ISO 10993-15-2000 Biological evaluation of medical devices - Part 15 Identification and quantification of degradation products from metals and alloys《医疗器械的生物学评价.pdf

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1、INTERNATIONAL STANDARD IS0 10993-1 5 First edition 2000-12-01 Corrected and reprinted 2001-04-01 Biological evaluation of medical devices - Part 15: Identification and quantification of degradation products from metals and alloys valuation biologique des dispositifs mdicaux - Partie 15: Identificati

2、on et quantification des produits de dgradation issus des mtaux et alliages Reference number IS0 10993-15:2000(E) 0 IS0 2000 IS0 10993-1 5:2000(E) - PDF disclaimer This PDF file may contain embedded typefaces. In accordance with Adobes licensing policy, this file may be printed or viewed but shall n

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5、ember bodies. In the unlikely event that a problem relating to it is found, please inform the Central Secretariat at the address given below. o 1s02000 ,411 rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized in any form or by any means. electronic

6、or mechanical. including photocopying and microfilm. without permission in writing from either IC0 at the address below or ISOs member body in the country of the requester. IS0 copyright office Case postale 56 CH-I21 1 Geneva 20 Tel. + 41 22 749 O1 11 Fax +41227490947 E-mail copyrightiso.ch Web www.

7、iso.ch Printed in Switzerland II O IS0 2000 - All rights reserved IS0 10993-1 5:2000(E) Contents Page Foreword . iv Introduction vi 1 2 3 4 4.1 4.2 5 5.1 5.2 5.3 6 6.1 6.2 6.3 6.4 6.5 7 7.1 7.2 7.3 8 9 Scope 1 Normative references 1 Terms and definitions . 2 Degradation test methods 2 General 2 Prer

8、equisites 3 Reagent and sample preparation . 3 Sample documentation . 3 Test solution (electrolyte) . 3 Preparation of test samples 3 Electrochemical tests 4 Apparatus . 4 Sample preparation . 4 Test conditions 5 Potentiodynamic measurements . 5 Potentiostatic measurements . 5 Immersion test . 5 App

9、aratus . 5 Sample preparation . 7 Immersion test procedure . 7 Ana lysis 8 Test report 8 Annex A (informative) Schematic diagram of the electrochemical measuring circuit . 9 Annex B (informative) Schematic drawing of an electrolytic cell 10 Annex C (informative) Examples of alternative electrolytes

10、for the electrochemical tests . 11 Bibliography 12 O is0 2000 . All rights reserved . . ._ . 111 IS0 10993-1 5:2000(E) Foreword IS0 (the International Organization for Standardization) is a worldwide federation of national standards bodies (IS0 member bodies). The work of preparing International Sta

11、ndards is normally carried out through IS0 technical committees. Each member body interested in a subject for which a technical committee has been established has the right to be represented on that committee. International organizations, governmental and non-governmental, in liaison with ISO, also

12、take part in the work. IS0 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 ISOAEC Directives, Part 3. Draft International Standards adopted

13、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 part of IS0 10993 may be the subject of

14、patent rights. IS0 shall not be held responsible for identifying any or all such patent rights. International Standard IS0 10993-1 5 was prepared by Technical Committee ISOnC 194, Biological evaluation of medical devices. IS0 10993 consists of the following parts, under the general title Biological

15、evaluation of medical devices: - Part 1: Evaluation and testing - Part 2: Animal welfare requirements - Part 3: Tests for genotoxicify, carcinogenicity and reproductive toxicity - Part 4: Selection of tests for interactions with blood - Part 5: Tests for in vitro cytotoxicity - Part 6: Tests for loc

16、al effects after implantation - Part 7: Ethylene oxide sterilization residuals - Part 8: Selection and qualification of reference materials for biological tests - Part 9: Framework for identification and quantification of potential degradation products - Part 1 O: Tests for irritation and delayed-ty

17、pe hypersensitiviy - 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 - Par

18、t 15: Identification and quantification of degradation products from metals and alloys - Part 16: Toxicokinetic study design for degradation products and leachables I iv 0 IS0 2000 -All rights reserved IS0 10993-1 5:2000(E) - Part 17: Establishment of allowable limits for leachable substances using

19、health-based risk assessment - Part 18: Chemical characterization of materials Future parts will deal with other relevant aspects of biological testing. Annexes A, B and C of this part of IS0 10993 are for information only. O IS0 2000 - All rights reserved V IS0 10993-1 5:2000(E) Introduction One of

20、 the potential health hazards resulting from medical devices may be due to the interactions of their electrochemically-induced degradation products with the biological system. Therefore, the evaluation of potential degradation products from metallic materials by methods suitable for testing the elec

21、trochemical behavior of these materials 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 of chloride, bicarbonate, phosphate and organic acids generally in concentrations bet

22、ween 2 x 1 O -3 mol and 150 x 10-3 mol. A range of organic molecules such as proteins, enzymes and lipoproteins is also present, but their concentrations may vary to a great extent. Earlier studies assumed that organic molecules did not exert a significant influence on the degradation of metallic im

23、plants, but newer investigations indicate that implant - protein interactions should be taken into account. Depending on a particular product or application, altering the pH of the testing environment may also need to be considered. In such biological environments, metallic materials may undergo a c

24、ertain degradation and the different degradation products may interact with the biological system in different ways. Therefore, the identification and quantification of these degradation products is an important step in evaluating the biological performance of medical devices. vi 0 IS0 2000 - All ri

25、ghts reserved - INTERNATIONAL STANDARD IS0 10993-1 5:2000( E) d Biological evaluation of medical devices - Part 15: Identification and quantification of degradation products from metals and alloys 1 Scope This part of IS0 10993 provides guidance on general requirements for the design of tests for id

26、entifying and quantifying degradation products from finished metallic medical devices or corresponding material samples finished as ready for clinical use. It is applicable only to those degradation products generated by chemical alteration of the finished metallic device in an in vitro accelerated

27、degradation test. Because of the accelerated nature of these tests, the test results may not reflect the implant or material behavior in the body. The described chemical methodologies are a means to generate degradation products for further assessments. This part of IS0 10993 is not applicable to de

28、gradation products induced by applied mechanical stress. NOTE Mechanically induced degradation, such as wear, may be covered in the appropriate product-specific standard. Where product-group standards provide applicable product-specific methodologies for the identification and quantification of degr

29、adation products, those standards should be considered. Because of the wide range of metallic materials used in medical devices, no specific analytical techniques are identified for quantifying the degradation products. The identification of trace elements (.: 10-6) contained in the specific metal o

30、r alloy is not addressed in this part of IS0 10993, nor are specific requirements for acceptable levels of degradation products provided in this part of IS0 10993. This part of IS0 10993 does not address the biological activity of the degradation products; see instead the applicable clauses of IS0 1

31、0993-1 and IS0 10993-17. 2 Normative references The following normative documents contain provisions which, through reference in this text, constitute provisions of this International Standard. For dated references, subsequent amendments to, or revisions of, any of these publications do not apply. H

32、owever, parties to agreements based on this International Standard are encouraged to investigate the possibility of applying the most recent editions of the normative documents indicated below. For undated references, the latest edition of the normative document referred to applies. Members of IS0 a

33、nd IEC maintain registers of currently valid International Standards. IS0 3585, Borosilicate glass 3.3 - Properties. IS0 3696, Water for analytical laboratory use - Specification and test methods. IS0 8044, Corrosion of metals and alloys - Basic terms and definitions. IS0 10993-1, Biological evaluat

34、ion of medical devices - Part 1: Evaluation and testing. IS0 10993-9, Biological evaluation of medical devices - Part 9: Framework for identification and quantification of potential degradation products. O IC0 2000 - Ali rights reserved 1 IS0 10993-1 5:2000(E) IS0 10993-1 2, Biological evaluation of

35、 medical devices - Part 12: Sample preparation and reference materials. IS0 10993-1 3, Biological evaluation of medical devices - Part 13: Identification and quantification of degradation products from polymeric medical devices IS0 10993-1 4, Biological evaluation of medical devices - Part 14: Ident

36、ification and quantification of degradation products from ceramics. IS0 10993-1 6, Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables. 3 Terms and definitions For the purposes of this part of IS0 10993, the terms and definitions giv

37、en in IS0 8044, IS0 10993-1, IS0 10993-9, IS0 10993-1 2 and the following apply. 3.1 alloy material composed of a metallic element with one or more addition(s) of other metallic and/or non-metallic elements 3.2 electrolyte solution containing ions with the capacity to conduct electric current 3.3 op

38、en-circuit potential potential of an electrode measured with respect to a reference electrode or another electrode when no current flows to or from it 3.4 passive limit potential Ea electrode potential of the positive limit of the passive range See Figure 1 3.5 breakdown potential critical electrode

39、 potential above which localized or transpassive corrosion is found to occur EP See Figure 1. 4 Degradation test methods 4.1 General To identify and quantify degradation products from metals and alloys in medical devices, a combination of two procedures is described. The choice of test procedure sha

40、ll be justified according to the function of the medical device. The first procedure described is a combination of a potentiodynamic test and a potentiostatic test. The second procedure described is an immersion test, The potentiodynamic test is used to determine the general electrochemical behavior

41、 of the material under consideration and to determine certain specific points (E, and EP) on the potential/current density curve. O IS0 2000 - All rights reserved 2 IS0 10993-15:2000(E) The immersion test is used to chemically degrade the test material to generate degradation products to be analysed

42、. If there is the possibility of the loss of a coating from a metallic substrate due to degradation, the potential degradation products from the substrate material shall be considered, as well as the coating itself. In addition, if a metallic substrate coated with a non-metallic material is to be te

43、sted, the requirements of IS0 10993-13 and/or IS0 10993-14 shall be considered in order to determine the potential degradation products of the coating. The identified and quantified degradation products form the basis for evaluation of biological response and, if appropriate, toxicokinetic studies i

44、n accordance with IS0 10993-1 6. 4.2 Prerequisites The rates of electrochemical degradation reactions are sensitive to small variations in test conditions, instrumentation, sample conditions and preparation. Therefore, electrochemical degradation testing shall be carried out in an appropriately equi

45、pped laboratory by experienced and qualified personnel. This includes proper maintenance and calibration of the test equipment. The methods and operating conditions of the equipment shall also be validated. NOTE Fulfilment of electrochemical test conditions for stability, warm-up time, etc., can be

46、demonstrated by conformance to l. 5 Reagent and sample preparation 5.1 Sample documentation The general composition of the material(s) under test shall be documented. 5.2 Test solution (electrolyte) The test solution (electrolyte) to be used shall be appropriate for the intended use of the medical d

47、evice. All chemicals shall be of analytical grade and dissolved in water of grade 2 in accordance with IS0 3696. The first choice for the electrolyte shall be an isotonic aqueous solution of 0,9 Oh sodium chloride. Other electrolytes may be used, such as artificial saliva or artificial plasma. Examp

48、les of alternative compositions are given in annex C. In the test report the choice of electrolyte shall be justified. If other than an aqueous solution of 0,9 Yo sodium chloride is used, the pH of the electrolyte shall be specified. 5.3 Preparation of test samples 5.3.1 Test samples The sensitivity

49、 of chemical degradation testing is related to variation in material composition, to material processing and to surface-finishing procedures. The sampling procedure, sample shape and surface preparation are critical. The samples shall be representative of the finished devices. 5.3.2 Sampling For each chemical test. at least two test samples shall be prepared as specified in IS0 10993-12. If substantial deviations in the test results are found, the reasons for the deviation shall be determined, and more samples shall be tested. O IC0 2000 - Ali rights reserved 3 IS0 10993-1 5: