ISO10993-6-2009医疗器械生物学评价――第6部分：植入后局部反应试验

1、BS EN ISO 10993-6:2009ICS 11.100.20NO COPYING WITHOUT BSI PERMISSION EXCEPT AS PERMITTED BY COPYRIGHT LAW BRITISH STANDARDBiological evaluation of medical devicesPart 6: Tests for local effects after implantation (ISO 10993-6:2007 This British Standard was published under the authority of the Standa

2、rds Policy and Strategy Committee on 30 June 2009.© BSI 2009ISBN 978 0 580 65662 0Amendments/corrigenda issued since publication Date CommentsBS EN ISO 10993-6:2009National forewordThis British Standard is the UK implementation of EN ISO10993-6:2009. It is identical to ISO 10993-6:2007. It supe

3、rsedes BS ENISO 10993-6:2007 which is withdrawn.The UK participation in its preparation was entrusted to TechnicalCommittee CH/194, Biological evaluation of medical devices.A list of organizations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 be obtained onrequest to its secretary.This publication does not purp

4、ort to include all the necessary provisionsof a contract. Users are responsible for its correct application.Compliance with a British Standard cannot confer immunityfrom legal obligations.EUROPEAN STANDARD NORME EUROPÉENNE EUROPÄISCHE NORM EN ISO 10993-6 May 2009ICS 11.100.20Supersedes EN

5、ISO 10993-6:2007English VersionBiological evaluation of medical devices - Part 6: Tests for localeffects after implantation (ISO 10993-6:2007Évaluation biologique des dispositifs médicaux - Partie 6: Essais concernant les effets locaux après implantation(ISO 10993-6:2007Biologische Be

6、urteilung von Medizinprodukten - Teil 6: Prüfungen auf lokale Effekte nach Implantationen (ISO10993-6:2007This European Standard was approved by CEN on 28 April 2009.CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this European

7、 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 Management Centre or to any CEN member.This European Standard exists in three official versions (English, F

8、rench, 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 Management Centre has the same status as the official versions.CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Cyprus

9、, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.EUROPEAN COMMITTEE FOR STANDARDIZATIONC O M

10、I TÉE U R O PÉE NDE N O R M A LI S A T I O NEUR OPÄIS C HES KOM ITEE FÜR NOR M UNGManagement Centre: Avenue Marnix 17, B-1000 Brussels© 2009 CEN All rights of exploitation in any form and by any means reservedworldwide for CEN national Members.Ref. No. EN ISO 10993-6:2009: E

11、BS EN ISO 10993-6:2009EN ISO 10993-6:2009 (EForewordThe text of ISO 10993-6:2007 has been prepared by Technical Committee ISO/TC 194 “Biological evaluation of medical devices” of the International Organization for Standardization (ISO and has been taken over as EN ISO 10993-6:2009 by Technical Commi

12、ttee 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 November 2009, and conflicting national standards

13、 shall be withdrawn at the latest by March 2010.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 10993-6

14、:2007.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 93/42/EEC on Medical Devices and 90/385/EEC on Active Implantable Medical Devices.For relationship with EU Direc

15、tives, see informative Annex ZA and ZB, which is an integral part of this 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, Cyprus, Czech Republic, Den

16、mark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and the United Kingdom.Endorsement noticeThe text of ISO 10993-6:2007 has been appro

17、ved by CEN as a EN ISO 10993-6:2009 without any modification.3BS EN ISO 10993-6:2009EN ISO 10993-6:2009 (E4 Annex ZA(informativeRelationship between this European Standard and the Essential Requirements ofEU Directive 93/42/EEC on Medical DevicesThis European Standard has been prepared under a manda

18、te given 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 Communities under that Directiv

19、e and has been implemented as a national standard in at least one Member State, compliance with the clauses of this standard given in table ZA confers, within the limits of the scope of this standard, a presumption of conformity with the corresponding Essential Requirements of that Directive and ass

20、ociated EFTA regulations.Table ZA Correspondence between this European Standard and Directive 93/42/EEC on medicaldevices Clause(s/sub-clause(s of this EN Essential Requirements (ERs of Directive 93/42/EECQualifying remarks/Notes4, 5, 6 & Annexes B,C, DAnnex I: 7.1, 7.2, 7.5WARNING Other require

21、ments and other EU Directives may be applicable to the product(s falling within the scope of this standard.EN ISO 10993-6:2009 (E 5Annex ZB(informativeRelationship between this European Standard and the Essential Requirements ofEU Directive 90/385/EEC on Active Implantable Medical DevicesThis Europe

22、an 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 Essential Requirements of the New Approach Directive 90/385/EEC on active implantable medical devices.Once this standard is cited in the O

23、fficial Journal of the European Communities under that Directive and has been implemented as a national standard in at least one Member State, compliance with the clauses of this standard given in table ZB confers, within the limits of the scope of this standard, a presumption of conformity with the

24、 corresponding Essential Requirements of that Directive and associated EFTA regulations.Table ZB Correspondence between this European Standard and Directive 90/385/EEC on activeimplantable medical devicesClause(s/sub-clause(s of this EN Essential Requirements (ERs of Directive 90/385/EECQualifying r

25、emarks/Notes4, 5, 6 & Annex B, C, D Annex I :9WARNING Other requirements and other EU Directives may be applicable to the product(s falling within the scope of this standard.ISO 10993-6:2007(EContents PageForeword (iv1Scope (12Normative references (13Terms and definitions (24Common provisions fo

26、r implantation test methods (24.1General (24.2Preparation of specimens for implantation (25Test methods, general aspects (35.1Tissue and implantation site (35.2Animals (35.3Test periods (45.4Surgery and testing conditions (55.5Evaluation (66Test report (8Annex A (informative General considerations r

27、egarding implantation periods and tissue responses to degradable/resorbable materials (9Annex B (normative Test methods for implantation in subcutaneous tissue (10Annex C (normative Test method for implantation in muscle (12Annex D (normative Test method for implantation in bone (14Annex E (informat

28、ive Examples of evaluation of local biological effects after implantation (17Bibliography (19© ISO 2007 All rights reserved iiiISO 10993-6:2007(EForewordISO (the International Organization for Standardization is a worldwide federation of national standards bodies (ISO member bodies. The work of

29、 preparing 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

30、, in liaison with ISO, also take part in the work. ISO collaborates closely with the International Electrotechnical Commission (IEC on all matters of electrotechnical standardization.International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.The main tas

31、k of technical committees is to prepare International Standards. Draft International Standards adopted by the technical committees are circulated to the member bodies for voting. Publication as an International Standard requires approval by at least 75 % of the member bodies casting a vote.Attention

32、 is drawn to the possibility that some 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.ISO 10993-6 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices.This secon

33、d edition cancels and replaces the first edition (ISO 10993-6:1994 which has been technically revised.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 systemPart 2: Animal welfare requi

34、rementsPart 3: Tests for genotoxicity, carcinogenicity and reproductive toxicityPart 4: Selection of tests for interactions with bloodPart 5: Tests for in vitro cytotoxicityPart 6: Tests for local effects after implantationPart 7: Ethylene oxide sterilization residualsPart 9: Framework for identific

35、ation and quantification of potential degradation productsPart 10: Tests for irritation and delayed-type hypersensitivityPart 11: Tests for systemic toxicityPart 12: Sample preparation and reference materialsPart 13: Identification and quantification of degradation products from polymeric medical de

36、vicesPart 14: Identification and quantification of degradation products from ceramicsPart 15: Identification and quantification of degradation products from metals and alloysiv © ISO 2007 All rights reservedISO 10993-6:2007(EPart 16: Toxicokinetic study design for degradation products and leach

37、ablesPart 17: Establishment of allowable limits for leachable substancesPart 18: Chemical characterization of materialsPart 19: Physico-chemical, morphological and topographical characterization of materialsPart 20: Principles and methods for immunotoxicology testing of medical devicesFor the purpos

38、es of this part of ISO 10993 the CEN annex regarding fulfilment of European Council Directives will be removed at publication stage.© ISO 2007 All rights reserved vINTERNATIONAL STANDARD ISO 10993-6:2007(EBiological evaluation of medical devices Part 6:Tests for local effects after implantation

39、1 ScopeThis part of ISO 10993 specifies test methods for the assessment of the local effects after implantation of biomaterials intended for use in medical devices.This part of ISO 10993 applies to materials that are:solid and non-biodegradable;degradable and/or resorbable;non-solid, such as porous

40、materials, liquids, pastes and particulates.The test specimen is implanted into a site and animal species appropriate for the evaluation of the biological safety of the material. These implantation tests are not intended to evaluate or determine the performance of the test specimen in terms of mecha

41、nical or functional loading. This part of ISO 10993 may also be applied to medical devices that are intended to be used topically in clinical indications where the surface or lining may have been breached, in order to evaluate local tissue responses.The local effects are evaluated by a comparison of

42、 the tissue response caused by a test specimen to that caused by control materials used in medical devices of which the clinical acceptability and biocompatibility characteristics have been established. The objective of the test methods is to characterize the history and evolution of the tissue resp

43、onse after implantation of a medical device/biomaterial including final integration or resorption/degradation of the material. In particular for degradable/resorbable materials the degradation characteristics of the material and the resulting tissue response should be determined.This part of ISO 109

44、93 does not deal with systemic toxicity, carcinogenicity, teratogenicity or mutagenicity. However, the long-term implantation studies intended for evaluation of local biological effects may provide insight into some of these properties. Systemic toxicity studies conducted by implantation may satisfy

45、 the requirements of this part of ISO 10993.2 Normative referencesThe following referenced documents are indispensable for the application of this document. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amen

46、dments applies.ISO 10993-1:2003, Biological evaluation of medical devices Part 1: Evaluation and testing within a risk management systemISO 10993-2, Biological evaluation of medical devices Part 2: Animal welfare requirementsISO 10993-11, Biological evaluation of medical devices Part 11: Tests for s

47、ystemic toxicityISO 10993-6:2007(EISO 10993-12, Biological evaluation of medical devices Part 12: Sample preparation and reference materialsISO 10993-16, Biological evaluation of medical devices Part 16: Toxicokinetic study design for degradation products and leachables3 Terms and definitionsFor the

48、 purposes of this document, the terms and definitions given in ISO 10993-1, ISO 10993-2, ISO 10993-12, ISO 10993-16 and the following apply.3.1degradationdecomposition of a materialISO 10993-9:1999, definition 3.13.2degradation productproduct of a material which is generated by the chemical breakdow

49、n or decomposition of the materialISO 10993-16:1997, definition 3.13.3biomaterialmaterial intended to interface with biological systems to evaluate, treat, augment or replace any tissue, organ or function of the bodyTaken from European Society Biomaterials Conference II4 Common provisions for implan

50、tation test methods4.1 GeneralIt is important that the study be planned in sufficient detail such that all relevant information can be extracted from the use of each animal and each study (see ISO 10993-2, ISO 10993-11 and ISO 10993-16.All animal studies shall be performed in a facility approved by

51、a nationally recognised organization and in accordance with all appropriate regulations dealing with laboratory animal welfare. These studies shall be performed under good laboratory practices or other recognized quality assurance systems, and comply with the requirements of ISO 10993-2.The provisio

52、ns of this clause shall apply to the test methods described in Annexes B, C and D.4.2 Preparation of specimens for implantationTest sample and reference or control material preparation shall be in compliance with ISO 10993-12. The implant size and shape shall be documented and justified. Test specim

53、ens for various implant sites are described in Annexes B, C and D. Physical characteristics (such as form, density, hardness, surface can influence the character of the tissue response to the test material and shall be recorded and taken into account when the response is characterized.Each implant s

54、hall be manufactured, processed, cleaned of contaminants and sterilized by the method intended for the final product and this shall be confirmed in the study documentation. After final preparation and sterilization, the implant specimens shall be handled aseptically and in such a way as to ensure th

55、at they are not damaged or contaminated in any way prior to or during implantation.ISO 10993-6:2007(E For materials used as scaffolds for tissue-engineered medical products, it may be appropriate not to use the final preparation pre-populated with cells, as the immune reaction of the animal to the c

56、ellular components of such products and the reaction of the cells to the animal, may interfere with the resulting local tissue response. For composite materials (e.g. bone cements, dental materials, the components may be mixed before use and allowed to set before implantation. However, materials tha

57、t are designed for use in devices with in situ polymerization shall be introduced in a manner such that in situ polymerization occurs. For certain types of study other procedures may be used. The procedure used shall be documented and justified.Non-solid materials (including powders may be contained

58、 in open-ended cylindrical tubes for the purpose of testing for local effects after implantation (see ISO 10993-12 for the selection of materials for tubes. Prepare the test material according to the manufacturers instructions and insert the material into the tube until level with the end, taking care not to contaminate the outer surface of the tube with the test material; if contamination occurs the sample shall not be implanted. Avoid entrapment of air in the tube and ensure that the end surfaces of the inserted material in the tube and the tube ends are smooth.NOTE