EN ISO 10993-11-2018 en Biological evaluation of medical devices - Part 11 Tests for systemic toxicity.pdf

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1、BSI Standards PublicationWB11885_BSI_StandardCovs_2013_AW.indd 1 15/05/2013 15:06Biological evaluation of medical devicesPart 11: Tests for systemic toxicityBS EN ISO 1099311:2018National forewordThis British Standard is the UK implementation of EN ISO 1099311:2018. It is identical to ISO 1099311:20

2、17. It supersedes BS EN ISO 1099311:2009, which is withdrawn.The UK participation in its preparation was entrusted to Technical Committee CH/194, Biological evaluation of medical devices.A list of organizations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 request to its secretary.This publicatio

3、n 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 91734 9ICS 11.100.20Compliance with a British Standard cannot confer immunity from

4、 legal obligations.This British Standard was published under the authority of the Standards Policy and Strategy Committee on 30 June 2018.Amendments/corrigenda issued since publicationDate Text affectedBRITISH STANDARDBS EN ISO 1099311:2018EUROPEAN STANDARDNORME EUROPENNEEUROPISCHE NORMEN ISO 109931

5、1May 2018ICS 11.100.20 Supersedes EN ISO 1099311:2009EUROPEAN COMMITTEE FOR STANDARDIZATIONCOMIT EUROPEN DE NORMALISATIONEUROPISCHES KOMITEE FR NORMUNGCENCENELEC Management Centre: Avenue Marnix 17, B1000 Brussels 2018 CEN Ref. No. EN ISO 1099311:2018: EAll rights of exploitation in any form and by

6、any means reserved worldwide for CEN national MembersBiological evaluation of medical devices Part 11: Tests for systemic toxicity (ISO 1099311:2017)valuation biologique des dispositifs mdicaux Partie 11: Essais de toxicit systmique (ISO 1099311:2017)Biologische Beurteilung von Medizinprodukten Teil

7、 11: Prfungen auf systemische Toxizitt (ISO 1099311:2017)This European Standard was approved by CEN on 31 July 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

8、 alteration. Uptodate lists and bibliographical references concerning 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 ma

9、de by translation under the responsibility of a CEN member into its 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, Eston

10、ia, Finland, Former Yugoslav Republic 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 United Kingdom.English VersionEN ISO

11、 1099311:2018 (E)European forewordThis document (EN ISO 1099311:2018) has been prepared by Technical Committee ISO/TC 194 “ Biological and clinical evaluation of medical devices “ in collaboration with Technical Committee CEN/TC 206 “Biological and clinical evaluation of medical devices” the secreta

12、riat 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 November 2018, and conflicting national standards shall be withdrawn at the latest by November 2018.Attention is drawn

13、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 1099311:2009.This document has been prepared under a mandate given to CEN by the European

14、 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 ZB, which is an integral part of this document.The following referenced documents are indispensable for the application of t

15、his 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 referenced documen

16、t 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, and otherwise

17、to the dated version of the ISO or IEC standard, as listed below.NOTE 1 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 1 Correlations between undated normative references and dated EN and ISO stand

18、ardsNormative references as listed in Clause 2 of the ISO standardEquivalent dated standardEN ISO or IECISO 109931 EN ISO 109931:2009 ISO 109931:2009ISO 109932 EN ISO 109932:2006 ISO 109932:2006NOTE 2 This part of EN ISO 10993 refers to ISO 109931 which itself refers to ISO 14971. In Europe, it shou

19、ld be assumed that the reference to ISO 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

20、, Estonia, Finland, Former Yugoslav Republic of Macedonia, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and the United Kingdom.Endorsement notice

21、The text of ISO 1099311:2017 has been approved by CEN as EN ISO 1099311:2018 without any modification.iiBS EN ISO 1099311:2018ISO 1099311:2017Foreword vIntroduction vi1 Scope . 12 Normative references 13 Terms and definitions . 14 General considerations 34.1 General . 34.2 Selection of animal specie

22、s . 34.3 Animal status 34.4 Animal care and husbandry . 34.5 Size and number of groups . 44.5.1 Size of groups 44.5.2 Number of groups . 44.5.3 Treatment controls 44.6 Route of exposure . 54.7 Sample preparation 54.8 Dosing . 54.8.1 Test sample administration 54.8.2 Dosage volumes 54.8.3 Dosage freq

23、uency 64.9 Body weight and food/water consumption . 64.10 Clinical observations 64.11 Clinical pathology . 64.12 Anatomic pathology 74.13 Study designs 74.14 Quality of investigation 75 Acute systemic toxicity . 75.1 General . 75.2 Study design 85.2.1 Preparations 85.2.2 Experimental animals 85.2.3

24、Test conditions. 85.2.4 Body weights . 95.2.5 Clinical observations 95.2.6 Pathology 95.3 Evaluation criteria . 105.3.1 General. 105.3.2 Evaluation of results 105.4 Final report . 106 Repeated exposure systemic toxicity (subacute, subchronic and chronic systemic toxicity) .126.1 General 126.2 Study

25、design . 126.2.1 Preparations .126.2.2 Experimental animals.126.2.3 Test conditions136.2.4 Body weights 136.2.5 Clinical observations .136.2.6 Pathology . 136.3 Evaluation criteria . 146.3.1 General. 146.3.2 Evaluation of results 15 ISO 2017 All rights reserved iiiContents PageBS EN ISO 1099311:2018

26、ISO 1099311:20176.4 Final report . 15Annex A (informative) Routes of administration .16Annex B (informative) Dosage volumes .18Annex C (informative) Common clinical signs and observations 19Annex D (informative) Suggested haematology, clinical chemistry and urinalysis measurements .20Annex E (inform

27、ative) Suggested organ list for histopathological evaluation .22Annex F (informative) Organ list for limited histopathology for medical devices subjected to systemic toxicity testing 24Annex G (informative) Information on materialmediated pyrogens .25Annex H (informative) Subchronic rat Dual routes

28、of parenteral administration .26Bibliography .28iv ISO 2017 All rights reservedBS EN ISO 1099311:2018ISO 1099311:2017ForewordISO (the International Organization for Standardization) is a worldwide federation of national standards bodies (ISO member bodies). The work of preparing International Standa

29、rds 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 nongovernmental, in liaison with ISO, also take

30、 part in the work. ISO collaborates closely with the International Electrotechnical Commission (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 part

31、icular the different approval criteria needed for the different types of ISO documents 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 t

32、his document may be the subject of patent rights. ISO shall not be held responsible for 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 ww

33、w.iso.org/patents).Any trade name used in this document is information given for the convenience 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 inf

34、ormation about ISOs adherence to the World Trade Organization (WTO) principles in the 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 e

35、dition cancels and replaces the second edition (ISO 1099311:2006), which has been technically revised with the following changes:a) reduction in group size for chronic toxicity testing in Table 1;b) a new Annex F was added;c) the original Annex F was moved to Annex G;d) a new Annex H was added;e) th

36、e Bibliography was updated.A list of all parts in the ISO 10993 series can be found on the ISO website. ISO 2017 All rights reserved vBS EN ISO 1099311:2018ISO 1099311:2017IntroductionSystemic toxicity is a potential adverse effect of the use of medical devices. Generalized effects, as well as organ

37、 and organ system effects can result from absorption, distribution and metabolism of leachates from the device or its materials to parts of the body with which they are not in direct contact. This document addresses the evaluation of generalized systemic toxicity, not specific target organ or organ

38、system toxicity, even though these effects may result from the systemic absorption and distribution of toxicants.Because of the broad range of medical devices, and their materials and intended uses, this document is not overly prescriptive. While it addresses specific methodological aspects to be co

39、nsidered in the design of systemic toxicity tests, proper study design has to be uniquely tailored to the nature of the devices materials and its intended clinical application.Other elements of this document are prescriptive in nature, including those aspects that address compliance with good labora

40、tory practices and elements for inclusion in reporting.While some systemic toxicity tests (e.g. long term implantation or dermal toxicity studies) can be designed to study systemic effects as well as local, carcinogenic or reproductive effects, this document focuses only on those aspects of such stu

41、dies, which are intended to address systemic effects. Studies which are intended to address other toxicological end points are addressed in ISO 109933, ISO 109936, ISO 1099310 and ISO/TS 1099320.Prior to conducting a systemic toxicity study, all reasonably available data and scientifically sound met

42、hods in the planning and refinement of the systemic toxicity study design should be reviewed. This includes the suitability of use of input data such as existing toxicological data, data from chemical characterization studies and/or other biological tests (including in vitro tests and less invasive

43、in vivo tests) for the refinement of study design, dose selection, and/or selection of pathological end points to cover in the evaluation of a study. For the repeated exposure systemic toxicity study in particular, the use of scientifically sound study design, the use of pilot studies and statistica

44、l study design and the use of unbiased, quantitative end points/methods in the pathological (including histopathological) and clinical chemistry methods are important so as to obtain data which have sufficient scientific validity.Finally, toxicology is an imperfect science. The outcome of any single

45、 test should not be the sole basis for making a determination of whether a device is safe for its intended use.vi ISO 2017 All rights reservedBS EN ISO 1099311:2018Biological evaluation of medical devices Part 11: Tests for systemic toxicity1 ScopeThis document specifies requirements and gives guida

46、nce on procedures to be followed in the evaluation of the potential for medical device materials to cause adverse systemic reactions.2 Normative referencesThe following documents are referred to in the text in such a way that some or all of their content constitutes requirements of this document. Fo

47、r 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 testing within a risk management processISO 109932, Biological eval

48、uation of medical devices Part 2: Animal welfare requirements3 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 Elect

49、ropedia: available at http:/www.electropedia.org/ ISO Online browsing platform: available at http:/www.iso.org/obp3.1dosedosageamount of test sample administered (e.g. mass, volume) expressed per unit of body weight or surface area3.2doseeffectrelationship between the dosage and the magnitude of a defined biological effect either in an individual or in a population sample3.3doseresponserelationship of dosage to the spectrum of effects related to the exposureNote 1 to entry: There are two typ