DIN EN ISO 10993-3-2015 Biological evaluation of medical devices - Part 3 Tests for genotoxicity carcinogenicity and reproductive toxicity (ISO 10993-3 2014) German version EN ISO .pdf

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1、February 2015 Translation by DIN-Sprachendienst.English price group 18No part of this translation may be reproduced without prior permission ofDIN Deutsches Institut fr Normung e. V., Berlin. Beuth Verlag GmbH, 10772 Berlin, Germany,has the exclusive right of sale for German Standards (DIN-Normen).I

2、CS 11.100.20!%B#“2293100www.din.deDDIN EN ISO 10993-3Biological evaluation of medical devices Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity(ISO 10993-3:2014);English version EN ISO 10993-3:2014,English translation of DIN EN ISO 10993-3:2015-02Biologische Beurteilung von M

3、edizinprodukten Teil 3: Prfungen auf Gentoxizitt, Karzinogenitt und Reproduktionstoxizitt(ISO 10993-3:2014);Englische Fassung EN ISO 10993-3:2014,Englische bersetzung von DIN EN ISO 10993-3:2015-02valuation biologique des dispositifs mdicaux Partie 3: Essais concernant la gnotoxicit, la cancrognicit

4、 et la toxicit sur lareproduction (ISO 10993-3:2014);Version anglaise EN ISO 10993-3:2014,Traduction anglaise de DIN EN ISO 10993-3:2015-02SupersedesDIN EN ISO 10993-3:2009-08www.beuth.deDocument comprises 45 pagesIn case of doubt, the German-language original shall be considered authoritative.01.15

5、 DIN EN ISO 10993-3:2015-02 2 A comma is used as the decimal marker. National foreword This standard has been prepared by Technical Committee ISO/TC 194 “Biological evaluation of medical devices” in collaboration with Technical Committee CEN/TC 206 “Biological evaluation of medical devices” (Secreta

6、riat: NEN, Netherlands). The responsible German body involved in its preparation was the DIN-Normenausschuss Feinmechanik und Optik (DIN Standards Committee Optics and Precision Mechanics), Working Committee NA 027-02-12 AA Biologische Beurteilung von Medizinprodukten. EN ISO 10993 consists of the f

7、ollowing parts, under the general title Biological evaluation of medical devices: Part 1: Evaluation and testing within a risk management system Part 2: Animal welfare requirements Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity Part 4: Selection of tests for interactions w

8、ith 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 products Part 10: Tests for irritation and skin sensitization Part 11:

9、Tests for systemic toxicity Part 12: Sample preparation and reference materials Part 13: Identification and quantification of degradation products from polymeric medical devices Part 14: Identification and quantification of degradation products from ceramics Part 15: Identification and quantificatio

10、n of degradation products from metals and alloys Part 16: Toxicokinetic study design for degradation products and leachables Part 17: Establishment of allowable limits for leachable substances Part 18: Chemical characterization of materials This standards series includes the following Technical Spec

11、ifications which have not been published as DIN EN ISO Standards: ISO/TS 10993-19, Physico-chemical, morphological and topographical characterization of materials ISO/TS 10993-20, Principles and methods for immunotoxicology testing of medical devices DIN EN ISO 10993-3:2015-02 3 The DIN Standards co

12、rresponding to the International Standards referred to in Clause 2 of this standard are as follows: ISO 10993-1 DIN EN ISO 10993-1 ISO 10993-2 DIN EN ISO 10993-2 ISO 10993-6 DIN EN ISO 10993-6 ISO 10993-12 DIN EN ISO 10993-12 ISO 10993-18 DIN EN ISO 10993-18 Amendments This standard differs from DIN

13、 EN ISO 10993-3:2009-08 as follows: a) the test strategy has been changed by inclusion of an in vivo test and a follow-up evaluation; b) an informative Annex A “Guidance on selecting an appropriate sample preparation procedure in genotoxicity testing” has been added; c) further in-vitro and in-vivo

14、tests for evaluating the genotoxic potential of medical devices have been included; d) an informative Annex B “Flowchart for follow-up evaluation” has been added; e) Annex E has been changed “Considerations for carcinogenicity studies performed as implantation studies” and made normative; f) an info

15、rmative Annex F “In-vitro tests for embryo toxicity” has been added. Previous editions DIN EN 30993-3: 1994-03 DIN EN ISO 10993-3: 2004-02, 2009-08 DIN EN ISO 10993-3:2015-02 4 National Annex NA (informative) Bibliography DIN EN ISO 10993-1, Biological evaluation of medical devices Part 1: Evaluatio

16、n and testing within a risk management system DIN EN ISO 10993-2, Biological evaluation of medical devices Part 2: Animal welfare requirements DIN EN ISO 10993-6, Biological evaluation of medical devices Part 6: Tests for local effects after implantation DIN EN ISO 10993-12, Biological evaluation of

17、 medical devices Part 12: Sample preparation and reference materials DIN EN ISO 10993-18, Biological evaluation of medical devices Part 18: Chemical characterization of materials EUROPEAN STANDARD NORME EUROPENNE EUROPISCHE NORM EN ISO 10993-3 October 2014 ICS 11.100.20 Supersedes EN ISO 10993-3:200

18、9English Version 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 109

19、93-3:2014) Biologische 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 stipu

20、late the conditions 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 S

21、tandard exists 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

22、national standards 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,

23、 Slovakia, Slovenia, 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

24、 means reserved worldwide for CEN national Members. Ref. No. EN ISO 10993-3:2014 EContents PageForeword .3Introduction .41 Scope . 52 Normative references 53 Terms and definitions . 64 Requirements for test strategies . 64.1 General . 64.2 Additional requirements for carcinogenicity testing . 74.3 A

25、dditional requirements for reproductive toxicity testing . 75 Genotoxicity tests 85.1 General . 85.2 Test strategy 85.3 Sample preparation . 106 Carcinogenicity tests . 116.1 General 116.2 Evaluation strategy . 116.3 Sample preparation . 126.4 Test methods 127 Reproductive and developmental toxicity

26、 tests 137.1 General 137.2 Test strategy . 137.3 Sample preparation . 147.4 Test methods 148 Test report 15Annex A (informative) Guidance on selecting an appropriate sample preparation procedure in genotoxicity testing 16Annex B (informative) Flowchart for follow-up evaluation .24Annex C (informativ

27、e) Rationale of test systems 25Annex D (informative) Cell transformation test systems .27Annex E (normative) Considerations for carcinogenicity studies performed as implantation studies .28Annex F (informative) In vitro tests for embryo toxicity.29Bibliography .34Annex ZA (informative) Relationship

28、between this European Standard and the Essential Requirements of EU Directive 93/42 EEC on medical devices 31 Annex ZB (informative) Relationship between this European Standard and the Essential Requirements of EU Directive 90/385/EEC on active implantable medical devices 33 DIN EN ISO 10993-3:2015-

29、02 EN ISO 10993-3:2014 (E) 2Foreword 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 Technical Committee CEN/TC 206 “Biological evaluation of medical devices” the secretariat of whic

30、h 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 standards shall be withdrawn at the latest by April 2015. Attention is drawn to the possibili

31、ty 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 10993-3:2009. This document has been prepared under a mandate given to CEN by the Europea

32、n 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 document. According to the CEN-CENELEC Internal Regulations, the national standards organ

33、izations 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, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg,

34、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 EN ISO 10993-3:2014 without any modification. DIN EN ISO 10993-3:2015-02 EN ISO 10993-3:20

35、14 (E) 3 IntroductionThe basis for biological evaluation of medical devices is often empirical and driven by the relevant concerns for human safety. The risk of serious and irreversible effects, such as cancer or second generation abnormalities, is of particular public concern. It is inherent in the

36、 provision of safe medical devices that such risks be minimised to the greatest extent feasible. The assessment of mutagenic, carcinogenic and reproductive hazards is an essential component of the control of these risks. Not all test methods for the assessment of genotoxicity, carcinogenicity or rep

37、roductive toxicity are equally well developed, nor is their validity well established for the testing of medical devices.Significant issues with test sample size and preparation, scientific understanding of disease processes and test validation can be cited as limitations of available methods. For e

38、xample, the biological significance of solid state carcinogenesis is poorly understood. It is expected that on-going scientific and medical advances will improve our understanding of and approaches to these important toxicological effects. At the time this document was prepared, the test methods pro

39、posed were those most acceptable. Scientifically sound alternatives to the proposed testing may be acceptable insofar as they address relevant matters of safety assessment.In the selection of tests needed to evaluate a particular medical device, there is no substitute for a careful assessment of exp

40、ected human uses and potential interactions of the medical device with various biological systems. These considerations will be particularly important in such areas as reproductive and developmental toxicology.This part of ISO 10993 presents test methods for the detection of specific biological haza

41、rds, and strategies for the selection of tests, where appropriate, that will assist in hazard identification. Testing is not always necessary or helpful in managing toxicological risks associated with exposure to medical device materials but, where it is appropriate, it is important that maximum tes

42、t sensitivity is achieved.In view of the multitude of possible outcomes and the importance of factors such as extent of exposure, species differences and mechanical or physical considerations, risk assessment have to be performed on a case-by-case basis.DIN EN ISO 10993-3:2015-02 EN ISO 10993-3:2014

43、 (E) 4 1 ScopeThis part of ISO 10993 specifies strategies for risk estimation, selection of hazard identification tests and risk management, with respect to the possibility of the following potentially irreversible biological effects arising as a result of exposure to medical devices: genotoxicity;

44、carcinogenicity; reproductive and developmental toxicity.This part of ISO 10993 is applicable when the need to evaluate a medical device for potential genotoxicity, carcinogenicity, or reproductive toxicity has been established.NOTE Guidance on selection of tests is provided in ISO 10993-1.2 Normati

45、ve referencesThe following documents, in whole or in part, are normatively referenced in this document and are indispensable for its application. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amendments) app

46、lies.ISO 10993-1, Biological evaluation of medical devices Part 1: Evaluation and testing within a risk management processISO 10993-2, Biological evaluation of medical devices Part 2: Animal welfare requirementsISO 10993-6, Biological evaluation of medical devices Part 6: Tests for local effects aft

47、er implantationISO 10993-12, Biological evaluation of medical devices Part 12: Sample preparation and reference materialsISO 10993-18, Biological evaluation of medical devices Part 18: Chemical characterization of materialsOECD 414, Prenatal Development Toxicity StudyOECD 415, One-Generation Reprodu

48、ction Toxicity StudyOECD 416, Two-generation Reproduction ToxicityOECD 421, Reproduction/Developmental Toxicity Screening TestOECD 451, Carcinogenicity StudiesOECD 453, Combined Chronic Toxicity/Carcinogenicity StudiesOECD 471, Bacterial Reverse Mutation TestOECD 473, In vitro Mammalian Chromosome Aberration TestDIN