication of an identical text or by endorsement, at the latest by April 2015, and conflicting national sta
13、ndards shall be withdrawn at the latest by April 2015. Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights. CEN and/or CENELEC shall not be held responsible for identifying any or all such patent rights. This document supersedes EN ISO
14、 10993-3:2009. This document has been prepared under a mandate given to CEN by the European Commission and the European Free Trade Association, and supports essential requirements of EU Directives. For relationship with EU Directives, see informative Annex ZA and ZB, which are integral parts of this
15、 document. According to the CEN-CENELEC Internal Regulations, the national standards organizations of the following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, Former Yugoslav Republic of Macedonia,
16、France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and the United Kingdom. Endorsement notice The text of ISO 10993-3:2014 has been approved by CEN as
17、EN ISO 10993-3:2014 without any modification. BS EN ISO 10993-3:2014EN ISO 10993-3:2014 (E) 4 Annex ZA (informative) Relationship between this European Standard and the Essential Requirements of EU Directive 93/42 EEC on medical devices This European Standard has been prepared under a mandate given
18、to CEN by the European Commission and the European Free Trade Association to provide a means of conforming to Essential Requirements of the New Approach Directive 93/42 EEC on medical devices. Once this standard is cited in the Official Journal of the European Union under that Directive and has been
19、 implemented as a national standard in at least one Member State, compliance with the clauses of this standard given in Table ZA.1 confers, within the limits of the scope of this standard, a presumption of conformity with the corresponding Essential Requirements of that Directive and associated EFTA
20、 regulations. Table ZA.1 Correspondence between this European Standard and Directive 93/42/EEC on medical devices Essential Requirements (ERs) of Directive 93/42/EEC Clause(s)/sub-clause(s) of this EN Qualifying remarks/Notes 7.1 (First and second indent) 4, 5, 6 and 7 ER 7.1 is only partly covered
21、by ISO 10993-3, since the standard does not provide requirements on design and manufacture. However, this standard provides a means to evaluate genotoxicity, carcinogenicity or reproductive toxicity risks associated with the materials which are used. 7.2 4, 5, 6 and 7 ER 7.2 is not covered by ISO 10
22、993-3, since the standard does not provide requirements on design and manufacture and does not oblige to minimize risk. However, this standard provides a means to evaluate genotoxicity, carcinogenicity or reproductive toxicity. This evaluation can be a preliminary step for risk minimization. Other f
23、orms of toxicity and flammability are not dealt with in this standard. 7.5 (First paragraph) 4, 5, 6 and 7 ER 7.5 is not covered by ISO 10993-3, since the standard does not provide requirements on design, manufacture and packaging and does not oblige to minimize risk. BS EN ISO 10993-3:2014EN ISO 10
24、993-3:2014 (E) 5 However, this standard provides a means to evaluate genotoxicity, carcinogenicity or reproductive toxicity. This evaluation can be a preliminary step for risk minimization. Other forms of toxicity and flammability are not dealt with in this standard. General Note: Presumption of con
25、formity depends on also complying with all relevant clauses/subclauses of ISO 10993-1. WARNING Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this standard. BS EN ISO 10993-3:2014EN ISO 10993-3:2014 (E) 6 Annex ZB (informative) Relationship
26、 between this European Standard and the Essential Requirements of EU Directive 90/385/EEC on active implantable medical devices This European Standard has been prepared under a mandate given to CEN by the European Commission and the European Free Trade Association to provide a means of conforming to
27、 Essential Requirements of the New Approach Directive 90/385 EEC on active implantable medical devices. Once this standard is cited in the Official Journal of the European Union under that Directive and has been implemented as a national standard in at least one Member State, compliance with the cla
28、uses of this standard given in Table ZB.1 confers, within the limits of the scope of this standard, a presumption of conformity with the corresponding Essential Requirements of that Directive and associated EFTA regulations. Table ZB.1 Correspondence between this European Standard and Directive 90/3
29、85/EEC on active implantable medical devices Essential Requirements (ERs) of Directive 90/385/EEC Clause(s)/sub-clause(s) of this EN Qualifying remarks/Notes 9 (First and second indent) 4, 5, 6 and 7 ER 9 is only partly covered by ISO 10993-3, since the standard does not provide requirements on desi
30、gn and manufacture. However, this standard provides a means to assess genotoxicity,carcinogenicity or reproductive toxicity used in the manufacture of medical devices. Other forms of toxicity are not covered. General Note: Presumption of conformity depends on also complying with all relevant clauses
31、/subclauses of ISO 10993-1. WARNING Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this standard. BS EN ISO 10993-3:2014ISO 10993-3:2014(E) ISO 2014 All rights reserved iiiContents PageForeword ivIntroduction vi1 Scope . 12 Normative refere
32、nces 13 Terms and definitions . 24 Requirements for test strategies . 24.1 General . 24.2 Additional requirements for carcinogenicity testing . 34.3 Additional requirements for reproductive toxicity testing . 35 Genotoxicity tests 45.1 General . 45.2 Test strategy 45.3 Sample preparation 66 Carcinog
33、enicity tests 76.1 General . 76.2 Evaluation strategy 76.3 Sample preparation 86.4 Test methods . 87 Reproductive and developmental toxicity tests . 97.1 General . 97.2 Test strategy 97.3 Sample preparation . 107.4 Test methods 108 Test report 11Annex A (informative) Guidance on selecting an appropr
34、iate sample preparation procedure in genotoxicity testing 12Annex B (informative) Flowchart for follow-up evaluation .20Annex C (informative) Rationale of test systems 21Annex D (informative) Cell transformation test systems .23Annex E (normative) Considerations for carcinogenicity studies performed
35、 as implantation studies .24Annex F (informative) In vitro tests for embryo toxicity.25Bibliography .27BS EN ISO 10993-3:2014ISO 10993-3:2014(E)ForewordISO (the International Organization for Standardization) is a worldwide federation of national standards bodies (ISO member bodies). The work of pre
36、paring International Standards is normally carried out through ISO technical committees. Each member body interested in a subject for which a technical committee has been established has the right to be represented on that committee. International organizations, governmental and non-governmental, in
37、 liaison with ISO, also take part in the work. ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.The procedures used to develop this document and those intended for its further maintenance are described in the ISO/IEC
38、 Directives, Part 1. In particular the different approval criteria needed for the different types of ISO documents should be noted. This document was drafted in accordance with the editorial rules of the ISO/IEC Directives, Part 2. www.iso.org/directivesAttention is drawn to the possibility that som
39、e of the elements of this document may be the subject of patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of any patent rights identified during the development of the document will be in the Introduction and/or on the ISO list of patent declara
40、tions received. www.iso.org/patentsAny trade name used in this document is information given for the convenience of users and does not constitute an endorsement.The committee responsible for this document is ISO/TC 194.This third edition of ISO 10993-3 cancels and replaces the second edition (ISO 10
41、993-3:2003), which has been technically revised.The major technical changes are the following:a) test strategy changed by inclusion of a in vivo test and a follow-up evaluation;b) new Annex A ” Guidance on selecting an appropriate sample preparation procedure in genotoxicity testing” included;c) Inc
42、lusion of further in vitro and in vivo test for evaluating the genotoxic potential of medical devices;d) new Annex B “Flowchart for follow-up evaluation” included;e) Annex E changed to “Considerations for carcinogenicity studies performed as implantation studies” and made normative;f) new Annex F “I
43、n vitro tests for embryo toxicity” included.ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices: Part 1: Evaluation and testing within a risk management process Part 2: Animal welfare requirements Part 3: Tests for genotoxicity, carcinogenicity
44、 and reproductive toxicity Part 4: Selection of tests for interactions with blood Part 5: Tests for in vitro cytotoxicity Part 6: Tests for local effects after implantation Part 7: Ethylene oxide sterilization residuals Part 9: Framework for identification and quantification of potential degradation
45、 products Part 10: Tests for irritation and skin sensitizationiv ISO 2014 All rights reservedBS EN ISO 10993-3:2014ISO 10993-3:2014(E) Part 11: Tests for systemic toxicity Part 12: Sample preparation and reference materials Part 13: Identification and quantification of degradation products from poly
46、meric medical devices Part 14: Identification and quantification of degradation products from ceramics Part 15: Identification and quantification of degradation products from metals and alloys Part 16: Toxicokinetic study design for degradation products and leachables Part 17: Establishment of allow
47、able limits for leachable substances Part 18: Chemical characterization of materials Part 19: Physico-chemical, morphological and topographical characterization of materials Technical specification Part 20: Principles and methods for immunotoxicology testing of medical devices Technical specificatio
48、nThe following part is under preparation: Part 33: Supplement to ISO 10993-3: Guidance on tests to evaluate genotoxicity Technical ReportThe following definitions apply in understanding how to implement an ISO International Standard and other normative ISO deliverables (TS, PAS, IWA): “shall” indica
49、tes a requirement; “should” indicates a recommendation; “may” is used to indicate that something is permitted; “can” is used to indicate that something is possible, for example, that an organization or individual is able to do something.ISO/IEC Directives, Part 2 (sixth edition, 2011), 3.3.1, defines a requirement as an “expression in the content of a document conveying criteria to be fulfilled if compliance with the document is to be claimed and from which no deviation is permitted.”ISO/IEC Directives, Part 2 (sixth edition,
