1、BS EN ISO10993-18:2009ICS 11.100.20NO COPYING WITHOUT BSI PERMISSION EXCEPT AS PERMITTED BY COPYRIGHT LAWBRITISH STANDARDBiological evaluationof medical devicesPart 18: Chemical characterization ofmaterials (ISO 10993-18:2005)This British Standardwas published under theauthority of the StandardsPoli
2、cy and StrategyCommittee on 30 June2009. BSI 2009ISBN 978 0 580 65822 8Amendments/corrigenda issued since publicationDate CommentsBS EN ISO 10993-18:2009National forewordThis British Standard is the UK implementation of EN ISO10993-18:2009. It is identical to ISO 10993-18:2005. It supersedes BS ENIS
3、O 10993-18:2005 which is withdrawn.The UK participation in its preparation was entrusted to TechnicalCommittee CH/194, Biological evaluation of medical devices.A list of organizations represented on this committee can be obtained onrequest to its secretary.This publication does not purport to includ
4、e all the necessary provisionsof a contract. Users are responsible for its correct application.Compliance with a British Standard cannot confer immunityfrom legal obligations.EUROPEAN STANDARDNORME EUROPENNEEUROPISCHE NORMEN ISO 10993-18April 2009ICS 11.100.20 Supersedes EN ISO 10993-18:2005 English
5、 VersionBiological evaluation of medical devices - Part 18: Chemicalcharacterization of materials (ISO 10993-18:2005)valuation biologique des dispositifs mdicaux - Partie 18:Caractrisation chimique des matriaux (ISO 10993-18:2005)Biologische Beurteilung von Medizinprodukten - Teil 18:Chemische Chara
6、kterisierung von Werkstoffen (ISO 10993-18:2005)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 alterati
7、on. 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 translati
8、onunder 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, Greec
9、e, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal,Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.EUROPEAN COMMITTEE FOR STANDARDIZATIONCOMIT EUROPEN DE NORMALISATIONEUROPISCHES KOMITEE FR NORMUNGManagement Cen
10、tre: Avenue Marnix 17, B-1000 Brussels 2009 CEN All rights of exploitation in any form and by any means reservedworldwide for CEN national Members.Ref. No. EN ISO 10993-18:2009: EBS EN ISO 10993-18:2009EN ISO 10993-18:2009 (E) 3 Foreword The text of ISO 10993-18:2005 has been prepared by Technical C
11、ommittee ISO/TC 194 “Biological evaluation of medical devices” of the International Organization for Standardization (ISO) and has been taken over as EN ISO 10993-18:2009 by Technical Committee CEN/TC 206 “Biological evaluation of medical devices” the secretariat of which is held by NEN. This Europe
12、an 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 element
13、s 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 10993-18:2005. This document has been prepared under a mandate given to CEN by the European Commission and the Europ
14、ean 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
15、 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, Lithuani
16、a, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and the United Kingdom. Endorsement notice The text of ISO 10993-18:2005 has been approved by CEN as a EN ISO 10993-18:2009 without any modification. BS EN ISO 10993-18:2009EN ISO 109
17、93-18:2009 (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
18、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, compl
19、iance 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
20、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 5, 6, 7, 8 b) the increased temperature could cause degradant materials to form that are not typically found in the finished device under use conditi
21、ons; c) the increased temperature could cause the disappearance of a leachable material typically found in the finished device. 3.7 simulated extraction extraction for evaluating potential risk to the patient or user during routine use of a device, using an extraction method with an appropriate medi
22、um that simulates product use NOTE See NOTE to 3.6. BS EN ISO 10993-18:2009ISO 10993-18:2005(E) ISO 2005 All rights reserved 34 Symbols and abbreviated terms The following abbreviated terms are used in Clause 7. Table 1 Methodology abbreviations Abbreviated term Analytical method DMTA Dynamic mechan
23、ical thermal analysis DSC Differential scanning calorimetry EDX-SEM Electron dispersal X-ray analysis scanning electron microscopy FTIR Fourier transform infra red (spectroscopy) GC Gas chromatography MS Mass spectroscopy aGPC Gel permeation chromatography HPLC High performance liquid chromatography
24、 ICP Inductively coupled plasmaIR Infrared (spectroscopy) NMR Nuclear magnetic resonance (spectroscopy) UV Ultraviolet (spectroscopy) XPS X-ray photoelectron spectroscopy XRF X-ray fluorescence 2D PAGE Two-dimensional polyacrylamide gel electrophoresis aMass spectroscopy is frequently combined with
25、chromatographic techniques such as GC-MS, LC-MS and MS-MS. 5 General principles Consideration of the chemical characterization of the materials from which a medical device is made is a necessary first step in assessing the biological safety of the device. It is also important in judging equivalence
26、of a) a proposed material to a clinically established material, and b) a prototype device to a final device. An overview of the chemical characterization procedure outlined in this document and its relationship to risk assessment is given in Annex A. Qualitative data shall be obtained to describe th
27、e chemical composition of a material. When relevant to biological safety, quantitative data shall also be obtained. For some materials compositional information may be readily available as part of the material specification. Materials such as polymers may possess more complex formulations and compos
28、itional details should be obtained from the supplier of the material. In the absence of such details appropriate analytical techniques should be applied to a material to yield compositional data. Identification of the constituents of a material intended for use in the manufacture of a medical device
29、 enables the intrinsic toxicity of each constituent to be investigated. The data obtained are intended for use by the medical device manufacturer as part of the overall biological safety evaluation of the medical device. It is therefore important that controls should be introduced to prevent a mater
30、ial supplier from changing the composition of a material supplied under a specific commercial trade name or supply agreement without prior BS EN ISO 10993-18:2009ISO 10993-18:2005(E) 4 ISO 2005 All rights reservednotification to the medical device manufacturer. The manufacturer should assess the con
31、sequences of any notified changes on the biological safety of the product. Any of the constituents of a material or additives used in the process of manufacture of a medical device are potentially bio-available. However it is necessary to obtain information demonstrating the extent to which the cons
32、tituents will be available under the actual conditions of use of the finished product to estimate the risk arising from them. This can be estimated from extraction tests on the material. Appropriate extraction conditions (simulated extraction) are used to ensure that any constituent which is likely
33、to be released during finished product use will be released into the extraction media. The extract obtained can be analysed qualitatively and/or quantitatively to generate data that can then be used in the biological safety evaluation of the medical device. The extent of chemical characterization re
34、quired should reflect the nature and duration of the clinical exposure and shall be determined by the toxicological risk assessor based on the data necessary to evaluate the biological safety of the device. It will also reflect the physical form of the materials used, e.g. liquids, gels, polymers, m
35、etals, ceramics, composites or biologically sourced material. The successful completion of the chemical characterization outlined in this document requires the close collaboration of material scientists, analytical chemists and toxicological risk assessors. In this partnership, the material scientis
36、t and analytical chemist provide the necessary qualitative and quantitative data that a risk assessor may use to determine device safety. 6 Characterization procedure 6.1 General The generation of chemical characterization data is a step-wise process linked to risk assessment and a flowchart compose
37、d of 5 steps is given in Annex A. The chemical characterization requirements and guidance at each step are specified in 6.2 to 6.6. The analytical methods shall be selected to give the required information for the toxicological evaluation. If suitable methods cannot be identified, appropriate new me
38、thods shall be developed. Prior to new method development, existing standards, monographs, scientific articles or other relevant scientific documents should be consulted to check for existing appropriate test methods. Methods from the literature may need to be adapted and validated before use. The a
39、nalytical methods used shall be validated, justified and reported (see Clause 8). The validation of an analytical method is the process by which it is established that the performance characteristics of the method meet the requirements for the intended analytical applications. Analytical methods sha
40、ll be validated as appropriate with respect to the following justified analytical characteristics: accuracy; precision; specificity; limit of detection; limit of quantification; linearity; range; ruggedness; robustness; system suitability. BS EN ISO 10993-18:2009ISO 10993-18:2005(E) ISO 2005 All rig
41、hts reserved 5At each step of the characterization procedure, a decision shall be made on the adequacy of the data obtained as a basis for the risk analysis. This procedure should consider each of the materials used in a medical device in addition to the requirement for chemical characterization of
42、the finished device. NOTE 1 Steps 2 and 4, 6.3 and 6.5 respectively, are part of the risk assessment process and are outside the scope of this part of ISO 10993. They are given for information to indicate the important interaction between chemical characterization and risk assessment. NOTE 2 The sup
43、plier can be a useful source of appropriate analytical methods. In the absence of any initial compositional data, a literature study to establish the likely nature of the starting material and any additives is recommended to assist in the selection of the most appropriate methods of analysis for the
44、 material concerned. If the material or device contacts the body directly or indirectly then this part of ISO 10993 is applicable (see 4.2.1 of ISO 10993-1:2003). 6.2 Step 1 Qualitative information Describe the material/device and its intended purpose. A documented, qualitative description is requir
45、ed of the composition of the finished device, including additives and processing residues for each material used in the device (see 3.3 and Clause 4 of ISO 10993-1:2003 and Annex B). The level of qualitative data provided/required shall reflect the category of medical device in terms of degree of in
46、vasiveness and clinical exposure duration as well as the nature of the materials and shall be justified. The qualitative description shall, where applicable, include details of batch or lot, supplier and material specification for each material. The use of a standardised material, e.g. ISO 5832-1, i
47、n its intended use is considered to meet this requirement. Medical device manufacturers should preferably obtain qualitative and quantitative compositional information from the supplier of the starting material. Qualitative information about any additional processing additives, for example, mould re
48、lease agents, should also be obtained from appropriate members of the manufacturing chain, including convertors and component manufacturers. The composition of materials shall either be in accordance with applicable materials standards or shall be specified by the manufacturer. Sufficient informatio
49、n shall be obtained at this stage to identify all toxic hazards arising from the chemical components of the material and sent for risk assessment (see 4.3 of ISO 14971:2000). 6.3 Step 2 Material equivalence Sufficient qualitative information shall be obtained to allow a comparison to determine whether the material is equivalent to that utilized in a device with the same clinical exposure/use and having had the same manufacturing and sterilization processes applied, e.g. established safe use of materials in a product to be used on intac
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