1、October 2009DEUTSCHE NORM English price group 12No 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!$Z=u“1552682
2、www.din.deDDIN EN ISO 10993-15Biological evaluation of medical devices Part 15: Identification and quantification of degradation products frommetals and alloys (ISO 10993-15:2000)English version of DIN EN ISO 10993-15:2009-10Biologische Beurteilung von Medizinprodukten Teil 15: Qualitativer und quan
3、titativer Nachweis von Abbauprodukten aus Metallen undLegierungen (ISO 10993-15:2000)Englische Fassung DIN EN ISO 10993-15:2009-10SupersedesDIN EN ISO 10993-15:2001-11See start of validitywww.beuth.deDocument comprises pages212 DIN EN ISO 10993-15:2009-10 Start of validity This standard takes effect
4、 on 1 October 2009. DIN EN ISO 10993-15:2001-11 may be 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 m
5、edical devices” (Secretariat: NEN, Netherlands). The 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 standar
6、d contains specifications meeting the essential requirements 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: Anima
7、l 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: Fr
8、amework for identification and quantification of potential 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 polyme
9、ric medical devices 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 Part 17: Establishment of allowab
10、le limits for leachable substances 3 The DIN Standards corresponding to the European and International Standards referred to in this document are as follows: ISO 3585 DIN ISO 3585 ISO 3696 DIN ISO 3696 ISO 8044 DIN EN ISO 8044 ISO 10993-1 DIN EN ISO 10993-1 ISO 10993-9 DIN EN ISO 10993-9 ISO 10993-1
11、2 DIN EN ISO 10993-12 ISO 10993-13 DIN EN ISO 10993-13 ISO 10993-14 DIN EN ISO 10993-14 ISO 10993-16 DIN EN ISO 10993-16 Amendments This standard differs from DIN EN ISO 10993-15:2001-11 as follows: a) Annex ZA (informative) concerning the relationship between this European Standard and the essentia
12、l requirements of EU Directive 93/42/EEC on medical devices has 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 to active impla
13、ntable 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 10993-15: 2001-11 DIN EN ISO 10993-15:2009-10 Part 18: Chemical characterization of materials Part 19: Physico-chemical, morphological and
14、topographical characterization of materials Technical Specification Part 20: Principles and methods for immunotoxicology testing of medical devices Technical Specification 4 National Annex NA (informative) Bibliography DIN ISO 3585, Borosilicate glass 3.3 Properties DIN ISO 3696, Water for analytica
15、l laboratory use Specification and test methods DIN EN ISO 8044, Corrosion of metals and alloys Basic terms and definitions DIN EN ISO 10993-1, Biological evaluation of medical devices Part 1: Evaluation and testing within a risk management system DIN EN ISO 10993-9, Biological evaluation of medical
16、 devices Part 9: Framework for identification and quantification of potential degradation products DIN EN ISO 10993-12, Biological evaluation of medical devices Part 12: Sample preparation and reference materials DIN EN ISO 10993-13, Biological evaluation of medical devices Part 13: Identification a
17、nd quantification of degradation products from polymeric medical devices DIN EN ISO 10993-14, Biological evaluation of medical devices Part 14: Identification and quantification of degradation products from ceramics DIN EN ISO 10993-16, Biological evaluation of medical devices Part 16: Toxicokinetic
18、 study design for degradation products and leachables DIN EN ISO 10993-15:2009-10 EUROPEAN STANDARDNORME EUROPENNEEUROPISCHE NORMEN ISO 10993-15June 2009ICS 11.100.20 Supersedes EN ISO 10993-15:2000 English VersionBiological evaluation of medical devices - Part 15: Identificationand quantification o
19、f degradation products from metals andalloys (ISO 10993-15:2000)valuation biologique des dispositifs mdicaux - Partie 15:Identification et quantification des produits de dgradationissus des mtaux et alliages (ISO 10993-15:2000)Biologische Beurteilung von Medizinprodukten - Teil 15:Qualitativer und q
20、uantitativer Nachweis vonAbbauprodukten aus Metallen und Legierungen 10993-15:2000)This European Standard was approved by CEN on 23 May 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 natio
21、nal 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
22、 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, Estoni
23、a, 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 STANDARDIZATIONCOMIT EUROPEN DE NORMALISATIONEUROPISCHES
24、 KOMITEE FR NORMUNGManagement Centre: 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 10993-15:2009: E(ISO2 Contents Page DIN EN ISO 10993-15:2009-10 EN ISO 10993-15:2009 (E) Foreword .3 Int
25、roduction.4 1 Scope5 2 Normative references5 3 Terms and definitions .6 4 Degradation test methods 6 4.1 General .6 4.2 Prerequisites7 5 Reagent and sample preparation.7 5.1 Sample documentation.7 5.2 Test solution (electrolyte).7 5.3 Preparation of test.7 6 Electrochemical tests8 6.1 Apparatus.8 6.
26、2 Sample preparation.8 6.3 Test conditions9 6.4 Potentiodynamic measurements .9 6.5 Potentiostatic measurements 9 7 Immersion test .9 7.1 Apparatus.9 7.2 Sample preparation.11 7.3 Immersion test procedure 11 8 Analysis12 9 Test report12 Annex A (informative) Schematic diagram of the electrochemical
27、measuring circuit 13 Annex B (informative) Schematic drawing of an electrolytic cell 14 Annex C (informative) Examples of alternative electrolytes for the electrochemical tests 15 Bibliography16 Annex ZA (informative) Relationship between this European Standard and the Essential Requirements of EU D
28、irective 93/42/EEC on Medical Devices.17 3 Foreword 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 December 2009, and conflicting national standards shall be withdrawn at the latest by March 2010
29、. 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 10993-15:2000. This document has been prepared under
30、 a mandate given to CEN by the European Commission and the European Free Trade Association, and supports essential requirements of EU Directive 93/42/EEC on Medical Devices. For relationship with the EU Directive, see informative Annex ZA, which is an integral part of this document. According to the
31、 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
32、a, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and the United Kingdom. Endorsement notice The text of ISO 10993-15:2000 has been approved by CEN as a EN ISO 10993-15:2009 without any modification. DIN EN ISO 10993-15:2009-10 EN IS
33、O 10993-15:2009 (E) The text of ISO 10993-15:2000 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 10993-15:2009 by Technical Committee CEN/TC 206 “Biological e
34、valuation of medical devices” the secretariat of which is held by NEN. IntroductionOne of the potential health hazards resulting from medical devices may be due to the interactions of theirelectrochemically-induced degradation products with the biological system. Therefore, the evaluation of potenti
35、aldegradation products from metallic materials by methods suitable for testing the electrochemical behavior of thesematerials is a necessary step in the biological performance testing of materials.The body environment typically contains cations of sodium, potassium, calcium and magnesium and anions
36、ofchloride, bicarbonate, phosphate and organic acids generally in concentrations between 2 Gb4 103mol and150 Gb4 103mol. A range of organic molecules such as proteins, enzymes and lipoproteins is also present, but theirconcentrations may vary to a great extent. Earlier studies assumed that organic m
37、olecules did not exert asignificant influence on the degradation of metallic implants, but newer investigations indicate that implant protein interactions should be taken into account. Depending on a particular product or application, altering thepH of the testing environment may also need to be con
38、sidered.In such biological environments, metallic materials may undergo a certain degradation and the differentdegradation products may interact with the biological system in different ways. Therefore, the identification andquantification of these degradation products is an important step in evaluat
39、ing the biological performance ofmedical devices.DIN EN ISO 10993-15:2009-10 EN ISO 10993-15:2009 (E) 41 ScopeThis part of ISO 10993 provides guidance on general requirements for the design of tests for identifying andquantifying degradation products from finished metallic medical devices or corresp
40、onding material samples finishedas ready for clinical use. It is applicable only to those degradation products generated by chemical alteration of thefinished metallic device in an in vitro accelerated degradation test. Because of the accelerated nature of thesetests, the test results may not reflec
41、t the implant or material behavior in the body. The described chemicalmethodologies are a means to generate degradation products for further assessments.This part of ISO 10993 is not applicable to degradation products induced by applied mechanical stress.NOTE Mechanically induced degradation, such a
42、s wear, may be covered in the appropriate product-specific standard.Where product-group standards provide applicable product-specific methodologies for the identification and quantification ofdegradation products, those standards should be considered.Because of the wide range of metallic materials u
43、sed in medical devices, no specific analytical techniques areidentified for quantifying the degradation products. The identification of trace elements (1011G57) and a sensitivity and accuracy todetect a change of 1 mV over a potential range between Gb1 2V.6.1.4 Current-measuring instrument capable o
44、f measuring a current to Gb1 1% of the absolute value over acurrent range between 109A and 101A.6.1.5 Working electrode (test sample).6.1.6 Counter-electrode(s) such as platinum (grid, plate, or wire) or vitreous carbon with an area at least 10times that of the working electrode.6.1.7 Reference elec
45、trode.6.1.8 pH-meter with a sensitivity of Gb1 0,1.A schematic diagram of the electrochemical measurement circuit which may be used as a system with variablepotential is given in annex A.A schematic drawing of an electrolytic cell is given in annex B.6.2 Sample preparationMount the test sample in a
46、watertight electrode holder so that only the test surface is in contact with the electrolyte.Take care to avoid the creation of conditions where crevice corrosion can occur due the formation of a crevicebetween the mounting and the sample. Before testing, clean the specimen ultrasonically for 10 min
47、 to 15 min inethanol, carefully rinse with water of grade 2 in accordance with ISO 3696 and immediately transfer into the testcell.8DIN EN ISO 10993-15:2009-10 EN ISO 10993-15:2009 (E) 6.3 Test conditionsFill the test cell with the test solution (electrolyte). If the electrochemical behaviour is tem
48、perature-sensitive in therange of 10 Gb0Cto50Gb0C, maintain the electrolyte cell at (37 Gb1 1) C. Reduce the oxygen level in the electrolyte bybubbling oxygen-free nitrogen or argon at a rate of approximately 100 cm3Gd7min1for not less than 30 min prior tothe start of the test. The electrolyte shall
49、 be agitated either by the bubbling gas or mechanical means to avoidconcentration gradients. If gas agitation is used, take care not to have any gas bubbles adhering to the active testsurface.Magnetic stirrers often interfere with electrochemical test cells. If they are used, their effect on the test cell shall bedetermined as part of the validation of test equipment, see 4.2.6.4 Potentiodynamic measurementsMeasure the open-circuit potential not less than 2 h after the immersion of the working electrode. Th
