1、BSI Standards PublicationWB11885_BSI_StandardCovs_2013_AW.indd 1 15/05/2013 15:06Biological evaluation of medical devicesPart 16: Toxicokinetic study design for degradation products and leachablesBS EN ISO 1099316:2017National forewordThis British Standard is the UK implementation of EN ISO 1099316:
2、2017. It is identical to ISO 1099316:2017. It supersedes BS EN ISO 1099316:2010, which is withdrawn.The UK participation in its preparation was entrusted to Technical Committee CH/194, Biological evaluation of medical devices.A list of organizations represented on this committee can be obtained on r
3、equest to its secretary.This publication does not purport to include all the necessary provisions of a contract. Users are responsible for its correct application. The British Standards Institution 2018 Published by BSI Standards Limited 2018ISBN 978 0 580 92910 6ICS 11.100.20Compliance with a Briti
4、sh Standard cannot confer immunity from legal obligations. This British Standard was published under the authority of the Standards Policy and Strategy Committee on 31 January 2018.Amendments/corrigenda issued since publicationDate Text affectedBRITISH STANDARDBS EN ISO 1099316:2017EUROPEAN STANDARD
5、NORME EUROPENNEEUROPISCHE NORMEN ISO 1099316December 2017ICS 11.100.20 Supersedes EN ISO 1099316:2010EUROPEAN COMMITTEE FOR STANDARDIZATIONCOMIT EUROPEN DE NORMALISATIONEUROPISCHES KOMITEE FR NORMUNGCENCENELEC Management Centre: Avenue Marnix 17, B1000 Brussels 2017 CEN Ref. No. EN ISO 1099316:2017:
6、 EAll rights of exploitation in any form and by any means reserved worldwide for CEN national MembersBiological evaluation of medical devices Part 16: Toxicokinetic study design for degradation products and leachables (ISO 1099316:2017)valuation biologique des dispositifs mdicaux Partie 16: Concepti
7、on des tudes toxicocintiques des produits de dgradation et des substances relargables (ISO 1099316:2017)Biologische Beurteilung von Medizinprodukten Teil 16: Entwurf und Auslegung toxikokinetischer Untersuchungen hinsichtlich Abbauprodukten und herauslsbaren Bestandteilen (ISO 1099316:2017)This Euro
8、pean Standard was approved by CEN on 9 August 2017.CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this European Standard the status of a national standard without any alteration. Uptodate lists and bibliographical references concer
9、ning such national standards may be obtained on application to the CENCENELEC Management 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 i
10、ts own language and notified to the CEN-CENELEC Management Centre has the same status as the official versions.CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, Former Yugoslav Republic of Macedonia, France, Germa
11、ny, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and United Kingdom.English VersionEN ISO 1099316:2017 (E)European forewordThe text of ISO 1099316:2017 ha
12、s been prepared by Technical Committee ISO/TC 194 “Biological and clinical evaluation of medical devices“ of the International Organization for Standardization (ISO) and has been taken over as EN ISO 11099316:2017 by Technical Committee CEN/TC 206 “Biological and clinical evaluation of medical devic
13、es” the secretariat of which is held by DIN.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 June 2018, and conflicting national standards shall be withdrawn at the latest by June 2018.Attention is
14、 drawn to the possibility that some of the elements of this document may be the subject of patent rights. CEN shall not be held responsible for identifying any or all such patent rights.This document supersedes EN ISO 1099316:2010.This document has been prepared under a mandate given to CEN by the E
15、uropean Commission and the European Free Trade Association, and supports essential requirements of EU Directive(s).For relationship with EU Directive(s), see informative Annex ZA and Annex ZB, which is an integral part of this document.The following referenced documents are indispensable for the app
16、lication of this document. For undated references, the latest edition of the referenced document (including any amendments) applies. For dated references, only the edition cited applies. However, for any use of this standard within the meaning of Annex ZA, the user should always check that any refer
17、enced document has not been superseded and that its relevant contents can still be considered the generally acknowledged stateofart.When an IEC or ISO standard is referred to in the ISO standard text, this shall be understood as a normative reference to the corresponding EN standard, if available, a
18、nd otherwise to the dated version of the ISO or IEC standard, as listed below.NOTE The way in which these referenced documents are cited in normative requirements determines the extent (in whole or in part) to which they apply.Table Correlations between undated normative references and dated EN and
19、ISO standardsNormative references as listed in Clause 2 of the ISO standardEquivalent dated standardEN ISO or IECISO 109931 EN ISO 109931:2009 ISO 109931:2009NOTE This part of EN ISO 10993 refers to ISO 109931 which itself refers to ISO 14971. In Europe, it should be assumed that the reference to IS
20、O 14971 is to EN ISO 14971:2012.According to the CENCENELEC 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, Former Yugoslav Rep
21、ublic of Macedonia, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and the United Kingdom.Endorsement noticeThe text of ISO 1099316:2017 ha
22、s been approved by CEN as EN ISO 1099316:2017 without any modification.2BS EN ISO 1099316:2017ISO 1099316:2017(E)Foreword ivIntroduction v1 Scope . 12 Normative references 13 Terms and definitions . 14 Principles for design of toxicokinetic studies 35 Guidance on test methods . 45.1 General consider
23、ations 45.2 Guidance on specific types of test . 55.2.1 General 55.2.2 Absorption . 65.2.3 Distribution 65.2.4 Metabolism and excretion . 6Annex A (normative) Circumstances in which toxicokinetic studies shall be considered . 8Bibliography .10 ISO 2017 All rights reserved iiiContents PageBS EN ISO 1
24、099316:2017ISO 1099316:2017(E)ForewordISO (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 interest
25、ed in a subject for which a technical committee has been established has the right to be represented on that committee. International organizations, governmental and nongovernmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the International Electrotechnical Com
26、mission (IEC) on all matters of electrotechnical standardization. The procedures used to develop this document and those intended for its further maintenance are described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the different types of ISO documents
27、 should be noted. This document was drafted in accordance with the editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).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 fo
28、r identifying any or all such patent rights. Details of any patent rights identified during the development of the document will be in the Introduction and/or on the ISO list of patent declarations received (see www.iso.org/patents).Any trade name used in this document is information given for the c
29、onvenience of users and does not constitute an endorsement. For an explanation on the voluntary nature of standards, the meaning of ISO specific terms and expressions related to conformity assessment, as well as information about ISOs adherence to the World Trade Organization (WTO) principles in the
30、 Technical Barriers to Trade (TBT) see the following URL: www.iso.org/iso/foreword.html.This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of medical devices.This third edition cancels and replaces the second edition (ISO 1099316:2010), which has been te
31、chnically revised with the following changes:a) definition in 3.1 has been modified for clarification;b) Clause 4 has been modified for clarification;c) Clause 5 has been modified for clarification;d) information regarding toxicokinetic studies on nano-objects have been added;e) A.4 has been modifie
32、d for clarification.A list of all the parts in the ISO 10993 series can be found on the ISO website.iv ISO 2017 All rights reservedBS EN ISO 1099316:2017ISO 1099316:2017(E)IntroductionToxicokinetics describe the absorption, distribution, metabolism and excretion, with time, of foreign compounds in t
33、he body. Essential to the evaluation of the safety of a medical device is consideration of the stability 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 t
34、he development of a medical device or in elucidating the mechanism of observed adverse reactions. Toxicokinetic studies can also be applicable to medical devices containing active ingredients, in which case, pharmaceutical legislation are to be considered. The need for and extent of toxicokinetic st
35、udies should be carefully considered based on the nature and duration of contact of the device with the body (see A.2). Existing toxicological literature and toxicokinetic data can be sufficient for this consideration.The potential hazard posed by a medical device can be attributed to the interactio
36、ns of its components or their metabolites with the biological system. Medical devices can release leachables (e.g. residual catalysts, processing aids, residual monomers, fillers, antioxidants, plasticizers, etc.) and/or degradation products which migrate from the material and have the potential to
37、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 Bibliography). The methodologies and techniques utilized in such studies form the basis of the guidance in this document. Annex A p
38、rovides a rationale for the use of this document. ISO 2017 All rights reserved vBS EN ISO 1099316:2017This page deliberately left blankBiological evaluation of medical devices Part 16: Toxicokinetic study design for degradation products and leachables1 ScopeThis document provides principles on desig
39、ning and performing toxicokinetic studies relevant to medical devices. Annex A describes the considerations for inclusion of toxicokinetic studies in the biological evaluation of medical devices.2 Normative referencesThe following documents are referred to in the text in such a way that some or all
40、of their content constitutes requirements 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 109931, Biological evaluation of medical devices Part 1: Evaluation and testi
41、ng within a risk management process3 Terms and definitionsFor the purposes of this document, the terms and definitions given in ISO 10993-1 and the following apply.ISO and IEC maintain terminological databases for use in standardization at the following addresses: IEC Electropedia: available at http
42、:/www.electropedia.org/ ISO Online browsing platform: available at http:/www.iso.org/obp 3.1absorptionprocess of uptake of substance into or across tissue, blood and/or lymph system3.2bioavailabilityextent of systemic absorption (3.1) of specified substance3.3biodegradationdegradation due to the bio
43、logical environmentNote 1 to entry: Biodegradation might be modelled by in vitro tests.3.4bioresorptionprocess by which a biomaterial is degraded in the physiological environment and the product(s) eliminated and/or absorbedINTERNATIONAL STANDARD ISO 1099316:2017(E) ISO 2017 All rights reserved 1BS
44、EN ISO 1099316:2017ISO 1099316:2017(E)3.5clearancerate of removal of a specified substance from the body or parts of the body by metabolism (3.14) and/or excretion (3.9) 3.6c maxmaximum concentration of a specified substance in plasmaNote 1 to entry: When the maximum concentration in fluid or tissue
45、 is being referred to, it should have an appropriate identifier, e.g. c max, liver, and be expressed in mass per unit volume or mass.3.7degradation productproduct of a material which is derived from the chemical breakdown of the original material3.8distributionprocess by which an absorbed substance
46、and/or its metabolites circulate and partition within the body3.9excretionprocess by which an absorbed substance and/or its metabolites are removed from the body3.10extractliquid that results from extraction of the test substance (3.15) or control3.11halflifet 1/2time for the concentration of a spec
47、ified substance to decrease to 50 % of its initial value in the same body fluid or tissue3.12leachablechemical that can migrate from a device or component under storage conditions or conditions of useNote 1 to entry: A leachable (e.g. additives, monomeric or oligomeric constituent of polymeric mater
48、ial) can be extracted under laboratory conditions that simulate normal conditions of exposure.3.13mean residence timestatistical moment related to half-life (3.11) which provides a quantitative estimate of the persistence of a specified substance in the body2 ISO 2017 All rights reservedBS EN ISO 10
49、99316:2017ISO 1099316:2017(E)3.14metabolismprocess by which an absorbed substance is structurally changed within the body by enzymatic and/or nonenzymatic reactionsNote 1 to entry: The products of the initial reaction can subsequently be modified by either enzymatic or non-enzymatic reactions prior to excretion (3.9).3.15test substancedegradation product (3.7) or leachable (3.12) used for toxicokinetic study3.16t maxtime at which c max(3.6) is observed3.17volume of distributionV dparameter for a s
