1、BSI Standards Publication PD ISO/TR 37137:2014 Cardiovascular biological evaluation of medical devices Guidance for absorbable implantsPD ISO/TR 37137:2014 PUBLISHED DOCUMENT National foreword This Published Document is the UK implementation of ISO/TR 37137:2014. The UK participation in its preparat
2、ion was entrusted to Technical Committee CH/194, Biological evaluation of medical devices. A list of organizations represented on this committee can be obtained on request to its secretary. This publication does not purport to include all the necessary provisions of a contract. Users are responsible
3、 for its correct application. The British Standards Institution 2014. Published by BSI Standards Limited 2014 ISBN 978 0 580 84352 5 ICS 11.040.40 Compliance with a British Standard cannot confer immunity from legal obligations. This Published Document was published under the authority of the Standa
4、rds Policy and Strategy Committee on 30 June 2014. Amendments issued since publication Date Text affectedPD ISO/TR 37137:2014 ISO 2014 Cardiovascular biological evaluation of medical devices Guidance for absorbable implants valuation biologique cardiovasculaire des dispositifs mdicaux Directives pou
5、r les implants absorbables TECHNICAL REPORT ISO/TR 37137 First edition 2014-05-15 Reference number ISO/TR 37137:2014(E)PD ISO/TR 37137:2014ISO/TR 37137:2014(E)ii ISO 2014 All rights reserved COPYRIGHT PROTECTED DOCUMENT ISO 2014 All rights reserved. Unless otherwise specified, no part of this public
6、ation may be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting on the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address below or ISOs member body in the countr
7、y 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 copyrightiso.org Web www.iso.org Published in SwitzerlandPD ISO/TR 37137:2014ISO/TR 37137:2014(E) ISO 2014 All rights reserved iii Contents Page Foreword iv 1 Scope . 1 2 T
8、erms and definitions . 1 3 General considerations 1 4 Sterilization considerations . 2 5 Drug-device combination product considerations . 3 6 Part listing and description of absorbable related issues in addition to the relevant parts of ISO 10993 series “Biological evaluation of medical devices” 4 6
9、.1 ISO 10993-1:2009, Evaluation and testing within a risk management process 4 6.2 ISO 10993-2:2006, Animal welfare requirements . 4 6.3 ISO 10993-3:2003, Tests for genotoxicity, carcinogenicity and reproductive toxicity . 4 6.4 ISO 10993-4:2002, Selection of tests for interactions with blood . . 4
10、6.5 ISO 10993-5:2009, Tests for in vitro cytotoxicity 5 6.6 ISO 10993-6:2007, Tests for local effects after implantation . 6 6.7 ISO 10993-7:2008, Ethylene oxide sterilization residuals 8 6.8 ISO 10993-9:2009, Framework for identification and quantification of potential degradation products 8 6.9 IS
11、O 10993-10:2010, Tests for irritation and delayed-type hypersensitivity 8 6.10 ISO 10993-11:2006, Biological evaluation of medical devices Part 11: Tests for systemic toxicity 9 6.11 ISO 10993-12:2012, Sample preparation and reference materials 9 6.12 ISO 10993-13:2010, Identification and quantifica
12、tion of degradation products from polymeric medical devices .13 6.13 ISO 10993-14:2001, Identification and quantification of degradation products from ceramics .13 6.14 ISO 10993-15:2000, Identification and quantification of degradation products from metals and alloys 13 6.15 ISO 10993-16:2010, Toxi
13、cokinetic study design for degradation products and leachables 13 6.16 ISO 10993-17:2002, Establishment of allowable limits for leachable substances .13 6.17 ISO 10993-18:2005, Chemical characterization of materials13 6.18 ISO/TS 10993-19:2006, Physico-chemical, morphological and topographical chara
14、cterization of materials .14 6.19 ISO/TS 10993-20:2006, Principles and methods for immunotoxicology testing of medical devices .14 Annex A (informative) Nomenclature of absorb, degrade and related terms 15 Bibliography .16PD ISO/TR 37137:2014ISO/TR 37137:2014(E) Foreword ISO (the International Organ
15、ization 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 establish
16、ed 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.
17、 The procedures used to develop this document and those intended for its further maintenance are described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the different types of ISO documents should be noted. This document was drafted in accordance with th
18、e editorial rules of the ISO/IEC Directives, Part 2. www.iso.org/directives 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. Details of any patent rig
19、hts identified during the development of the document will be in the Introduction and/or on the ISO list of patent declarations received. www.iso.org/patents Any trade name used in this document is information given for the convenience of users and does not constitute an endorsement. The committees
20、responsible for this document are ISO/TC 194, Biological evaluation of medical devices and ISO/TC 150/SC 2, Cardiovascular implants and extracorporeal systems.iv ISO 2014 All rights reservedPD ISO/TR 37137:2014TECHNICAL REPORT ISO/TR 37137:2014(E) Cardiovascular biological evaluation of medical devi
21、ces Guidance for absorbable implants 1 Scope The objective of this Technical Report is to provide interim Part-by-Part guidance on potential adjustments to various test methods within the 10993 series to account for the intentional release of soluble components or degradation products from absorbabl
22、e medical devices. The content is intended to add clarity and present potentially acceptable approaches for reducing the possibility of erroneous or misleading results due to the nature of the absorbable material. All suggestions should be considered as preliminary and subject to change, with final
23、dispositions implemented through direct modification to the respective parts of ISO 10993. Thus, interim adoption of any of the described adjustments requires an accompanying written justification. 2 T erms a nd definiti ons For the purposes of this document, the following terms and definitions appl
24、y. 2.1 absorbaction of a non-endogenous (foreign) material or substance passing through or being assimilated by cells and/or tissue over time 2.2 degradation productany intermediate or final result from the physical, metabolic, and/or chemical decomposition of a material or substance 2.3 degrade to
25、physically, metabolically, and/or chemically decompose a material or substance 2.4 leachable substances that can be released from a medical device or material during clinical use Note 1 to entry: In absorbable devices, leachables can be substances released from the as-manufactured product or substan
26、ces generated and released as a consequence of its degradation (i.e degradation products). SOURCE: ISO 10993-12:2012, 3.10 modified Note 1 to entry has been added. 3 General considerations Biological evaluation is the assessment of the ability of a device, device component, or a material to be prese
27、nt in the body without creating an adverse systemic impact and/or local effect on the surrounding cells and/or tissue. Biological evaluation of an absorbable material should be conducted in accordance with ISO 10993-1:2009 and other relevant parts (see ISO 10993-1:2009, Table A.1). NOTE 1 General gu
28、idance regarding evaluation of devices in accordance with ISO 10993 series can be found in ISO/TR 15499. By design, polymeric, ceramic, or metallic absorbable materials inherently produce relatively low molar mass degradation products when in vivo. The relatively elevated presence of these same prod
29、ucts within the culture media can potentially impact the results of some biocompatibility tests. For example, in rare ISO 2014 All rights reserved 1PD ISO/TR 37137:2014ISO/TR 37137:2014(E) cases if the degradation rate of an absorbable material is sufficiently rapid, elevated concentrations of one o
30、r more of the intended products could alter the pH and/or osmolality of an in vitro test system. Since the in vivo condition provides the combined presence of perfusion and carbonate equilibria, when evaluating intentionally degradable (i.e. absorbable) materials it can be considered acceptable, if
31、necessary, to adjust the in vitro test solution pH and/or osmolality to bring the cell culture into a physiologic range provided there is documented evidence this(these) factor(s) is(are) the potential source of an adverse result and post-adjustment testing within a physiologic range produces a succ
32、essful result. Such adjustment of pH (using a buffer-appropriate acid or base) and/or osmolality (via dilution) to better approximate the in vivo environment helps to mitigate the presence of expected degradation products, functionally allowing the test solution to be evaluated for other causation.
33、Any pH or osmolality adjustment shall be justified. If under standard test conditions an adverse result is obtained, one should consider the cell type, cell media, culture conditions, and degradation products when determining the amount of osmolality adjustment to be used, if any. For example, with
34、magnesium alloys evaluated with an human osteoblast cell type, it may not be appropriate to dilute the culture medium to less than 105 % of normal osmolality. NOTE 2 Minimum value of 105 % derived from review of experimental results obtained from 10993 to 12 extraction of magnesium and magnesium all
35、oy samples see Reference. 23 To directly address these and other absorbable-specific method concerns, a list of relevant testing precautions for each relevant part of ISO 10993 has been compiled and is presented in Clause 6. All suggestions should be considered as preliminary and subject to change,
36、with final dispositions implemented through direct modification to the respective parts of ISO 10993. Thus, interim adoption of any of the described adjustments requires an accompanying written justification. As a part of any justification, both local and systemic effects should be considered, as lo
37、cal pH and osmolality changes could result in toxicities that are clinically relevant. Degradation products may be released into the media/tissue or reside in the degrading implant. Released degradation products that are generated either prior to product use (i.e. during processing or shelf-life) or
38、 during degradation should be characterized (e.g. chemical identity, quantity, and toxicity). Identification of the degradation products may be derived from chemical analyses of the implant or through a theoretical analysis. Literature data for implants manufactured from absorbable materials with an
39、 established history of safe clinical use (e.g. PGA) at the intended location may be helpful in identifying expected degradation products and potential toxicities - if one can demonstrate that equivalent manufacturing processes were used. A toxicological risk assessment using information from chemic
40、al analyses of degradation products over time, in conjunction with toxicity data from the literature may be sufficient to support an omission of biocompatibility testing from various stages of material degradation (either during device storage or in clinical use). NOTE 3 Guidance regarding the ident
41、ification and assessment of chemical degradation products and leachables can be found in ISO 10993-9 and ISO 10993-17. Since absorbable materials are intended to degrade, potential exists for generation of transient particulate matter as the device breaks down. While an understanding of the potentia
42、l clinical impact of such degradation is needed, a separate biocompatibility assessment of the absorbable particulates alone may not be necessary if the particles are both produced and absorbed at a rate that is similar to other materials of the same chemistry with a history of safe use in the inten
43、ded clinical application. However, formulation chemistry as well as particle size could affect biological responses, so additional information and/or testing may be necessary to establish sufficient equivalency to support omission of full biocompatibility testing. Guidance regarding the determinatio
44、n of whether identification and/or quantification of particulates are needed can be found in ISO 10993-9:2009, Annex A. 4 Sterilization considerations While biological evaluation can be conducted on any component at any stage in the manufacturing process, finished product evaluation needs to be cond
45、ucted on sterilized finished devices or test samples that are representative of the final device. Evaluations should be conducted following terminal sterilization at a level that meets or exceeds anticipated commercial exposure. While higher sterilization 2 ISO 2014 All rights reservedPD ISO/TR 3713
46、7:2014ISO/TR 37137:2014(E) durations and intensities are generally considered as providing a more stringent evaluation, caution should be undertaken when sterilizing under harsher conditions (i.e. higher radiation dose) as more and different chemical by-products may be produced. If the final sterili
47、zed device is not used for testing, a rationale shall be provided that includes: a) a description of all manufacturing differences between the test article and the final, sterilized device; b) data that demonstrates that all differences between the test article and the final device do not impact the
48、ir chemistry or degradation kinetics. NOTE If potentially significant differences exist between the test article and final device (e.g. surface properties or device geometry when hemocompatibility testing), some test end points can be affected. In such situations, use of a test article cannot be rep
49、resentative of a final device. 5 Drug-device combination product considerations For devices that include an active pharmaceutical ingredient (API), the presence of a pharmaceutical can affect the biological response. As such, separate testing of both the finished device including the API and devices constructed excluding any drug component should be considered. In addition, any potential for interaction between the pharmaceutical ingredient(s) and the as-manufactured or degrading absorbable component(s) should be both understood and assessed for
