1、ANSI/AAMI/ISO 10993-16: 2010/(R)2014Biological evaluation of medical devices Part 16: Toxicokinetic study design for degradation products and leachablesAmerican National StandardObjectives and uses of AAMI standards and recommended practices It is most important that the objectives and potential use
2、s of an AAMI product standard or recommended practice are clearly understood. The objectives of AAMIs technical development program derive from AAMIs overall mission: the advancement of medical instrumentation. Essential to such advancement are (1) a continued increase in the safe and effective appl
3、ication of current technologies to patient care, and (2) the encouragement of new technologies. It is AAMIs view that standards and recommended practices can contribute significantly to the advancement of medical instrumentation, provided that they are drafted with attention to these objectives and
4、provided that arbitrary and restrictive uses are avoided. A voluntary standard for a medical device recommends to the manufacturer the information that should be provided with or on the product, basic safety and performance criteria that should be considered in qualifying the device for clinical use
5、, and the measurement techniques that can be used to determine whether the device conforms with the safety and performance criteria and/or to compare the performance characteristics of different products. Some standards emphasize the information that should be provided with the device, including per
6、formance characteristics, instructions for use, warnings and precautions, and other data considered important in ensuring the safe and effective use of the device in the clinical environment. Recommending the disclosure of performance characteristics often necessitates the development of specialized
7、 test methods to facilitate uniformity in reporting; reaching consensus on these tests can represent a considerable part of committee work. When a drafting committee determines that clinical concerns warrant the establishment of minimum safety and performance criteria, referee tests must be provided
8、 and the reasons for establishing the criteria must be documented in the rationale. A recommended practice provides guidelines for the use, care, and/or processing of a medical device or system. A recommended practice does not address device performance per se, but rather procedures and practices th
9、at will help ensure that a device is used safely and effectively and that its performance will be maintained. Although a device standard is primarily directed to the manufacturer, it may also be of value to the potential purchaser or user of the device as a frame of reference for device evaluation.
10、Similarly, even though a recommended practice is usually oriented towards healthcare professionals, it may be useful to the manufacturer in better understanding the environment in which a medical device will be used. Also, some recommended practices, while not addressing device performance criteria,
11、 provide guidelines to industrial personnel on such subjects as sterilization processing, methods of collecting data to establish safety and efficacy, human engineering, and other processing or evaluation techniques; such guidelines may be useful to health care professionals in understanding industr
12、ial practices. In determining whether an AAMI standard or recommended practice is relevant to the specific needs of a potential user of the document, several important concepts must be recognized: All AAMI standards and recommended practices are voluntary (unless, of course, they are adopted by gove
13、rnment regulatory or procurement authorities). The application of a standard or recommended practice is solely within the discretion and professional judgment of the user of the document. Each AAMI standard or recommended practice reflects the collective expertise of a committee of health care profe
14、ssionals and industrial representatives, whose work has been reviewed nationally (and sometimes internationally). As such, the consensus recommendations embodied in a standard or recommended practice are intended to respond to clinical needs and, ultimately, to help ensure patient safety. A standard
15、 or recommended practice is limited, however, in the sense that it responds generally to perceived risks and conditions that may not always be relevant to specific situations. A standard or recommended practice is an important reference in responsible decision-making, but it should never replace res
16、ponsible decision-making. Despite periodic review and revision (at least once every five years), a standard or recommended practice is necessarily a static document applied to a dynamic technology. Therefore, a standards user must carefully review the reasons why the document was initially developed
17、 and the specific rationale for each of its provisions. This review will reveal whether the document remains relevant to the specific needs of the user. Particular care should be taken in applying a product standard to existing devices and equipment, and in applying a recommended practice to current
18、 procedures and practices. While observed or potential risks with existing equipment typically form the basis for the safety and performance criteria defined in a standard, professional judgment must be used in applying these criteria to existing equipment. No single source of information will serve
19、 to identify a particular product as “unsafe“. A voluntary standard can be used as one resource, but the ultimate decision as to product safety and efficacy must take into account the specifics of its utilization and, of course, cost-benefit considerations. Similarly, a recommended practice should b
20、e analyzed in the context of the specific needs and resources of the individual institution or firm. Again, the rationale accompanying each AAMI standard and recommended practice is an excellent guide to the reasoning and data underlying its provision. In summary, a standard or recommended practice
21、is truly useful only when it is used in conjunction with other sources of information and policy guidance and in the context of professional experience and judgment. INTERPRETATIONS OF AAMI STANDARDS AND RECOMMENDED PRACTICES Requests for interpretations of AAMI standards and recommended practices m
22、ust be made in writing, to the AAMI Vice President, Standards Policy and Programs. An official interpretation must be approved by letter ballot of the originating committee and subsequently reviewed and approved by the AAMI Standards Board. The interpretation will become official and representation
23、of the Association only upon exhaustion of any appeals and upon publication of notice of interpretation in the “Standards Monitor“ section of the AAMI News. The Association for the Advancement of Medical Instrumentation disclaims responsibility for any characterization or explanation of a standard o
24、r recommended practice which has not been developed and communicated in accordance with this procedure and which is not published, by appropriate notice, as an official interpretation in the AAMI News. American National Standard ANSI/AAMI/ISO 10993-16:2010/(R)2014(Revision of ANSI/AAMI/ISO 10993-16:
25、1997/(R)2009) Biological evaluation of medical devices Part 16: Toxicokinetic study design for degradation products and leachables Approved 8 March 2010 by Association for the Advancement of Medical Instrumentation Approved 20 April 2010 and Reaffirmed 8 October 2014 by by American National Standard
26、s Institute Abstract: Specifies principles on how toxicokinetic studies relevant to medical devices should be designedand performed. Includes an annex that describes considerations for inclusion of toxicokinetic studies in the biological evaluation of medical devices. Keywords: toxicokinetics, leach
27、ablesAAMI Standard This Association for the Advancement of Medical Instrumentation (AAMI) standard implies a consensus of those substantially concerned with its scope and provisions. The existence of an AAMI standard does not in any respect preclude anyone, whether they have approved the standard or
28、 not, from manufacturing, marketing, purchasing, or using products, processes, or procedures not conforming to the standard. AAMI standards are subject to periodic review, and users are cautioned to obtain the latest editions. CAUTION NOTICE: This AAMI standard may be revised or withdrawn at any tim
29、e. AAMI procedures require that action be taken to reaffirm, revise, or withdraw this standard no later than 5 years from the date of publication. Interested parties may obtain current information on all AAMI standards by calling or writing AAMI, or by visiting the AAMI website at www.aami.org. All
30、AAMI standards, recommended practices, technical information reports, and other types of technical documents developed by AAMI are voluntary, and their application is solely within the discretion and professional judgment of the user of the document. Occasionally, voluntary technical documents are a
31、dopted by government regulatory agencies or procurement authorities, in which case the adopting agency is responsible for enforcement of its rules and regulations. Published by Association for the Advancement of Medical Instrumentation 4301 N. Fairfax Drive, Suite 301 Arlington, VA 22203-1633 www.aa
32、mi.org 2010 by the Association for the Advancement of Medical Instrumentation All Rights Reserved This publication is subject to copyright claims of ISO, ANSI, and AAMI. No part of this publication may be reproduced or distributed in any form, including an electronic retrieval system, without the pr
33、ior written permission of AAMI. All requests pertaining to this document should be submitted to AAMI. It is illegal under federal law (17 U.S.C. 101, et seq.) to make copies of all or any part of this document (whether internally or externally) without the prior written permission of the Association
34、 for the Advancement of Medical Instrumentation. Violators risk legal action, including civil and criminal penalties, and damages of $100,000 per offense. For permission regarding the use of all or any part of this document, complete the reprint request form at www.aami.org or contact AAMI, 4301 N.
35、Fairfax Drive, Suite 301, Arlington, VA 22203-1633. Phone: (703) 525-4890; Fax: (703) 276-0793. Printed in the United States of America ISBN 1-57020-386-5 Contents Page Glossary of equivalent standards iv Committee representation .vi Background of ANSI/AAMI adoption of ISO 10993-16:2010 .vii Forewor
36、dviii Introduction x 1 Scope1 2 Normative references .1 3 Terms and definitions.1 4 Principles for design of toxicokinetic studies .3 5 Guidance on test methods.4 5.1 General considerations 4 5.2 Guidance on specific types of test5 5.2.1 General.5 5.2.2 Absorption .6 5.2.3 Distribution 6 5.2.4 Metab
37、olism and excretion6 Annex A (normative) Circumstances in which toxicokinetic studies shall be considered 8 Bibliography .10 Glossary of equivalent standards International Standards adopted in the United States may include normative references to other International Standards. For each International
38、 Standard that has been adopted by AAMI (and ANSI), the table below gives the corresponding U.S. designation and level of equivalency to the International Standard. NOTE: Documents are sorted by international designation. The code in the US column, “(R)20xx” indicates the year the document was offic
39、ially reaffirmed by AAMI. E.g., ANSI/AAMI/ISO 10993-4:2002/(R)2009 indicates that 10993-4, originally approved and published in 2002, was reaffirmed without change in 2009. Other normatively referenced International Standards may be under consideration for U.S. adoption by AAMI; therefore, this list
40、 should not be considered exhaustive. International designation U.S. designation Equivalency Major technical variations IEC 60601-1:2005 ANSI/AAMI ES60601-1:2005 and ANSI/AAMI ES60601-1:2005/A2:2010 Technical Corrigendum 1 and 2 ANSI/AAMI ES60601-1:2005/C1:2009 (amdt) C1 Identical to Corrigendum 1 i
41、n practice the constraints of the analytical method may necessitate a compromise. 5 Guidance on test methods 5.1 General considerations 5.1.1 The study should be performed in an appropriate sex and species. Healthy young adult animals should be acclimatized to laboratory conditions for at least 7 d.
42、 They should be transferred to individual metabolism cages, when used, for an acclimatization period of at least 24 h. The environmental conditions should be as recommended in guidelines for the care and use of animals (see ISO 10993-2). During the study, conventional animal diets and drinking water
43、 should be freely available unless otherwise specified in the protocol. Animals should be randomly selected into groups for each time period studied; group sizes of at least three for small animals and at least two for larger species should be used. At the appropriate specified times, animals should
44、 be humanely killed. 5.1.2 A non-radiolabeled test substance may be utilized provided suitable validated assay procedures for the test substance in the relevant samples exist and the metabolism of the test substance is well characterized. 5.1.3 If necessary, the test substance should be radiolabeled
45、 in a metabolically stable position, preferably with 14C or 3H, and of a suitable radiochemical purity ( 97 %). When using 3H, the possibility of tritium exchange should be considered. The radiolabeled compound should be diluted, when appropriate, with a non-radiolabeled substance. 5.1.4 When using
46、a radiolabeled compound, the specific activity and radiochemical purity of the test substance shall be known. 5.1.5 The test substance should be administered by an appropriate route. This route should be relevant to the use of the medical device. The test substance should be prepared in a suitable v
47、ehicle taking into account the physicochemical properties of the test substance (leachable or degradation product) using appropriate route and dose of administration. The stability of the sample under the proposed conditions administration should be known and reported. NOTE The study design might re
48、quire the inclusion of other route(s) for comparison of percent absorption. 5.1.6 In dose balance studies, animals should be housed only in metabolism cages. 5.1.7 Urine and feces should be collected in low temperature vessels (or in vessels containing preservative that does not interfere with the a
49、nalysis) to prevent post-elimination microbial or spontaneous modification. Blood for whole-blood or plasma analysis should be collected in the presence of a suitable anticoagulant. 4 2010 Association for the Advancement of Medical Instrumentation ANSI/AAMI/ISO 10993-16:2010 5.1.8 Controls should, wherever possible, be collected prior to dosing. In some studies collection of controls (e.g. tissues) is not possible from the test animals and these should be obtained from a control group. 5.1.9 Collection times should be appropriate to the type of study being performed, and may be
