SIST EN ISO 10993-11:2009
(Main)Biological evaluation of medical devices - Part 11: Tests for systemic toxicity (ISO 10993-11:2006)
Biological evaluation of medical devices - Part 11: Tests for systemic toxicity (ISO 10993-11:2006)
This part of ISO 10993 specifies requirements and gives guidance on procedures to be followed in the evaluation of the potential for medical device materials to cause adverse systemic reactions.
Biologische Beurteilung von Medizinprodukten - Teil 11: Prüfungen auf systemische Toxizität (ISO 10993-11:2006)
Dieser Teil von ISO 10993 legt Anforderungen an Verfahren fest und gibt eine Anleitung, die bei der Beurteilung des Potenzials von Materialien für Medizinprodukte zur Auslösung nachteiliger systemischer Re-aktionen zu befolgen sind.
Évaluation biologique des dispositifs médicaux - Partie 11 : Essais de toxicité systémique (ISO 10993-11:2006)
L'ISO 10993-11:2006 spécifie des exigences et fournit des directives quant aux modes opératoires à suivre pour évaluer la possibilité de réactions systémiques défavorables de la part de matériaux de dispositifs médicaux.
Biološko ovrednotenje medicinskih pripomočkov - 11. del: Preskusi sistemske toksičnosti (ISO 10993-11:2006)
General Information
Relations
Standards Content (Sample)
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.Biologische Beurteilung von Medizinprodukten - Teil 11: Prüfungen auf systemische Toxizität (ISO 10993-11:2006)Évaluation biologique des dispositifs médicaux - Partie 11 : Essais de toxicité systémique (ISO 10993-11:2006)Biological evaluation of medical devices - Part 11: Tests for systemic toxicity (ISO 10993-11:2006)11.100.20Biological evaluation of medical devicesICS:Ta slovenski standard je istoveten z:EN ISO 10993-11:2009SIST EN ISO 10993-11:2009en01-julij-2009SIST EN ISO 10993-11:2009SLOVENSKI
STANDARDSIST EN ISO 10993-11:20061DGRPHãþD
SIST EN ISO 10993-11:2009
EUROPEAN STANDARDNORME EUROPÉENNEEUROPÄISCHE NORMEN ISO 10993-11April 2009ICS 11.100.20Supersedes EN ISO 10993-11:2006
English VersionBiological evaluation of medical devices - Part 11: Tests forsystemic toxicity (ISO 10993-11:2006)Évaluation biologique des dispositifs médicaux - Partie 11:Essais de toxicité systémique (ISO 10993-11:2006)Biologische Beurteilung von Medizinprodukten - Teil 11:Prüfungen auf systemische Toxizität (ISO 10993-11:2006)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 10993-11:2009: ESIST EN ISO 10993-11:2009
EN ISO 10993-11:2009 (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 . Error! Bookmark not defined.Annex 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 10993-11:2009
EN ISO 10993-11:2009 (E) 3 Foreword The text of ISO 10993-11:2006 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 10993-11:2009 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 10993-11:2006. 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 EU Directives, see informative Annex ZA and ZB, which are integral parts 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 10993-11:2006 has been approved by CEN as a EN ISO 10993-11:2009 without any modification. SIST EN ISO 10993-11:2009
EN ISO 10993-11:2009 (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, 6
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 10993-11:2009
EN ISO 10993-11:2009 (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, 6 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 10993-11:2009
SIST EN ISO 10993-11:2009
Reference numberISO 10993-11:2006(E)© ISO 2006
INTERNATIONAL STANDARD ISO10993-11Second edition2006-08-15Biological evaluation of medical devices — Part 11: Tests for systemic toxicity Évaluation biologique des dispositifs médicaux — Partie 11: Essais de toxicité systémique
SIST EN ISO 10993-11:2009
ISO 10993-11:2006(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 2006 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
copyright@iso.org Web
www.iso.org Published in Switzerland
ii © ISO 2006 – All rights reserved
SIST EN ISO 10993-11:2009
ISO 10993-11:2006(E) © ISO 2006 – All rights reserved iiiContents Page Foreword.iv Introduction.vi 1 Scope.1 2 Normative references.1 3 Terms and definitions.1 4 General considerations.2 4.1 General.2 4.2 Selection of animal species.3 4.3 Animal status.3 4.4 Animal care and husbandry.3 4.5 Size and number of groups.3 4.6 Route of exposure.4 4.7 Sample preparation.4 4.8 Dosing.5 4.9 Body weight and food/water consumption.6 4.10 Clinical observations.6 4.11 Clinical pathology.6 4.12 Anatomic pathology.7 4.13 Study designs.7 4.14 Quality of investigation.7 5 Acute systemic toxicity.7 5.1 General.7 5.2 Study design.8 5.3 Evaluation criteria.9 5.4 Final report.10 6 Repeated exposure systemic toxicity (subacute, subchronic and chronic systemic toxicity).11 6.1 General.11 6.2 Study design.12 6.3 Evaluation criteria.14 6.4 Final report.15 Annex A (informative)
Routes of administration.16 Annex B (informative)
Dosage volumes.18 Annex C (informative)
Common clinical signs and observations.19 Annex D (informative)
Suggested haematology, clinical chemistry and urinalysis measurements.20 Annex E (informative)
Suggested organ list for histopathological evaluation.22 Annex F (informative)
Information on material-mediated pyrogens.24 Bibliography.26
SIST EN ISO 10993-11:2009
ISO 10993-11:2006(E) iv © ISO 2006 – 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 10993-11 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices. This second edition cancels and replaces the first edition (ISO 10993-11:1993) 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 9: Framework for 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 ⎯ Part 15: Identification and quantification of degradation products from metals and alloys SIST EN ISO 10993-11:2009
ISO 10993-11:2006(E) © ISO 2006 – All rights reserved v⎯ 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 ⎯ Part 19: Physico-chemical, morphological and topographical characterization ⎯ Part 20: Principles and methods for immunotoxicology testing of medical devices SIST EN ISO 10993-11:2009
ISO 10993-11:2006(E) vi © ISO 2006 – All rights reserved Introduction Systemic toxicity is a potential adverse effect of the use of medical devices. Generalized effects, as well as organ 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 part of ISO 10993 addresses the evaluation of generalized systemic toxicity, not specific target organ or organ 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 part of ISO 10993 is not overly prescriptive. Whilst it addresses specific methodological aspects to be considered in the design of systemic toxicity tests, proper study design must be uniquely tailored to the nature of the device’s materials and its intended clinical application. Other elements of this part of ISO 10993 are prescriptive in nature, including those aspects that address compliance with good laboratory 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 studies, which are intended to address systemic effects. Studies which are intended to address other toxicological endpoints are addressed in ISO 10993-3, ISO 10993-6, ISO 10993-10 and ISO/TS 10993-20. Pyrogenicity (see Annex F) represents an additional systemic effect which has historically been included in this part of ISO 10993. However, efforts are being taken to address pyrogenicity in a dedicated, stand-alone standard. Finally, toxicology is an imperfect science. The outcome of any single test should not be the sole basis for making a determination of whether a device is safe for its intended use.
SIST EN ISO 10993-11:2009
INTERNATIONAL STANDARD ISO 10993-11:2006(E) © ISO 2006 – All rights reserved 1Biological evaluation of medical devices — Part 11: Tests for systemic toxicity 1 Scope This part of ISO 10993 specifies requirements and gives guidance on procedures to be followed in the evaluation of the potential for medical device materials to cause adverse systemic reactions. 2 Normative references The following referenced documents are indispensable for the application of this document. For undated references, the latest edition of the referenced document (including any amendments) applies. ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference materials 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 dose dosage amount of test sample administered (e.g. mass, volume) expressed per unit of body weight or surface area 3.2 dose-effect relationship between the dosage and the magnitude of a defined biological effect either in an individual or in a population sample 3.3 dose-response relationship of dosage to the spectrum of effects related to the exposure NOTE There are two types of dose-response relationships. The first type is the response of an individual to a range of doses. The second type is the distribution of responses of a population of individuals to a range of doses. 3.4 leachable substance chemical removed from a device or material by the action of water or other liquids related to the use of the device NOTE Examples of leachable substances are additives, sterilant residues, process residues, degradation products, solvents, plasticizers, lubricants, catalysts, stabilizers, anti-oxidants, colouring agents, fillers and monomers. SIST EN ISO 10993-11:2009
ISO 10993-11:2006(E) 2 © ISO 2006 – All rights reserved 3.5 limit test use of a single group treated at a suitable dosage of test sample in order to delineate the presence or absence of a toxic hazard 3.6 systemic toxicity toxicity that is not limited to adverse effects at the site of contact between the body and the device NOTE Systemic toxicity requires absorption and distribution of a toxicant from its entry point to a distant site at which deleterious effects are produced. 3.7 acute systemic toxicity adverse effects occurring at any time after single, multiple or continuous exposures of a test sample within 24 h 3.8 subacute systemic toxicity adverse effects occurring after multiple or continuous exposure between 24 h and 28 d NOTE Since this term is semantically incorrect, the adverse effects occurring within the specified time period may also be described as a short-term repeated exposure systemic toxicity study. The selection of time intervals between 14 d and 28 d is consistent with most international regulatory guidelines and considered a reasonable approach. Subacute intravenous studies are generally defined as treatment durations of > 24 h but < 14 d. 3.9 subchronic systemic toxicity adverse effects occurring after the repeated or continuous administration of a test sample for a part of the lifespan NOTE Subchronic toxicity studies are usually 90 d in rodents but not exceeding 10 % of the lifespan of other species. Subchronic intravenous studies are generally defined as treatment durations of 14 d to 28 d. 3.10 chronic systemic toxicity adverse effects occurring after the repeated or continuous administration of a test sample for a major part of the life span NOTE Chronic toxicity studies usually have a duration of 6 months to 12 months. 3.11 test sample material, device, device portion, component, extract or portion thereof that is subjected to biological or chemical testing or evaluation 4 General considerations 4.1 General Selection of the appropriate test(s) for a device shall be in accordance with ISO 10993-1, giving due consideration to mode and duration of contact. Testing shall be performed on the final product and/or representative component samples of the final product and/or materials. Test samples shall reflect the conditions under which the device is normally manufactured and processed. If deviations are necessary, they shall be recorded in the test report, together with their justification. For hazard identification purposes, it may be necessary to exaggerate exposure to the test samples. SIST EN ISO 10993-11:2009
ISO 10993-11:2006(E) © ISO 2006 – All rights reserved 3Physical and chemical properties of the test sample including, for example, pH, stability, viscosity, osmolality, buffering capacity, solubility and sterility, are some factors to consider when designing the study. When animal tests are considered, to satisfy the provisions of ISO 10993-2, all reasonably and practically available replacement, reduction and refinement alternatives should be identified and implemented. For in vivo acute toxicity testing, in vitro cytotoxicity data are useful in estimating starting doses [9]. 4.2 Selection of animal species There is no absolute criterion for selecting a particular animal species for systemic toxicity testing of medical devices. However, the species used shall be scientifically justified and in line with the provisions of ISO 10993-2. For acute oral, intravenous, dermal and inhalation studies of medical devices the mouse or rat is preferred with the option of the rabbit in the case of dermal and implantation studies. Non-rodent species may also need to be considered for testing, recognizing that a number of factors might dictate the number or choice of species for study. It is preferred that a single animal species and strain is used when a series of systemic toxicity studies of different durations are performed, e.g. acute, subacute, subchronic and/or chronic systemic toxicity. This controls the variability between species and strains and facilitates an evaluation related solely to study duration. Should multiple species or strains be used, justification for their selection shall be documented. 4.3 Animal status Generally, healthy purpose-bred young adult animals of known origin and with defined microbiological health status should be used. At the commencement of the study, the weight variation of animals used within a sex should not exceed ± 20 % of the mean weight. When females are used, they should be nulliparous and non-pregnant. Animal selection shall be justified. 4.4 Animal care and husbandry Care and handling of animals shall conform to accepted animal husbandry guidelines. Animals shall be acclimatized to the laboratory conditions prior to treatment and the period of time documented. Control of environmental conditions and proper animal care techniques are necessary for meaningful results. Dietary constituents and bedding materials that are known to produce or influence toxicity should be properly characterized and their potential to influence test results taken into account. 4.5 Size and number of groups 4.5.1 Size of groups The precision of the systemic toxicity test is dependent to a large extent on the number of animals used per dose level. The degree of precision needed and, in turn, the number of animals per dose group needed depends on the purpose of the study. Group sizes should logically increase with the duration of treatment, such that at the end of the study enough animals in every group are available for thorough biological evaluation. However, the minimum number of animals should be used consistent with obtaining meaningful results (see ISO 10993-2). Recommended minimum group sizes, all routes considered, are given in Table 1. SIST EN ISO 10993-11:2009
ISO 10993-11:2006(E) 4 © ISO 2006 – All rights reserved Table 1 — Recommended minimum group sizes Study type Rodent Non-rodent Acute a 5 3 Subacute 10 (5 per sex) a 6 (3 per sex) a Subchronic 20 (10 per sex) a 8 (4 per sex) a Chronic 40 (20 per sex) b, c c a Testing in a single sex is acceptable. When a device is intended for use in only one sex, testing should be done in that sex. b The recommendation refers to one dose-level group testing. Where additional exaggerated dose groups are included the recommended group size may be reduced to 10 per sex. c Expert statistical consultation for chronic study group size is recommended. The number of animals tested should be based on the minimum required to provide meaningful data. Enough animals must remain at the termination of the study to ensure proper statistical evaluation of the results. 4.5.2 Number of groups One dose group treated at a suitable dosage of test sample in a single species could delineate the presence or absence of a toxic hazard (i.e., limit test). However, other multi-dose or dose response studies require multiple groups to delineate the toxic response. Group numbers may increase when attempting to exaggerate the dose. The following examples for exaggerating dose should be considered: ⎯ multiples of the clinical surface area exposure; ⎯ multiples of the duration of exposure; ⎯ multiples of the extractable fraction or the individual chemicals; ⎯ multiple administrations within a 24-h period. Other methods to exaggerate the dose may be acceptable. The method used shall be justified. 4.5.3 Treatment controls Depending on the objective of the study, the nature of the test article and the route of exposure, negative, vehicle and/or sham-treated controls should be incorporated into all systemic toxicity studies. These controls shall mimic the test sample preparation and treatment procedure. 4.6 Route of exposure Medical devices or their leachable substances may gain access to the body by multiple routes of exposure. The test route of exposure shall be the most clinically relevant to the use of the device,
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2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.Biologische Beurteilung von Medizinprodukten - Teil 11: Prüfungen auf systemische Toxizität (ISO 10993-11:2006)Évaluation biologique des dispositifs médicaux - Partie 11 : Essais de toxicité systémique (ISO 10993-11:2006)Biological evaluation of medical devices - Part 11: Tests for systemic toxicity (ISO 10993-11:2006)11.100.20Biological evaluation of medical devicesICS:Ta slovenski standard je istoveten z:prEN ISO 10993-11kSIST prEN ISO 10993-11:2009en01-marec-2009kSIST prEN ISO 10993-11:2009SLOVENSKI
STANDARD
kSIST prEN ISO 10993-11:2009
EUROPEAN STANDARDNORME EUROPÉENNEEUROPÄISCHE NORMFINAL DRAFTprEN ISO 10993-11December 2008ICS 11.100.20Will supersede EN ISO 10993-11:2006
English VersionBiological evaluation of medical devices - Part 11: Tests forsystemic toxicity (ISO 10993-11:2006)Évaluation biologique des dispositifs médicaux - Partie 11:Essais de toxicité systémique (ISO 10993-11:2006)Biologische Beurteilung von Medizinprodukten - Teil 11:Prüfungen auf systemische Toxizität (ISO 10993-11:2006)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 10993-11:2008: EkSIST prEN ISO 10993-11:2009
prEN ISO 10993-11:2008 (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 10993-11:2009
prEN ISO 10993-11:2008 (E) 3 Foreword The text of ISO 10993-11:2006 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 10993-11:2008 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 10993-11:2006. 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 EU Directives, see informative Annex ZA and ZB, which is an integral part of this document. Endorsement notice The text of ISO 10993-11:2006 has been approved by CEN as a prEN ISO 10993-11:2008 without any modification. kSIST prEN ISO 10993-11:2009
prEN ISO 10993-11:2008 (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, 6
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 10993-11:2009
prEN ISO 10993-11:2008 (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, 6 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 10993-11:2009
kSIST prEN ISO 10993-11:2009
Reference numberISO 10993-11:2006(E)© ISO 2006
INTERNATIONAL STANDARD ISO10993-11Second edition2006-08-15Biological evaluation of medical devices — Part 11: Tests for systemic toxicity Évaluation biologique des dispositifs médicaux — Partie 11: Essais de toxicité systémique
kSIST prEN ISO 10993-11:2009
ISO 10993-11:2006(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 2006 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
copyright@iso.org Web
www.iso.org Published in Switzerland
ii © ISO 2006 – All rights reserved
kSIST prEN ISO 10993-11:2009
ISO 10993-11:2006(E) © ISO 2006 – All rights reserved iiiContents Page Foreword.iv Introduction.vi 1 Scope.1 2 Normative references.1 3 Terms and definitions.1 4 General considerations.2 4.1 General.2 4.2 Selection of animal species.3 4.3 Animal status.3 4.4 Animal care and husbandry.3 4.5 Size and number of groups.3 4.6 Route of exposure.4 4.7 Sample preparation.4 4.8 Dosing.5 4.9 Body weight and food/water consumption.6 4.10 Clinical observations.6 4.11 Clinical pathology.6 4.12 Anatomic pathology.7 4.13 Study designs.7 4.14 Quality of investigation.7 5 Acute systemic toxicity.7 5.1 General.7 5.2 Study design.8 5.3 Evaluation criteria.9 5.4 Final report.10 6 Repeated exposure systemic toxicity (subacute, subchronic and chronic systemic toxicity).11 6.1 General.11 6.2 Study design.12 6.3 Evaluation criteria.14 6.4 Final report.15 Annex A (informative)
Routes of administration.16 Annex B (informative)
Dosage volumes.18 Annex C (informative)
Common clinical signs and observations.19 Annex D (informative)
Suggested haematology, clinical chemistry and urinalysis measurements.20 Annex E (informative)
Suggested organ list for histopathological evaluation.22 Annex F (informative)
Information on material-mediated pyrogens.24 Bibliography.26
kSIST prEN ISO 10993-11:2009
ISO 10993-11:2006(E) iv © ISO 2006 – 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 10993-11 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices. This second edition cancels and replaces the first edition (ISO 10993-11:1993) 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 9: Framework for 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 ⎯ Part 15: Identification and quantification of degradation products from metals and alloys kSIST prEN ISO 10993-11:2009
ISO 10993-11:2006(E) © ISO 2006 – All rights reserved v⎯ 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 ⎯ Part 19: Physico-chemical, morphological and topographical characterization ⎯ Part 20: Principles and methods for immunotoxicology testing of medical devices kSIST prEN ISO 10993-11:2009
ISO 10993-11:2006(E) vi © ISO 2006 – All rights reserved Introduction Systemic toxicity is a potential adverse effect of the use of medical devices. Generalized effects, as well as organ 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 part of ISO 10993 addresses the evaluation of generalized systemic toxicity, not specific target organ or organ 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 part of ISO 10993 is not overly prescriptive. Whilst it addresses specific methodological aspects to be considered in the design of systemic toxicity tests, proper study design must be uniquely tailored to the nature of the device’s materials and its intended clinical application. Other elements of this part of ISO 10993 are prescriptive in nature, including those aspects that address compliance with good laboratory 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 studies, which are intended to address systemic effects. Studies which are intended to address other toxicological endpoints are addressed in ISO 10993-3, ISO 10993-6, ISO 10993-10 and ISO/TS 10993-20. Pyrogenicity (see Annex F) represents an additional systemic effect which has historically been included in this part of ISO 10993. However, efforts are being taken to address pyrogenicity in a dedicated, stand-alone standard. Finally, toxicology is an imperfect science. The outcome of any single test should not be the sole basis for making a determination of whether a device is safe for its intended use.
kSIST prEN ISO 10993-11:2009
INTERNATIONAL STANDARD ISO 10993-11:2006(E) © ISO 2006 – All rights reserved 1Biological evaluation of medical devices — Part 11: Tests for systemic toxicity 1 Scope This part of ISO 10993 specifies requirements and gives guidance on procedures to be followed in the evaluation of the potential for medical device materials to cause adverse systemic reactions. 2 Normative references The following referenced documents are indispensable for the application of this document. For undated references, the latest edition of the referenced document (including any amendments) applies. ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference materials 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 dose dosage amount of test sample administered (e.g. mass, volume) expressed per unit of body weight or surface area 3.2 dose-effect relationship between the dosage and the magnitude of a defined biological effect either in an individual or in a population sample 3.3 dose-response relationship of dosage to the spectrum of effects related to the exposure NOTE There are two types of dose-response relationships. The first type is the response of an individual to a range of doses. The second type is the distribution of responses of a population of individuals to a range of doses. 3.4 leachable substance chemical removed from a device or material by the action of water or other liquids related to the use of the device NOTE Examples of leachable substances are additives, sterilant residues, process residues, degradation products, solvents, plasticizers, lubricants, catalysts, stabilizers, anti-oxidants, colouring agents, fillers and monomers. kSIST prEN ISO 10993-11:2009
ISO 10993-11:2006(E) 2 © ISO 2006 – All rights reserved 3.5 limit test use of a single group treated at a suitable dosage of test sample in order to delineate the presence or absence of a toxic hazard 3.6 systemic toxicity toxicity that is not limited to adverse effects at the site of contact between the body and the device NOTE Systemic toxicity requires absorption and distribution of a toxicant from its entry point to a distant site at which deleterious effects are produced. 3.7 acute systemic toxicity adverse effects occurring at any time after single, multiple or continuous exposures of a test sample within 24 h 3.8 subacute systemic toxicity adverse effects occurring after multiple or continuous exposure between 24 h and 28 d NOTE Since this term is semantically incorrect, the adverse effects occurring within the specified time period may also be described as a short-term repeated exposure systemic toxicity study. The selection of time intervals between 14 d and 28 d is consistent with most international regulatory guidelines and considered a reasonable approach. Subacute intravenous studies are generally defined as treatment durations of > 24 h but < 14 d. 3.9 subchronic systemic toxicity adverse effects occurring after the repeated or continuous administration of a test sample for a part of the lifespan NOTE Subchronic toxicity studies are usually 90 d in rodents but not exceeding 10 % of the lifespan of other species. Subchronic intravenous studies are generally defined as treatment durations of 14 d to 28 d. 3.10 chronic systemic toxicity adverse effects occurring after the repeated or continuous administration of a test sample for a major part of the life span NOTE Chronic toxicity studies usually have a duration of 6 months to 12 months. 3.11 test sample material, device, device portion, component, extract or portion thereof that is subjected to biological or chemical testing or evaluation 4 General considerations 4.1 General Selection of the appropriate test(s) for a device shall be in accordance with ISO 10993-1, giving due consideration to mode and duration of contact. Testing shall be performed on the final product and/or representative component samples of the final product and/or materials. Test samples shall reflect the conditions under which the device is normally manufactured and processed. If deviations are necessary, they shall be recorded in the test report, together with their justification. For hazard identification purposes, it may be necessary to exaggerate exposure to the test samples. kSIST prEN ISO 10993-11:2009
ISO 10993-11:2006(E) © ISO 2006 – All rights reserved 3Physical and chemical properties of the test sample including, for example, pH, stability, viscosity, osmolality, buffering capacity, solubility and sterility, are some factors to consider when designing the study. When animal tests are considered, to satisfy the provisions of ISO 10993-2, all reasonably and practically available replacement, reduction and refinement alternatives should be identified and implemented. For in vivo acute toxicity testing, in vitro cytotoxicity data are useful in estimating starting doses [9]. 4.2 Selection of animal species There is no absolute criterion for selecting a particular animal species for systemic toxicity testing of medical devices. However, the species used shall be scientifically justified and in line with the provisions of ISO 10993-2. For acute oral, intravenous, dermal and inhalation studies of medical devices the mouse or rat is preferred with the option of the rabbit in the case of dermal and implantation studies. Non-rodent species may also need to be considered for testing, recognizing that a number of factors might dictate the number or choice of species for study. It is preferred that a single animal species and strain is used when a series of systemic toxicity studies of different durations are performed, e.g. acute, subacute, subchronic and/or chronic systemic toxicity. This controls the variability between species and strains and facilitates an evaluation related solely to study duration. Should multiple species or strains be used, justification for their selection shall be documented. 4.3 Animal status Generally, healthy purpose-bred young adult animals of known origin and with defined microbiological health status should be used. At the commencement of the study, the weight variation of animals used within a sex should not exceed ± 20 % of the mean weight. When females are used, they should be nulliparous and non-pregnant. Animal selection shall be justified. 4.4 Animal care and husbandry Care and handling of animals shall conform to accepted animal husbandry guidelines. Animals shall be acclimatized to the laboratory conditions prior to treatment and the period of time documented. Control of environmental conditions and proper animal care techniques are necessary for meaningful results. Dietary constituents and bedding materials that are known to produce or influence toxicity should be properly characterized and their potential to influence test results taken into account. 4.5 Size and number of groups 4.5.1 Size of groups The precision of the systemic toxicity test is dependent to a large extent on the number of animals used per dose level. The degree of precision needed and, in turn, the number of animals per dose group needed depends on the purpose of the study. Group sizes should logically increase with the duration of treatment, such that at the end of the study enough animals in every group are available for thorough biological evaluation. However, the minimum number of animals should be used consistent with obtaining meaningful results (see ISO 10993-2). Recommended minimum group sizes, all routes considered, are given in Table 1. kSIST prEN ISO 10993-11:2009
ISO 10993-11:2006(E) 4 © ISO 2006 – All rights reserved Table 1 — Recommended minimum group sizes Study type Rodent Non-rodent Acute a 5 3 Subacute 10 (5 per sex) a 6 (3 per sex) a Subchronic 20 (10 per sex) a 8 (4 per sex) a Chronic 40 (20 per sex) b, c c a Testing in a single sex is acceptable. When a device is intended for use in only one sex, testing should be done in that sex. b The recommendation refers to one dose-level group testing. Where additional exaggerated dose groups are included the recommended group size may be reduced to 10 per sex. c Expert statistical consultation for chronic study group size is recommended. The number of animals tested should be based on the minimum required to provide meaningful data. Enough animals must remain at the termination of the study to ensure proper statistical evaluation of the results. 4.5.2 Number of groups One dose group treated at a suitable dosage of test sample in a single species could delineate the presence or absence of a toxic hazard (i.e., limit test). However, other multi-dose or dose response studies require multiple groups to delineate the toxic response. Group numbers may increase when attempting to exaggerate the dose. The following examples for exaggerating dose should be considered: ⎯ multiples of the clinical surface area exposure; ⎯ multiples of the duration of exposure; ⎯ multiples of the extractable fraction or the individual chemicals; ⎯ multiple administrations within a 24-h period. Other methods to exaggerate the dose may be acceptable. The method used shall be justified. 4.5.3 Treatment controls Depending on the objective of the study, the nature of the test article and the route of exposure, negative, vehicle and/or sham-treated controls should be incorporated into all systemic toxicity studies. These controls shall mimic the test sample preparation and treatment procedure. 4.6 Route of exposure Medical devices or their leachable substances may gain access to the body by multiple routes of exposure. The test route of exposure shall be the most clinically relevant to the use of the device, where possible. If an alternative route of exposure is necessary, it shall be justified. Examples of routes of administration can be found in Annex A. 4.7 Sample preparation Guidance on sample preparation and stability is given in ISO 10993-12. kSIST prEN ISO 10993-11:2009
ISO 10993-11:2006(E) © ISO 2006 – All rights reserved 54.8 Dosing 4.8.1 Test sample administration Procedures should be designed to avoid physiological changes or animal welfare problems not directly related to the toxicity of the test material. If a single daily dose of a sufficient volume or concentration is not possib
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