1、ANSI/AAMI/ISO 10993-3: 2014Biological evaluation of medical devices Part 3: Tests for genotoxicity, carcinogenicity, and reproductive toxicityAmerican National StandardAmerican National Standard ANSI/AAMI/ISO 10993-3:2014 (Revision of ANSI/AAMI/ISO 10993-3:2003/(R)2009) Biological evaluation of medi
2、cal devices Part 3: Tests for genotoxicity, carcinogenicity, and reproductive toxicity Approved 28 July 2014 by Association for the Advancement of Medical Instrumentation Approved 14 August 2014 by American National Standards Institute Abstract: specifies strategies for hazard identification and tes
3、ts on medical devices for genotoxicity, carcinogenicity, and reproductive and developmental toxicity. Applicable when the need to evaluate a medical device for potential genotoxicity, carcinogenicity, or reproductive toxicity has been established Keywords: biological evaluation, hazard identificatio
4、n, tests, genotoxicity, carcinogenicity, reproductive toxicity, developmental toxicity, toxicity AAMI Standard This Association for the Advancement of Medical Instrumentation (AAMI) standard implies a consensus of those substantially concerned with its scope and provisions. The existence of an AAMI
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8、onally, voluntary technical documents are adopted by government regulatory agencies or procurement authorities, in which case the adopting agency is responsible for enforcement of its rules and regulations. Published by Association for the Advancement of Medical Instrumentation 4301 N. Fairfax Dr.,
9、Ste. 301 Arlington, VA 22203-1633 2014 by the Association for the Advancement of Medical Instrumentation All Rights Reserved This publication is subject to copyright claims of ISO, ANSI, and AAMI. No part of this publication may be reproduced or distributed in any form, including an electronic retri
10、eval system, without the prior written permission of AAMI. All requests pertaining to this draft should be submitted to AAMI. It is illegal under federal law (17 U.S.C. 101, et seq.) to make copies of all or any part of this document (whether internally or externally) without the prior written permi
11、ssion of the Association for the Advancement of Medical Instrumentation. Violators risk legal action, including civil and criminal penalties, and damages of $100,000 per offense. For permission regarding the use of all or any part of this document, contact AAMI, 4301 N. Fairfax Dr., Ste. 301, Arling
12、ton, VA 22203-1633. Phone: (703) 525-4890; Fax: (703) 525-1067. Printed in the United States of America ISBN 1-57020-561-2 Contents Page Glossary of equivalent standards . v Committee representation xi Background of ANSI/AAMI adoption of ISO 10993-3:2014 viii Foreword ix Introduction . xi 1 Scope 1
13、2 Normative references 1 3 Terms and definitions 2 4 Requirements for test strategies 2 4.1 General . 2 4.2 Additional requirements for carcinogenicity testing 3 4.3 Additional requirements for reproductive toxicity testing . 3 5 Genotoxicity tests 4 5.1 General . 4 5.2 Test strategy 4 5.2.1 General
14、 . 4 5.2.2 Test battery 4 5.2.3 Follow-up evaluation . 5 5.3 Sample preparation . 6 6 Carcinogenicity tests. 7 6.1 General . 7 6.2 Evaluation strategy 7 6.3 Sample preparation . 8 6.4 Test methods . 8 7 Reproductive and developmental toxicity tests 9 7.1 General . 9 7.2 Test strategy 9 7.3 Sample pr
15、eparation . 10 7.4 Test methods . 10 8 Test report 10 Annex A (informative) Guidance on selecting an appropriate sample preparation procedure in genotoxicity testing . 12 A.1 General . 12 A.2 Device materials 13 A.2.1 Low Molecular Weight Chemicals (LMWC) 13 A.2.2 Polymers (including naturally occur
16、ring polymers) . 13 A.2.2.1 LMWC contained in polymers . 13 A.2.2.2 Oligomers . 13 A.2.2.3 Biodegradable polymers . 14 A.2.3 Inorganic materials: Wear debris from metals, alloys and ceramics 14 A.3 Sample Preparation Methods . 14 A.3.1 General . 14 Figure A.1 Structured approach to select a sample p
17、reparation procedure 15 Table A.1 Common extraction solvents 16 A.3.2 Method A 16 A.3.3 Method B 16 A.3.3.1 General . 16 A.3.3.2 Test sample preparation . 17 A.3.3.3 Procedure . 17 A.3.3.4 Expression of results 18 A.3.4 Method C 18 A.3.4.1 General . 18 A.3.4.2 Procedure . 18 A.4 Additional guidance
18、on special sample preparation procedures 19 A.4.1 Biodegradable polymers . 19 A.4.2 Inorganic materials: Wear debris from metals, alloys and ceramics 19 A.4.3 LMWC 19 Annex B (informative) Flowchart for follow-up evaluation 20 Figure B.1 Flowchart for follow-up evaluation 20 Annex C (informative) Ra
19、tionale of test systems . 21 C.1 Genotoxicity tests 21 C.2 Carcinogenicity tests. 22 C.3 Reproductive/developmental toxicity tests . 22 Annex D (informative) Cell transformation test systems 23 Annex E (normative) Considerations for carcinogenicity studies performed as implantation studies 24 E.1 Fo
20、reign body carcinogenesis . 24 E.2 Animal welfare considerations . 24 Annex F (informative) In vitro tests for embryo toxicity 25 Table F.1 Criteria defined by the management team of the study to evaluate test performance . 25 Table F.2 Summary of the classification results (all data88) . 26 Annex Z
21、A (informative) Relationship between this European Standard and the Essential Requirements of EU Directive 93/42 EEC on medical devices . 27 Table ZA.1 Correspondence between this European Standard and Directive 93/42/EEC on medical devices 27 Annex ZB (informative) Relationship between this Europea
22、n Standard and the Essential Requirements of EU Directive 90/385/EEC on active implantable medical devices . 29 Table ZB.1 Correspondence between this European Standard and Directive 90/385/EEC on active implantable medical devices 29 Bibliography . 30 Glossary of equivalent standards International
23、Standards adopted in the United States may include normative references to other International Standards. AAMI maintains a current list of each International Standard that has been adopted by AAMI (and ANSI). Available on the AAMI website at the address below, this list gives the corresponding U.S.
24、designation and level of equivalency to the International Standard. www.aami.org/standards/glossary.pdf 2014 Association for the Advancement of Medical Instrumentation ANSI/AAMI/ISO 10993-3:2014 v Committee representation Association for the Advancement of Medical Instrumentation Biological Evaluati
25、on Committee The adoption of ISO 10993-3:2014 as an American National Standard was initiated by the AAMI Biological Evaluation Committee, which also functions as a U.S. Technical Advisory Group to the relevant work in the International Organization for Standardization (ISO) and the AAMI Mutagenicity
26、, Carcinogenicity, and Reproductive Toxicity Working Group. At the time this document was published, the AAMI Biological Evaluation Committee had the following members: Co-chairs Ronald P. Brown, FDA/CDRH Jon Cammack, PhD DABT, Medimmune LLC Members James M. Anderson, MD PhD, Case Western Reserve Un
27、iv Joseph Carraway, DVM, NAMSA Philippe Hasgall, Zimmer Inc Richard W. Hutchinson, DVM PhD DABT, Johnson b) new Annex A ” Guidance on selecting an appropriate sample preparation procedure in genotoxicity testing” included; c) Inclusion of further in vitro and in vivo test for evaluating the genotoxi
28、c 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 “In vitro tests for embryo toxicity” included. ISO 10993 consists of t
29、he 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, and reproductive toxicity Part 4: Selection of tests for interact
30、ions 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 products 2014 Association for the Advancement of Medical Instrume
31、ntation ANSI/AAMI/ISO 10993-3:2014 ix Part 10: Tests for irritation and skin sensitization Part 11: 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: Identificatio
32、n 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 allowable limits for leachable substances Part 18
33、: 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 specification The following part is under preparation: P
34、art 33: Supplement to ISO 10993-3: Guidance on tests to evaluate genotoxicity Technical Report The following definitions apply in understanding how to implement an ISO International Standard and other normative ISO deliverables (TS, PAS, IWA): “shall” indicates a requirement; “should” indicates a re
35、commendation; “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
36、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, 2011), 3.3.2, defines a recommendation as an “expression in the content of a document conveying that among s
37、everal possibilities one is recommended as particularly suitable, without mentioning or excluding others, or that a certain course of action is preferred but not necessarily required, or that (in the negative form) a certain possibility or course of action is deprecated but not prohibited.” x 2014 A
38、ssociation for the Advancement of Medical Instrumentation ANSI/AAMI/ISO 10993-3:2014 Introduction The 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 gen
39、eration abnormalities, is of particular public concern. It is inherent in the provision of safe medical devices that such risks be minimized to the greatest extent feasible. The assessment of mutagenic, carcinogenic and reproductive hazards is an essential component of the control of these risks. No
40、t all test methods for the assessment of genotoxicity, carcinogenicity or reproductive 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 process
41、es and test validation can be cited as limitations of available methods. For example, 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 toxic
42、ological effects. At the time this document was prepared, the test methods proposed 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 pa
43、rticular medical device, there is no substitute for a careful assessment of expected 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
44、of ISO 10993 presents test methods for the detection of specific biological hazards, 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
45、 device materials but, where it is appropriate, it is important that maximum test sensitivity is achieved. In the 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 t
46、o be performed on a case-by-case basis. 2014 Association for the Advancement of Medical Instrumentation ANSI/AAMI/ISO 10993-3:2014 xi xii 2014 Association for the Advancement of Medical Instrumentation ANSI/AAMI/ISO 10993-3:2014 American National Standard ANSI/AAMI/ISO 10993-3:2014 Quality of dialys
47、is fluid for hemodialysis and related Biological evaluation of medical devices Part 3: Tests for genotoxicity, carcinogenicity, and reproductive toxicity 1 Scope This part of ISO 10993 specifies strategies for risk estimation, selection of hazard identification tests and risk management, with respec
48、t to the possibility of the following potentially irreversible biological effects arising as a result of exposure to medical devices: genotoxicity; carcinogenicity; reproductive and developmental toxicity. This part of ISO 10993 is applicable when the need to evaluate a medical device for potential
49、genotoxicity, carcinogenicity, or reproductive toxicity has been established. NOTE Guidance on selection of tests is provided in ISO 10993-1. 2 Normative references The 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) applies. ISO 10993-1, Biological evaluation of
