ISO-10993-3-2003.pdf

Reference number ISO 10993-3:2003(E) © ISO 2003 INTERNATIONAL STANDARD ISO 10993-3 Second edition 2003-10-15 Biological evaluation of medical devices Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity Évaluation biologique des dispositifs médicaux Partie 3: Essais concernant la génotoxicité, la cancérogénicité et la toxicité sur la reproduction ISO 10993-3:2003(E) PDF disclaimer This PDF file may contain embedded typefaces. In accordance with Adobe's licensing policy, this file may be printed or viewed but shall not be edited unless the typefaces which are embedded are licensed to and installed on the computer performing the editing. In downloading this file, parties accept therein the responsibility of not infringing Adobe's licensing policy. The ISO Central Secretariat accepts no liability in this area. Adobe is a trademark of Adobe Systems Incorporated. Details of the software products used to create this PDF file can be found in the General Info relative to the file; the PDF-creation parameters were optimized for printing. Every care has been taken to ensure that the file is suitable for use by ISO member bodies. In the unlikely event that a problem relating to it is found, please inform the Central Secretariat at the address given below. © ISO 2003 All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying and microfilm, without permission in writing from either ISO at the address below or ISO's member body in the country of the requester. ISO copyright office Case postale 56 CH-1211 Geneva 20 Tel. + 41 22 749 01 11 Fax + 41 22 749 09 47 E-mail copyrightiso.org Web www.iso.org Published in Switzerland ii © ISO 2003 All rights reserved ISO 10993-3:2003(E) © ISO 2003 All rights reserved iii Contents Page Forewordiv Introduction .vi 1 Scope1 2 Normative references .1 3 Terms and definitions.2 4 Genotoxicity tests.3 4.1 General.3 4.2 Test strategy3 4.3 Sample preparation.4 4.4 Test methods.4 4.4.1 In vitro genotoxicity tests.4 4.4.2 In vivo genotoxicity tests.4 5 Carcinogenicity tests5 5.1 General.5 5.2 Test strategy5 5.3 Sample preparation.5 5.4 Test methods.5 6 Reproductive and developmental toxicity tests 6 6.1 General.6 6.2 Test strategy6 6.3 Sample preparation.6 6.4 Test methods.7 7 Test report7 Annex A (informative) Cell transformation test system .8 Annex B (informative) Rationale of test systems9 Annex C (informative) Role of implantation carcinogenicity studies11 Bibliography .13 ISO 10993-3:2003(E) iv © ISO 2003 All rights reserved Foreword ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies (ISO member bodies). The work of 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, 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 task 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 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 10993-3 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices. This second edition cancels and replaces the first edition (ISO 10993-3:1992), 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 Part 2: Animal welfare requirements Part 3: Tests for genotoxicity, carcinogenicity 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 8: Selection and qualification of reference materials for biological tests Part 9: Framework for the identification and quantification of potential degradation products Part 10: Tests for irritation and delayed-type hypersensitivity 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: Identification and quantification of degradation products from ceramics ISO 10993-3:2003(E) © ISO 2003 All rights reserved v 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: Chemical characterization of materials Future parts will deal with other relevant aspects of biological testing. ISO 10993-3:2003(E) vi © ISO 2003 All rights reserved 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-generation 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. Not 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 in test sample size and preparation, scientific understanding of disease processes 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 ongoing scientific and medical advances will alter our understanding of and approaches to these important toxicity test methods. At the time this part of ISO 10993 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 particular 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 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 hazard identification but, where it is appropriate, it is important that maximum test sensitivity be achieved. Most tests included in this part of ISO 10993 refer to Guidelines for Testing of Chemicals, prepared by the Organization for Economic Cooperation and Development (OECD). The interpretation of findings and their implications for human health effects are beyond the scope of this part of ISO 10993. Because 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 has to be performed on a case-by-case basis. INTERNATIONAL STANDARD ISO 10993-3:2003(E) © ISO 2003 All rights reserved 1 Biological evaluation of medical devices Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity 1 Scope This part of ISO 10993 specifies strategies for hazard identification and tests on medical devices for the following biological aspects: genotoxicity, carcinogenicity, and reproductive and developmental toxicity. This part of ISO 10993 is applicable for evaluation of a medical device whose potential for genotoxicity, carcinogenicity or reproductive toxicity has been identified. NOTE Guidance on selection of tests is provided in ISO 10993-1. 2 Normative references The 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 amendments) applies. ISO 10993-1:1997, Biological evaluation of medical devices Part 1: Evaluation and testing ISO 10993-2:1992, Biological evaluation of medical devices Part 2: Animal welfare requirements ISO 10993-6:1994, Biological evaluation of medical devices Part 6: Tests for local effects after implantation ISO 10993-12:2002, Biological evaluation of medical devices Part 12: Sample preparation and reference materials ISO 10993-18, Biological evaluation of medical devices Part 18: Chemical characterization of materials. OECD 4141), Prenatal Development Toxicity Study OECD 415, One-Generation Reproduction Toxicity Study OECD 416, Two-Generation Reproduction Toxicity 1) Organization for Economic Cooperation and Development. ISO 10993-3:2003(E) 2 © ISO 2003 All rights reserved OECD 421, Reproduction/Developmental Toxicity Screening Test OECD 451, Carcinogenicity Studies OECD 453, Combined Chronic Toxicity/Carcinogenicity Studies OECD 471, Bacterial Reverse Mutation Test OECD 473, In vitro Mammalian Chromosome Aberration Test OECD 476, In vitro Mammalian Cell Gene Mutation Test 3 Terms and definitions For the purposes of this document, the terms and definitions given in ISO 10993-1, ISO 10993-12 and the following apply. 3.1 carcinogenicity test test to determine the tumorigenic potential of medical devices, materials and/or extracts using either single or multiple exposures over a major portion of the life span of the test animal NOTE These tests may be designed to examine both chronic toxicity and tumorigenicity in a single experimental study. When chronic toxicity and carcinogenicity are evaluated within a single study, care in study design with emphasis on dose selection should be exercised. This will help to ensure that premature mortality from chronic/cumulative toxicity does not compromise the statistical evaluation of animals that survive until scheduled study termination (i.e. normal life-span). 3.2 energy-depositing medical device device intended to exert its therapeutic or diagnostic effect by the delivery of electromagnetic radiation, ionizing radiation or ultrasound NOTE This does not include medical devices that deliver simple electrical current, such as electrocautery medical devices, pacemakers or functional electrical stimulators. 3.3 genotoxicity test test using mammalian or non-mammalian cells, bacteria, yeasts or fungi to determine whether gene mutations, changes in chromosome structure, or other DNA or gene changes are caused by the test samples NOTE These tests can include whole animals. 3.4 maximum tolerated dose MTD maximum dose that a test animal can tolerate without any adverse physical effects 3.5 reproductive and developmental toxicity test test to evaluate the potential effects of test samples on reproductive function, embryonic morphology (teratogenicity), and prenatal and early postnatal development ISO 10993-3:2003(E) © ISO 2003 All rights reserved 3 4 Genotoxicity tests 4.1 General Before a decision to perform a genotoxicity test is made, ISO 10993-1 and the chemical characterization of materials (ISO 10993-18) shall be taken into account. The rationale for a test programme, taking into consideration all relevant factors, shall be documented. ISO 10993-1 indicates circumstances where the potential for genotoxicity is a relevant hazard for consideration in an overall biological safety evaluation (see ISO 10993-1:1997, Table 1). Testing for genotoxicity, however, is not necessary for medical devices, and components thereof, made only from materials known to show no genotoxicity. Testing for genotoxicity is indicated where a review of the composition of the materials reveals the possible presence in the final medical device of compounds that might interact with genetic material, or when the chemical composition of the medical device is unknown. In such circumstances, the genotoxic potential of suspect chemical components should be assessed, bearing in mind the potential for synergy, in preference to carrying out genotoxicity tests on the material or medical device as a whole. When the genotoxicity of a medical device has to be experimentally assessed, a series of in vitro tests shall be used. This series shall include either two tests if 4.2.1.2 is performed which uses the mouse lymphoma assay incorporating colony number and size determination, or three tests if 4.2.1.1 is performed. When tests are performed, at least two tests, investigating different end-points, shall use mammalian cells. 4.2 Test strategy 4.2.1 Genotoxicity testing shall be performed on the basis of an initial decision to test in accordance with either Option 1 (4.2.1.1) or Option 2 (4.2.1.2). 4.2.1.1 Option 1 a) a test for gene mutations in bacteria (OECD 471); and b) a test for gene mutations in mammalian cells (OECD 476); and c) a test for clastogenicity in mammalian cells (OECD 473) 4.2.1.2 Option 2 a) a test for gene mutations in bacteria (OECD 471); and b) a test for gene mutations in mammalian cells (OECD 476), specifically a mouse lymphoma assay incorporating colony number and size determination in order to cover both endpoints (clastogenicity and gene mutations). 4.2.2 If the results of all in vitro tests performed in accordance with 4.2.1 are negative, further genotoxicity testing in animals is not normally justified and should not be performed, in the interest of preventing undue use of animals. In vivo testing shall be performed in accordance with ISO 10993-2. 4.2.3 If any of the in vitro tests is positive, either in vivo mutagenicity tests shall be performed (see 4.2.4) or the presumption shall be made that the compound is mutagenic. 4.2.4 Any in vivo test shall be chosen on the basis of the most appropriate endpoint identified by the in vitro tests. An attempt shall be made to demonstrate that the test substance has reached the target organ. If this cannot be demonstrated, a second in vivo