SIST EN ISO 10993-16:2009
(Main)Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables (ISO 10993-16:1997)
Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables (ISO 10993-16:1997)
This part of IS0 10993 gives principles on how toxicokinetic studies relevant to medical devices should be designed and performed. Annex A describes the considerations for inclusion of toxicokinetic studies in the biological evaluation of medical devices.
Biologische Beurteilung von Medizinprodukten - Teil 16: Entwurf und Auslegung toxikokinetischer Untersuchungen hinsichtlich Abbauprodukten und Extrakten (ISO 10993-16:1997)
Dieser Teil von ISO 10993 beschreibt Prinzipien dafür, wie toxikokinetische Untersuchungen, die bei Medizinprodukten von Bedeutung sind, entworfen und durchgeführt werden sollten. Anhang A beschreibt die Überlegungen zur Durchführung toxikokinetischer Untersuchungen zur biologischen Beurteilung von Medizinprodukten.
Évaluation biologique des dispositifs médicaux - Partie 16 : Conception des études toxicocinétiques des produits de dégradation et des substances relargables (ISO 10993-16:1997)
NEW!IEC 60601-2-16:2018 est disponible sous forme de IEC 60601-2-16:2018 RLV qui contient la Norme internationale et sa version Redline, illustrant les modifications du contenu technique depuis l'édition précédente.
L'IEC 60601-2-16:2018 s'applique à la sécurité de base et aux performances essentielles des appareils d'hémodialyse, d'hémodiafiltration et d'hémofiltration. L'IEC 60601-2-16:2018 ne prend pas en compte le système de contrôle du liquide de dialyse de l'appareil d'hémodialyse utilisant la régénération du liquide de dialyse et les systèmes de transmission centralisés. Toutefois, elle prend en compte les exigences de sécurité spécifiques de l'appareil d'hémodialyse concernant la sécurité électrique et la sécurité du patient. L'IEC 60601-2-16:2018 spécifie les exigences minimales de sécurité relatives aux appareils d'hémodialyse. Ces appareils sont destinés à être utilisés soit par le personnel médical, soit par le patient, soit par d'autres personnes formées, sous le contrôle d'un personnel ayant une bonne compétence médicale. La présente Norme internationale s'applique à tout appareil electromédical destiné à fournir un traitement d'hémodialyse, d'hémodiafiltration et d'hémofiltration à un patient souffrant d'insuffisance rénale. Cette cinquième édition annule et remplace la quatrième édition de l'IEC 60601-2-16 parue en 2012. Cette édition constitue une révision technique. Cette édition inclut les modifications techniques majeures suivantes par rapport à l'édition précédente:
a) actualisation des références à l'IEC 60601-1:2005 et l'IEC 60601-1:2005/AMD1:2012, des références et des exigences à l'IEC 60601-1-2:2014, des références à l'IEC 60601-1-6:2010 et l'IEC 60601-1-6:2010/AMD1:2013, des références et des exigences à l'IEC 60601-1-8:2006 et l'IEC 60601-1-8:2006/AMD1:2012, des références à l'IEC 60601-1-9:2007 et l'IEC 60601-1-9:2007/AMD1:2013, des références à l'IEC 60601-1-10:2007 et l'IEC 60601-1-10:2007/AMD1:2013 ainsi que des références à l'IEC 60601-1-11:2015;
b) élargissement du domaine d'application;
c) améliorations d'ordre rédactionnel;
d) ajout d'exigences concernant les dispositifs de transmission d'anticoagulant;
e) quelques autres modifications techniques limitées.
Biološko ovrednotenje medicinskih pripomočkov - 16. del: Načrt toksikokinetičnih raziskav razgradnih produktov in izlužnin (ISO 10993-16:1997)
General Information
Relations
Standards Content (Sample)
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.NVLNRNLQHWLþQLKBiologische Beurteilung von Medizinprodukten - Teil 16: Entwurf und Auslegung toxikokinetischer Untersuchungen hinsichtlich Abbauprodukten und Extrakten (ISO 10993-16:1997)Évaluation biologique des dispositifs médicaux - Partie 16 : Conception des études toxicocinétiques des produits de dégradation et des substances relargables (ISO 10993-16:1997)Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables (ISO 10993-16:1997)11.100.20Biological evaluation of medical devicesICS:Ta slovenski standard je istoveten z:EN ISO 10993-16:2009SIST EN ISO 10993-16:2009en01-julij-2009SIST EN ISO 10993-16:2009SLOVENSKI
STANDARDSIST EN ISO 10993-16:20001DGRPHãþD
SIST EN ISO 10993-16:2009
EUROPEAN STANDARDNORME EUROPÉENNEEUROPÄISCHE NORMEN ISO 10993-16April 2009ICS 11.100.20Supersedes EN ISO 10993-16:1997
English VersionBiological evaluation of medical devices - Part 16: Toxicokineticstudy design for degradation products and leachables (ISO10993-16:1997)Évaluation biologique des dispositifs médicaux - Partie 16:Conception des études toxicocinétiques des produits dedégradation et des substances relargables (ISO 10993-16:1997)Biologische Beurteilung von Medizinprodukten - Teil 16:Entwurf und Auslegung toxikokinetischer Untersuchungenhinsichtlich Abbauprodukten und Extrakten (ISO 10993-16:1997)This European Standard was approved by CEN on 12 April 2009.CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this EuropeanStandard the status of a national standard without any alteration. Up-to-date lists and bibliographical references concerning such nationalstandards may be obtained on application to the CEN 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 translationunder the responsibility of a CEN member into its own language and notified to the CEN Management Centre has the same status as theofficial versions.CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland,France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal,Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.EUROPEAN COMMITTEE FOR STANDARDIZATIONCOMITÉ EUROPÉEN DE NORMALISATIONEUROPÄISCHES KOMITEE FÜR NORMUNGManagement Centre:
Avenue Marnix 17,
B-1000 Brussels© 2009 CENAll rights of exploitation in any form and by any means reservedworldwide for CEN national Members.Ref. No. EN ISO 10993-16:2009: ESIST EN ISO 10993-16:2009
EN ISO 10993-16:2009 (E) 2 Contents Page Foreword .3Annex ZA (informative)
Relationship between this
European
Standard and the Essential Requirements
of EU Directive 93/42/EEC on Medical Devices .4Annex ZB (informative)
Relationship between this
European
Standard and the Essential Requirements
of EU Directive 90/385/EEC on Active Implantable Medical Devices .5 SIST EN ISO 10993-16:2009
EN ISO 10993-16:2009 (E) 3 Foreword The text of ISO 10993-16:1997 has been prepared by Technical Committee ISO/TC 194 “Biological evaluation of medical devices” of the International Organization for Standardization (ISO) and has been taken over as EN ISO 10993-16:2009 by Technical Committee CEN/TC 206 “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 October 2009, and conflicting national standards shall be withdrawn at the latest by March 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 10993-16:1997. This 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 93/42/EEC on Medical Devices and 90/385/EEC on Active Implantable Medical Devices. For relationship with the EU Directives, see informative Annexes ZA and ZB, which is an integral part of this document. According to the CEN/CENELEC Internal Regulations, the national standards organizations of the following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and the United Kingdom. Endorsement notice The text of ISO 10993-16:1997 has been approved by CEN as a EN ISO 10993-16:2009 without any modification. SIST EN ISO 10993-16:2009
EN ISO 10993-16:2009 (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 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 Communities under that Directive and has been implemented as a national standard in at least one Member State, compliance with the clauses of this standard given in table ZA 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 regulations. Table ZA — Correspondence between this European Standard and Directive 93/42/EEC on medical devices Clause(s)/sub-clause(s) of this EN Essential Requirements (ERs) of Directive 93/42/EEC Qualifying remarks/Notes 4, 5 & Annex A
Annex I: 7.1, 7.2, 7.5
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this standard.
SIST EN ISO 10993-16:2009
EN ISO 10993-16:2009 (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 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 standard is cited in the Official Journal of the European Communities under that Directive and has been implemented as a national standard in at least one Member State, compliance with the clauses of this standard given in table ZB 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 regulations. Table ZB — Correspondence between this European Standard and Directive 90/385/EEC on active implantable medical devices Clause(s)/sub-clause(s) of this EN Essential Requirements (ERs) of Directive 90/385/EEC Qualifying remarks/Notes 4, 5 & Annex A Annex I : 9
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this standard.
SIST EN ISO 10993-16:2009
SIST EN ISO 10993-16:2009
INTERNATIONAL STANDARD IS0 109934 6 First edition 1997-09-01 Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables halua tion biologique des dispositifs medicaux - Partie 16: Conception des etudes toxicocinktiques des produits de dhgradation et des substances relargables Reference number IS0 1099346:1997(E) SIST EN ISO 10993-16:2009
ISOlO993=16:1997(E) Contents 1 Scope .,.,.,.*.~~~~~~~~~~~~**~~B~~~*9~*~~~~~~9~~~~~~~~~~~D~~~. 1 2 Normative reference . . . . . . .‘.‘.‘. 1 3 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .~. 1 4 Principles for design of toxicokinetic studies . . . . . . . . . . . . . . . . . . .~.~. 2 5 Guidance on test methods .,,.,,.,.~,.,.,.~.* 3 5.1 General considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .*. 3 5.2 Guidance on specific types of test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .~. 4 Annexes A Circumstances in which toxicokinetic studies shall be considered . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 B Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .~~~~D~8~~~~~~~~~~~BB~~*~~89=~~~9.~. 8 0 IS0 1997 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 the publisher. International Organization for Standardization Case postale 56 l CH-1211 Geneve 20 l Switzerland Internet central @ iso.ch x.400 c=ch; a=40Onet; p=iso; o=isocs; s=central Printed in Switzerland ii SIST EN ISO 10993-16:2009
0 IS0 IS0 10993=16:1997(E) Foreword IS0 (the International Organization for Standardization) is a worldwide federation of national standards bodies (IS0 member bodies). The work of preparing International Standards is normally carried out through IS0 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. IS0 collaborates closely with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization. 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. International Standard IS0 10993 was prepared by Technical Committee ISOmC 194, Ho/ogica/ evaluation of medical devices. IS0 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 cytotoxicity: in vitro methods - Part 6: Tests for local effects after implantation - Part 7: Ethylene oxide sterilization residuals - Part 9: Framework for the identification and quantification of potentia - Part 10: Tests for irritation and sensitization - Part 11: Tests for systemic toxicity - Part 12: Sample preparation and reference materials II degradation products rechnica - Part 13: Identification and quantification of degradation products from polymers - Part 14: Identification 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 Future parts will deal with other relevant aspects of biological testing. Annex A forms an integral part of this part of IS0 10993. Annex 6 is for information only. ,I Report] . . . III SIST EN ISO 10993-16:2009
IS0 10993=16:1997(E) 0 IS0 Introduction This part of IS0 10993 provides guidance and requirements on the design and performance of toxicokinetic studies. Toxicokinetics describes the absorption, distribution, metabolism and excretion of foreign compounds in the body with time. 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 leachables and degradation products. Toxicokinetic studies may 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. 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. The potential hazard posed by a medical device may be attributed to the interactions of its components or their metabolites with the biological system. Medical devices may release leachables (e.g. residual catalysts, processing aids, residual monomers, 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 annex B). The methodologies and techniques utilized in such studies form the basis of the guidance in this standard. A rationale for the use of this part of IS0 10993 is given in annex A. SIST EN ISO 10993-16:2009
INTERNATIONAL STANDARD o IS0 IS0 109934 6: 1997(E) Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables 1 Scope This part of IS0 10993 gives principles on how toxicokinetic studies relevant to medical devices should be designed and performed. Annex A describes the considerations for inclusion of toxicokinetic studies in the biological evaluation of medical devices. 2 Normative reference The following standard contains provisions which, through reference in this text, constitute provisions of this part of IS0 10993. At the time of publication, the edition indicated was valid. All standards are subject to revision, and parties to agreements based on this part of IS0 10993 are encouraged to investigate the possibility of applying the most recent edition of the standard indicated below. Members of IEC and IS0 maintain register of currently valid International Standards. IS0 10993-I : 1992, Biological evaluation of medical devices - Part I: Guidance on selection of tests. 3 Definitions For the purposes of this part of IS0 10993, the definitions given in IS0 10993-I and the following definitions apply. 3.1 degradation product: Product of a material which is generated by the chemical breakdown or decompo- sition of the material. 3.2 leachable: Extractable component, such as an additive, monomeric or oligomeric constituent of polymeric material. 3.3 test substance: Degradation product or leachable used for toxicokinetic study. 3.4 absorption: Process by which a substance enters the blood and/or lymph system. 3.5 distribution: Process by which an absorbed substance and/or its metabolites circulate and partition within the body. 3.6 metabolism: Process by which an absorbed substance is structurally changed within the body by chemical and/or enzymatic reactions. NOTE - The products of the initial reaction may subsequently be modified by either enzymatic or non-enzymatic reactions prior to excretion. 3.7 excretion: Process by which an absorbed substance and/or its metabolites are removed from the body. SIST EN ISO 10993-16:2009
IS0 10993=16:1997(E) 0 IS0 3.8 bioavailability: Extent of systemic absorption of intact substance. 3.9 clearance: Rate of removal of a substance from the body by metabolism and/or excretion. 3.10 half-life (t1/2): Time for the concentration of a particular molecular species to decrease to 50% of its initial value in the same body fluid or tissue. 3.11 mean residence time: Statistical moment the persistence of a substance in the body. related to half-life which provides a quantitative estimate of 3.12 Cmax: Maximum concentration of a substance in plasma expressed in mass per unit volume. NOTE - When the maximum concentration in fluid or tissue is being refe identifier emg- cmax, liver and be expressed in mass per unit volume or mass. rred to, it should have an appropriate 3.13 tmax: Time at which Cmax is observed. 3.14 AUCo+ Area under the plasma concentration versus time curve, from time zero to time tfollowing a single dose of a substance. NOTE - t is normally extrapolated to infinity. 3.15 AUMCO-~ : Area under the first moment plasma concentration versus time curve, from time zero to time tfollowing a single dose of a substance. NOTE - t is normally extrapolated to infinity. 3.16 volume of distribution (vd): Parameter for a single-compartment model describing the apparent volume which would contain the amount of test substance in the body if it were uniformly distributed. 3.17 extract liquid: Liquid which is the result of the extraction process on the test material. 3.18 biodegradation: Alteration of a medical device or biomaterial involving loss of integrity and/or performance when exposed to a physiological or simulated environment. 3.19 bioresorption: Process by which product(s) eliminated and/or absorbed. a biomaterial is degraded in the physiological environment a
...
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.NVLNRNLQHWLþQLKBiologische Beurteilung von Medizinprodukten - Teil 16: Entwurf und Auslegung toxikokinetischer Untersuchungen hinsichtlich Abbauprodukten und Extrakten (ISO 10993-16:1997)Évaluation biologique des dispositifs médicaux - Partie 16 : Conception des études toxicocinétiques des produits de dégradation et des substances relargables (ISO 10993-16:1997)Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables (ISO 10993-16:1997)11.100.20Biological evaluation of medical devicesICS:Ta slovenski standard je istoveten z:prEN ISO 10993-16kSIST prEN ISO 10993-16:2009en01-marec-2009kSIST prEN ISO 10993-16:2009SLOVENSKI
STANDARD
kSIST prEN ISO 10993-16:2009
EUROPEAN STANDARDNORME EUROPÉENNEEUROPÄISCHE NORMFINAL DRAFTprEN ISO 10993-16December 2008ICS 11.100.20Will supersede EN ISO 10993-16:1997
English VersionBiological evaluation of medical devices - Part 16: Toxicokineticstudy design for degradation products and leachables (ISO10993-16:1997)Évaluation biologique des dispositifs médicaux - Partie 16:Conception des études toxicocinétiques des produits dedégradation et des substances relargables (ISO 10993-16:1997)Biologische Beurteilung von Medizinprodukten - Teil 16:Entwurf und Auslegung toxikokinetischer Untersuchungenhinsichtlich Abbauprodukten und Extrakten (ISO 10993-16:1997)This draft European Standard is submitted to CEN members for unique acceptance procedure. It has been drawn up by the TechnicalCommittee CEN/TC 206.If this draft becomes a European Standard, CEN members are bound to comply with the CEN/CENELEC Internal Regulations whichstipulate the conditions for giving this European Standard the status of a national standard without any alteration.This draft European Standard was established by CEN in three official versions (English, French, German). A version in any other languagemade by translation under the responsibility of a CEN member into its own language and notified to the CEN Management Centre has thesame status as the official versions.CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland,France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal,Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.Warning : This document is not a European Standard. It is distributed for review and comments. It is subject to change without notice andshall not be referred to as a European Standard.EUROPEAN COMMITTEE FOR STANDARDIZATIONCOMITÉ EUROPÉEN DE NORMALISATIONEUROPÄISCHES KOMITEE FÜR NORMUNGManagement Centre: rue de Stassart, 36
B-1050 Brussels© 2008 CENAll rights of exploitation in any form and by any means reservedworldwide for CEN national Members.Ref. No. prEN ISO 10993-16:2008: EkSIST prEN ISO 10993-16:2009
prEN ISO 10993-16:2008 (E) 2 Contents Page Foreword .3Annex ZA (informative)
Relationship between this
European
Standard and the Essential Requirements
of EU Directive 93/42/EEC on Medical Devices .4Annex ZB (informative)
Relationship between this
European
Standard and the Essential Requirements
of EU Directive 90/385/EEC on Active Implantable Medical Devices .5 kSIST prEN ISO 10993-16:2009
prEN ISO 10993-16:2008 (E) 3 Foreword The text of ISO 10993-16:1997 has been prepared by Technical Committee ISO/TC 194 “Biological evaluation of medical devices” of the International Organization for Standardization (ISO) and has been taken over as prEN ISO 10993-16:2008 by Technical Committee CEN/TC 206 “Biological evaluation of medical devices” the secretariat of which is held by NEN. This document is currently submitted to the Unique Acceptance Procedure. This document will supersede EN ISO 10993-16:1997. This 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 93/42/EEC on Medical Devices and 90/385/EEC on Active Implantable Medical Devices. For relationship with the EU Directives, see informative Annexes ZA and ZB, which is an integral part of this document. Endorsement notice The text of ISO 10993-16:1997 has been approved by CEN as a prEN ISO 10993-16:2008 without any modification. kSIST prEN ISO 10993-16:2009
prEN ISO 10993-16:2008 (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 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 Communities under that Directive and has been implemented as a national standard in at least one Member State, compliance with the clauses of this standard given in table ZA 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 regulations. Table ZA — Correspondence between this European Standard and Directive 93/42/EEC on medical devices Clause(s)/sub-clause(s) of this EN Essential Requirements (ERs) of Directive 93/42/EEC Qualifying remarks/Notes 4, 5 & Annex A
Annex I: 7.1, 7.2, 7.5
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this standard.
kSIST prEN ISO 10993-16:2009
prEN ISO 10993-16:2008 (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 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 standard is cited in the Official Journal of the European Communities under that Directive and has been implemented as a national standard in at least one Member State, compliance with the clauses of this standard given in table ZB 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 regulations.
Table ZB — Correspondence between this European Standard and Directive 90/385/EEC on active implantable medical devices Clause(s)/sub-clause(s) of this EN Essential Requirements (ERs) of Directive 90/385/EEC Qualifying remarks/Notes 4, 5 & Annex A Annex I : 9
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this standard.
kSIST prEN ISO 10993-16:2009
kSIST prEN ISO 10993-16:2009
INTERNATIONAL STANDARD IS0 109934 6 First edition 1997-09-01 Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables halua tion biologique des dispositifs medicaux - Partie 16: Conception des etudes toxicocinktiques des produits de dhgradation et des substances relargables Reference number IS0 1099346:1997(E) kSIST prEN ISO 10993-16:2009
ISOlO993=16:1997(E) Contents 1 Scope .,.,.,.*.~~~~~~~~~~~~**~~B~~~*9~*~~~~~~9~~~~~~~~~~~D~~~. 1 2 Normative reference . . . . . . .‘.‘.‘. 1 3 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .~. 1 4 Principles for design of toxicokinetic studies . . . . . . . . . . . . . . . . . . .~.~. 2 5 Guidance on test methods .,,.,,.,.~,.,.,.~.* 3 5.1 General considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .*. 3 5.2 Guidance on specific types of test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .~. 4 Annexes A Circumstances in which toxicokinetic studies shall be considered . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 B Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .~~~~D~8~~~~~~~~~~~BB~~*~~89=~~~9.~. 8 0 IS0 1997 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 the publisher. International Organization for Standardization Case postale 56 l CH-1211 Geneve 20 l Switzerland Internet central @ iso.ch x.400 c=ch; a=40Onet; p=iso; o=isocs; s=central Printed in Switzerland ii kSIST prEN ISO 10993-16:2009
0 IS0 IS0 10993=16:1997(E) Foreword IS0 (the International Organization for Standardization) is a worldwide federation of national standards bodies (IS0 member bodies). The work of preparing International Standards is normally carried out through IS0 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. IS0 collaborates closely with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization. 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. International Standard IS0 10993 was prepared by Technical Committee ISOmC 194, Ho/ogica/ evaluation of medical devices. IS0 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 cytotoxicity: in vitro methods - Part 6: Tests for local effects after implantation - Part 7: Ethylene oxide sterilization residuals - Part 9: Framework for the identification and quantification of potentia - Part 10: Tests for irritation and sensitization - Part 11: Tests for systemic toxicity - Part 12: Sample preparation and reference materials II degradation products rechnica - Part 13: Identification and quantification of degradation products from polymers - Part 14: Identification 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 Future parts will deal with other relevant aspects of biological testing. Annex A forms an integral part of this part of IS0 10993. Annex 6 is for information only. ,I Report] . . . III kSIST prEN ISO 10993-16:2009
IS0 10993=16:1997(E) 0 IS0 Introduction This part of IS0 10993 provides guidance and requirements on the design and performance of toxicokinetic studies. Toxicokinetics describes the absorption, distribution, metabolism and excretion of foreign compounds in the body with time. 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 leachables and degradation products. Toxicokinetic studies may 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. 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. The potential hazard posed by a medical device may be attributed to the interactions of its components or their metabolites with the biological system. Medical devices may release leachables (e.g. residual catalysts, processing aids, residual monomers, 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 annex B). The methodologies and techniques utilized in such studies form the basis of the guidance in this standard. A rationale for the use of this part of IS0 10993 is given in annex A. kSIST prEN ISO 10993-16:2009
INTERNATIONAL STANDARD o IS0 IS0 109934 6: 1997(E) Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables 1 Scope This part of IS0 10993 gives principles on how toxicokinetic studies relevant to medical devices should be designed and performed. Annex A describes the considerations for inclusion of toxicokinetic studies in the biological evaluation of medical devices. 2 Normative reference The following standard contains provisions which, through reference in this text, constitute provisions of this part of IS0 10993. At the time of publication, the edition indicated was valid. All standards are subject to revision, and parties to agreements based on this part of IS0 10993 are encouraged to investigate the possibility of applying the most recent edition of the standard indicated below. Members of IEC and IS0 maintain register of currently valid International Standards. IS0 10993-I : 1992, Biological evaluation of medical devices - Part I: Guidance on selection of tests. 3 Definitions For the purposes of this part of IS0 10993, the definitions given in IS0 10993-I and the following definitions apply. 3.1 degradation product: Product of a material which is generated by the chemical breakdown or decompo- sition of the material. 3.2 leachable: Extractable component, such as an additive, monomeric or oligomeric constituent of polymeric material. 3.3 test substance: Degradation product or leachable used for toxicokinetic study. 3.4 absorption: Process by which a substance enters the blood and/or lymph system. 3.5 distribution: Process by which an absorbed substance and/or its metabolites circulate and partition within the body. 3.6 metabolism: Process by which an absorbed substance is structurally changed within the body by chemical and/or enzymatic reactions. NOTE - The products of the initial reaction may subsequently be modified by either enzymatic or non-enzymatic reactions prior to excretion. 3.7 excretion: Process by which an absorbed substance and/or its metabolites are removed from the body. kSIST prEN ISO 10993-16:2009
IS0 10993=16:1997(E) 0 IS0 3.8 bioavailability: Extent of systemic absorption of intact substance. 3.9 clearance: Rate of removal of a substance from the body by metabolism and/or excretion. 3.10 half-life (t1/2): Time for the concentration of a particular molecular species to decrease to 50% of its initial value in the same body fluid or tissue. 3.11 mean residence time: Statistical moment the persistence of a substance in the body. related to half-life which provides a quantitative estimate of 3.12 Cmax: Maximum concentration of a substance in plasma expressed in mass per unit volume. NOTE - When the maximum concentration in fluid or tissue is being refe identifier emg- cmax, liver and be expressed in mass per unit volume or mass. rred to, it should have an appropriate 3.13 tmax: Time at which Cmax is observed. 3.14 AUCo+ Area under the plasma concentration versus time curve, from time zero to time tfollowing a single dose of a substance. NOTE - t is normally extrapolated to infinity. 3.15 AUMCO-~ : Area under the first moment plasma concentration versus time curve, from time zero to time tfollowing a single dose of a substance. NOTE - t is normally extrapolated to infinity. 3.16 volume of distribution (vd): Parameter for a single-compartment model describing the apparent volume which would contain the amount of test substance in the body if it were uniformly distributed. 3.17 extract liquid: Liquid which is the result of the extraction process on the test material. 3.18 biodegradation: Alteration of a medical device or biomaterial involving loss of integrity and/or performance when exposed to a physiological or simulated environment. 3.19 bioresorption: Process by which product(s) eliminated and/or absorbed. a biomaterial is degraded in the physiological environment and the 4 Principles for design of toxicokinetic studies 4.1 Toxicokinetic studies should be designed on a case-by-case basis. 4.2 A study protocol shall be written prior to commencement of the study. The study design, including methods, shall be defined in this protocol. Details of areas to be defined are given below and in c
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