1、August 2009DEUTSCHE NORM English price group 16No part of this standard may be reproduced without prior permission ofDIN Deutsches Institut fr Normung e. V., Berlin. Beuth Verlag GmbH, 10772 Berlin, Germany,has the exclusive right of sale for German Standards (DIN-Normen).ICS 11.100.20!$XK“1539840ww
2、w.din.deDDIN EN ISO 10993-17Biological evaluation of medical devices Part 17: Establishment of allowable limits for leachable substances(ISO 10993-17:2002)English version of DIN EN ISO 10993-17:2009-08Biologische Beurteilung von Medizinprodukten Teil 17: Nachweis zulssiger Grenzwerte fr herauslsbare
3、 Bestandteile(ISO 10993-17:2002)Englische Fassung DIN EN ISO 10993-17:2009-08SupersedesDIN EN ISO 10993-17:2003-06See start of validitywww.beuth.deDocument comprises 36 pagesDIN EN ISO 10993-17:2009-08 2 Start of validity This standard takes effect on 1 August 2009. DIN EN ISO 10993-17:2003-06 may b
4、e used in parallel until 21 March 2010. National foreword This standard has been prepared by Technical Committee ISO/TC 194 “Biological evaluation of medical devices” in collaboration with Technical Committee CEN/TC 206 “Biological evaluation of medical devices” (Secretariat: NEN, Netherlands). The
5、responsible German body involved in its preparation was the Normenausschuss Feinmechanik und Optik (Optics and Precision Mechanics Standards Committee), Technical Committee NA 027-02-12 AA Biologische Beurteilung von Medizinprodukten. This standard contains specifications meeting the essential requi
6、rements set out in EU Directive 93/42/EEC on medical devices. ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices: Part 1: Evaluation and testing within a risk management system Part 2: Animal welfare requirements Part 3: Tests for genotoxicity
7、, 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 pote
8、ntial degradation products Part 10: Tests for irritation and skin sensitization Part 11: Tests for systemic toxicity Part 12: Sample preparation and reference materials Part 13: Identification and quantification of degradation products from polymeric medical devices Part 14: Identification and quant
9、ification 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 Part 17: Establishment of allowable limits for leachable substances Part 18: Chemical
10、characterization of materials DIN EN ISO 10993-17:2009-08 3 Part 19: Physico-chemical, morphological and topographical characterization of materials Technical Specification Part 20: Principles and methods for immunotoxicology testing of medical devices Technical Specification The DIN Standard corres
11、ponding to the International Standard referred to in clause 2 of this document is as follows: ISO 10993-1 DIN EN ISO 10993-1 Amendments This standard differs from DIN EN ISO 10993-17:2003-06 as follows: a) Annexes ZA and ZB (informative) concerning the relationship between this European Standard and
12、 the essential requirements of EU Directive 93/42/EEC on medical devices have been updated on the basis of EU Directive 2007/47/EC of the European Parliament and of the Council of 5 September 2007 amending Council Directives 90/385/EEC on the approximation of the laws of the Member States relating t
13、o active implantable medical devices and 93/42/EEC on medical devices and EU Directive 98/8/EC on the placing on the market of biocidal products. Previous editions DIN EN ISO 10993-17: 2003-06 National Annex NA (informative) Bibliography DIN EN ISO 10993-1, Biological evaluation of medical devices P
14、art 1: Evaluation and testing DIN EN ISO 10993-17:2009-08 4 This page is intentionally blank EUROPEAN STANDARD NORME EUROPENNE EUROPISCHE NORM EN ISO 10993-17 April 2009 ICS 11.100.20 Supersedes EN ISO 10993-17:2002 English Version Biological evaluation of medical devices - Part 17: Establishment of
15、 allowable limits for leachable substances (ISO 10993-17:2002) valuation biologique des dispositifs mdicaux - Partie 17: tablissement des limites admissibles des substances relargables (ISO 10993-17:2002) Biologische Beurteilung von Medizinprodukten - Teil 17: Nachweis zulssiger Grenzwerte fr heraus
16、lsbare Bestandteile (ISO 10993-17:2002) 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 European Standard the status of a national standard without any alteration. Up
17、-to-date lists and bibliographical references concerning such national standards 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 translation u
18、nder the responsibility of a CEN member into its own language and notified to the CEN Management Centre has the same 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
19、, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom. EUROPEAN COMMITTEE FOR STANDARDIZATION COMIT EUROPEN DE NORMALISATION EUROPISCHES KOMITEE FR NORMUNG Management
20、 Centre: Avenue Marnix 17, B-1000 Brussels 2009 CEN All rights of exploitation in any form and by any means reserved worldwide for CEN national Members. Ref. No. EN ISO 10993-17:2009: E2 Contents Page Foreword3 Introduction.4 1 Scope 5 2 Normative reference5 3 Terms and definitions .5 4 General prin
21、ciples for establishing allowable limits8 5 Establishment of tolerable intake (TI) for specific leachable substances.9 5.1 General9 5.2 Exposure considerations for TI calculation11 5.3 Collection and evaluation of data 11 5.4 Set TI for noncancer endpoints12 5.5 Set TI for cancer endpoints 14 5.6 Es
22、tablishment of tolerable contact levels (TCLs) 15 5.7 Risk assessment of mixtures .17 6 Calculation of tolerable exposure (TE)17 6.1 General17 6.2 Exposure population.18 6.3 Calculation of utilization factor from intended use pattern 18 6.4 Tolerable exposure19 7 Feasibility evaluation 20 8 Benefit
23、evaluation20 9 Allowable limits21 10 Reporting requirements21 Annex A (informative) Some typical assumptions for biological parameters 22 Annex B (informative) Risk assessment for mixtures of leachable substances24 Annex C (informative) Conversion of allowable limits for systemic exposure and for bo
24、dy surface contact to maximum dose to patient from a medical device 25 Annex D (informative) Risk analysis report27 Bibliography28 Annex ZA (informative) Relationship between this European Standard and the Essential Requirements of EU Directive 93/42/EEC on Medical Devices 30 Annex ZB (informative)
25、Relationship between this European Standard and the Essential Requirements of EU Directive 90/385/EEC on Active Implantable Medical Devices .31 Annex ZC (informative) Normative references to international publications with their relevant European publications32 DIN EN ISO 10993-17:2009-08 EN ISO 109
26、93-17:2009 (E) 3 Foreword The text of ISO 10993-17:2002 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 10993-17:2009 by Technical Committee CEN/TC 206 “Biolog
27、ical 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
28、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 10993-17:2002. This document
29、 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 inf
30、ormative 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, Eston
31、ia, 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 10993-17:2002 has been approved by C
32、EN as a EN ISO 10993-17:2009 without any modification. EN ISO 10993-17:2009 (E) DIN EN ISO 10993-17:2009-08 Introduction The determination of the suitability of a medical device for a particular use involves balancing any identified risks with the clinical benefit to the patient associated with its
33、use. Among the risks to be considered are those arising from exposure to leachable substances arising from medical devices. Risks associated with exposure to hazardous leachable substances are managed by identifying the leachable substances, quantifying the associated risks and limiting exposure wit
34、hin tolerable levels. This part of ISO 10993 provides a method by which maximum tolerable levels can be calculated from available data on health risks. Allowable limits may be based upon health risks that can be systemic or local, immediate or delayed, and range in severity from minor localized adve
35、rse effects to life-threatening risks. These allowable limits are intended to be derived, using this part of ISO 10993, by toxicologists or other knowledgeable and experienced individuals, capable of making informed decisions based upon scientific data and a knowledge of medical devices. The allowab
36、le limits derived may be used by anyone. In addition to use by ISO, other standards-developing organizations, government agencies, regulatory bodies, and other users for setting allowable limits as standards or regulations, manufacturers and processors may use the allowable limits derived to optimiz
37、e processes and aid in the choice of materials in order to protect patient health. Where risks associated with exposure to particular leachable substances are unacceptable, this part of ISO 10993 can be used to qualify alternative materials or processes. 4 DIN EN ISO 10993-17:2009-08 EN ISO 10993-17
38、:2009 (E) 1 Scope This part of ISO 10993 specifies a method for the determination of allowable limits for substances leachable from medical devices. It is intended for use in deriving standards and estimating appropriate limits where standards do not exist. It describes a systematic process through
39、which identified risks arising from toxicologically hazardous substances present in medical devices can be quantified. This part of ISO 10993 is not applicable to devices that have no patient contact (e.g. in vitro diagnostic devices). Exposure to a particular chemical substance may arise from sourc
40、es other than the device, such as food, water or air. This part of ISO 10993 does not address the potential for exposure from such sources. 2 Normative reference The following normative document contains provisions which, through reference in this text, constitute provisions of this part of ISO 1099
41、3. For dated references, subsequent amendments to, or revisions of, any of these publications do not apply. However, parties to agreements based on this part of ISO 10993 are encouraged to investigate the possibility of applying the most recent edition of the normative document indicated below. For
42、undated references, the latest edition of the normative document referred to applies. Members of ISO and IEC maintain registers of currently valid International Standards. ISO 10993-1, Biological evaluation of medical devices Part 1: Evaluation and testing 3 Terms and definitions For the purposes of
43、 this part of ISO 10993, the terms and definitions given in ISO 10993-1 and the following apply. 3.1 allowable limit AL largest amount of a leachable substance that is deemed acceptable on a daily basis, when taken into the body through exposure to a medical device NOTE Allowable limits are expresse
44、d in dose to the patient for each applicable exposure period. The units used are mass per unit time, e.g. milligrams per day. These doses represent tolerable risks for medical devices under the circumstances of intended use. 3.2 benefit factor BF numerical factor that takes into account the health b
45、enefit from use of the medical device(s) containing the leachable substance in question 5 EN ISO 10993-17:2009 (E) DIN EN ISO 10993-17:2009-08 3.3 concomitant exposure factor CEF numerical factor that accounts for patient exposure to many medical devices containing the same leachable substance NOTE
46、This factor is used to adjust the product of TI and body mass downward. 3.4 default value to be used, in the absence of data, for an uncertainty or other factor used in the calculation of the allowable limit 3.5 harm to health physical injury and/or damage to health 3.6 health benefit likelihood of
47、maintaining or improving health 3.7 health hazard potential source of harm to health 3.8 health risk combination of the likelihood of occurrence of harm to health and the severity of that harm 3.9 health risk analysis use of available information to identify health hazards and to estimate health ris
48、k 3.10 leachable substance chemical removed from a medical device by the action of water or other liquids related to the use of the device EXAMPLE Additives, sterilant residues, process residues, degradation products, solvents, plasticizers, lubricants, catalysts, stabilizers, anti-oxidants, colouri
49、ng agents, fillers and monomers, among others. 3.11 lowest observed adverse effect level LOAEL lowest concentration or amount of a substance found by experiment or observation which causes detectable adverse alteration of morphology, functional capacity, growth, development or life span of the target organism under defined conditions of exposure NOTE Alterations in morphology, functional capacity, growth, development or life span of the target organism may be detected which are judged not to be adverse. 3.12 minimally
