1、BS EN ISO10993-16:2010ICS 11.100.20NO COPYING WITHOUT BSI PERMISSION EXCEPT AS PERMITTED BY COPYRIGHT LAWBRITISH STANDARDBiological evaluationof medical devicesPart 16: Toxicokinetic study design fordegradation products and leachables(ISO 10993-16:2010)This British Standardwas published under theaut
2、hority of the StandardsPolicy and StrategyCommittee on 31 March2010 BSI 2010ISBN 978 0 580 64243 2Amendments/corrigenda issued since publicationDate CommentsBS EN ISO 10993-16:2010National forewordThis British Standard is the UK implementation of EN ISO10993-16:2010. It supersedes BS EN ISO 10993-16
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 be obtained onrequest to its secretary.This publication does not purport to include all the n
4、ecessary provisionsof a contract. Users are responsible for its correct application.Compliance with a British Standard cannot confer immunityfrom legal obligations.EUROPEAN STANDARD NORME EUROPENNE EUROPISCHE NORM EN ISO 10993-16 February 2010 ICS 11.100.20 Supersedes EN ISO 10993-16:2009English Ver
5、sion Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables (ISO 10993-16:2010) valuation biologique des dispositifs mdicaux - Partie 16: Conception des tudes toxicocintiques des produits de dgradation et des substances relargables (ISO
6、 10993-16:2010) Biologische Beurteilung von Medizinprodukten - Teil 16: Entwurf und Auslegung toxikenitischer Untersuchungen hinsichtlich Abbauprodukten und herauslsbaren Bestandteilen (ISO 10993-16:2010) This European Standard was approved by CEN on 20 January 2010. CEN members are bound to comply
7、with the CEN/CENELEC Internal Regulations which stipulate 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 Management
8、 Centre or to any CEN member. This European Standard 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 Management Centre has the same status as the of
9、ficial versions. CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, S
10、lovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom. EUROPEAN COMMITTEE FOR STANDARDIZATION COMIT EUROPEN DE NORMALISATION EUROPISCHES KOMITEE FR NORMUNG Management Centre: Avenue Marnix 17, B-1000 Brussels 2010 CEN All rights of exploitation in any form and by any means reserved worldw
11、ide for CEN national Members. Ref. No. EN ISO 10993-16:2010: EBS EN ISO 10993-16:2010EN ISO 10993-16:2010 (E) 3 Foreword This document (EN ISO 10993-16:2010) has been prepared by Technical Committee ISO/TC 194 “Biological evaluation of medical devices“ in collaboration Technical Committee CEN/TC 206
12、 “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 August 2010, and conflicting national standards shall be withdr
13、awn at the latest by August 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 10993-16:2009. This
14、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 document. According
15、 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, France, Germany, Greece, Hungary, Iceland, Ireland, Italy,
16、Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and the United Kingdom. Endorsement notice The text of ISO 10993-16:2010 has been approved by CEN as a EN ISO 10993-16:2010 without any modification. BS EN ISO 10993-1
17、6:2010EN ISO 10993-16:2010 (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 to CEN by the European Commission and the European Free Trade
18、 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 implemented as a national standard in at least one Member St
19、ate, compliance with the clauses of this International Standard given in Table ZA.1 confers, within the limits of the scope of this European Standard, a presumption of conformity with the corresponding Essential Requirements of that Directive and associated EFTA regulations. Table ZA.1 Correspondenc
20、e between this European Standard and Directive 93/42/EEC on medical devices Clause(s)/sub-clause(s) of this European Standard Essential Requirements (ERs) of Directive 93/42/EEC Qualifying remarks/Notes 4, 5, Annex A 7.1, 7.2, 7.5 These relevant Essential Requirements are only partly addressed in th
21、is International Standard GENERAL NOTE Presumption of conformity 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 10993-16:2010EN
22、ISO 10993-16:2010 (E) 5 Annex ZB (informative) Relationship 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
23、 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 International Standard is cited in the Official Journal of the European Union under that Directive and has been implemented as
24、a national standard in at least one Member State, compliance with the clauses of this International 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 r
25、egulations. Table ZB.1 Correspondence between this European Standard and Directive 90/385/EEC on Active Implantable Medical Devices Clause(s)/sub-clause(s) of this European Standard Essential Requirements (ERs) of Directive 90/385/EEC Qualifying remarks/Notes4, 5, Annex A 9 (First and second indents
26、 only) The first and second indents of this relevant Essential Requirement are only partly addressed in this International Standard GENERAL NOTE Presumption of conformity depends on also complying with all relevant clauses/subclauses of ISO 10993-1. WARNING Other requirements and other EU Directives
27、 may be applicable to the product(s) falling within the scope of this standard. BS EN ISO 10993-16:2010ISO 10993-16:2010(E) ISO 2010 All rights reserved iiiContents Page Foreword iv Introductionvi 1 Scope1 2 Normative references1 3 Terms and definitions .1 4 Principles for design of toxicokinetic st
28、udies3 5 Guidance on test methods .4 5.1 General considerations.4 5.2 Guidance on specific types of test 5 5.2.1 General .5 5.2.2 Absorption5 5.2.3 Distribution 6 5.2.4 Metabolism and excretion 6 Annex A (normative) Circumstances in which toxicokinetic studies shall be considered.7 Bibliography8 BS
29、EN ISO 10993-16:2010ISO 10993-16:2010(E) iv ISO 2010 All rights reservedForeword 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 tech
30、nical 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
31、 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 I
32、nternational 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
33、 may be the subject of patent rights. ISO shall not be held responsible for identifying any or all such patent rights. ISO 10993-16 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices. This second edition cancels and replaces the first edition (ISO 10993-16:1997)
34、, 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 process Part 2: Animal welfare requirements Part 3: Tests for genotoxicity, carcinogenicity and r
35、eproductive 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 produ
36、cts 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: Identification and quantification of degradatio
37、n products from ceramics Part 15: Identification and quantification of degradation products from metals and alloys BS EN ISO 10993-16:2010ISO 10993-16:2010(E) ISO 2010 All rights reserved v Part 16: Toxicokinetic study design for degradation products and leachables Part 17: Establishment of allowabl
38、e 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 Specification B
39、S EN ISO 10993-16:2010ISO 10993-16:2010(E) vi ISO 2010 All rights reservedIntroduction Toxicokinetics describe the absorption, distribution, metabolism and excretion, with time, of foreign compounds in the body. Essential to the evaluation of the safety of a medical device is consideration of the st
40、ability of the material(s) in vivo and the disposition of intended and unintended leachables and degradation products. Toxicokinetic studies can be of value in assessing the safety of materials used in the development of a medical device or in elucidating the mechanism of observed adverse reactions.
41、 Toxicokinetic studies can also be applicable to medical devices containing active ingredients. The need for and extent of such studies should be carefully considered based on the nature and duration of contact of the device with the body (see Annex A). Existing toxicological literature and toxicoki
42、netic data can be sufficient for this consideration. The potential hazard posed by a medical device can be attributed to the interactions of its components or their metabolites with the biological system. Medical devices can release leachables (e.g. residual catalysts, processing aids, residual mono
43、mers, fillers, antioxidants, plasticizers) and/or degradation products which migrate from the material and have the potential to cause adverse effects in the body. A considerable body of published literature exists on the use of toxicokinetic methods to study the fate of chemicals in the body (see B
44、ibliography). The methodologies and techniques utilized in such studies form the basis of the guidance in this part of ISO 10993. Annex A provides a rationale for the use of this part of ISO 10993. BS EN ISO 10993-16:2010INTERNATIONAL STANDARD ISO 10993-16:2010(E) ISO 2010 All rights reserved 1Biolo
45、gical evaluation of medical devices Part 16: Toxicokinetic study design for degradation products and leachables 1 Scope This part of ISO 10993 gives principles on how toxicokinetic studies relevant to medical devices should be designed and performed. Annex A describes the considerations for inclusio
46、n of toxicokinetic studies in the biological evaluation of medical devices. 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 refere
47、nced document (including any amendments) applies. ISO 10993-1, Biological evaluation of medical devices Part 1: Evaluation and testing within a risk management process ISO 10993-2, Biological evaluation of medical devices Part 2: Animal welfare requirements ISO 10993-12, Biological evaluation of med
48、ical devices Part 12: Sample preparation and reference materials ISO 10993-17, Biological evaluation of medical devices Part 17: Establishment of allowable limits for leachable substances ISO 10993-18, Biological evaluation of medical devices Part 18: Chemical characterization of materials ISO 14971
49、, Medical devices Application of risk management to medical devices 3 Terms and definitions For the purposes of this document, the terms and definitions given in ISO 10993-1 and the following apply. 3.1 absorption process by which a substance enters the blood and/or lymph system 3.2 bioavailability extent of systemic absorption of specified substance BS EN ISO 10993-16:2010ISO 10993-16:2010(E) 2 ISO 2010 All rights reserved3.3 biodegradation degradation due to the biological environment N
