Association for the Advancementof Medical Instrumentation

ANSI/AAMI/ISO 10993-11:2006

Biological evaluationof medical devices—

Part 11: Tests for systemic toxicity

AmericanNationalStandard

The Objectives and Uses of AAMI Standards andRecommended Practices

It is most important that the objectives and potential uses of an AAMIproduct standard or recommended practice are clearly understood.The objectives of AAMI's technical development program derivefrom AAMI's overall mission: the advancement of medicalinstrumentation. Essential to such advancement are (1) a continuedincrease in the safe and effective application of current technologiesto patient care, and (2) the encouragement of new technologies. It isAAMI's view that standards and recommended practices cancontribute significantly to the advancement of medicalinstrumentation, provided that they are drafted with attention to theseobjectives and provided that arbitrary and restrictive uses are avoided.

A voluntary standard for a medical device recommends to themanufacturer the information that should be provided with or on theproduct, basic safety and performance criteria that should be con-sidered in qualifying the device for clinical use, and the measurementtechniques that can be used to determine whether the device conformswith the safety and performance criteria and/or to compare the per-formance characteristics of different products. Some standards em-phasize the information that should be provided with the device,including performance characteristics, instructions for use, warningsand precautions, and other data considered important in ensuring thesafe and effective use of the device in the clinical environment.Recommending the disclosure of performance characteristics oftennecessitates the development of specialized test methods to facilitateuniformity in reporting; reaching consensus on these tests canrepresent a considerable part of committee work. When a draftingcommittee determines that clinical concerns warrant the establishmentof minimum safety and performance criteria, referee tests must beprovided and the reasons for establishing the criteria must bedocumented in the rationale.

A recommended practice provides guidelines for the use, care,and/or processing of a medical device or system. A recommendedpractice does not address device performance per se, but ratherprocedures and practices that will help ensure that a device is usedsafely and effectively and that its performance will be maintained.

Although a device standard is primarily directed to the manufac-turer, it may also be of value to the potential purchaser or user of thedevice as a frame of reference for device evaluation. Similarly, eventhough a recommended practice is usually oriented towards healthcare professionals, it may be useful to the manufacturer in betterunderstanding the environment in which a medical device will beused. Also, some recommended practices, while not addressing deviceperformance criteria, provide guidelines to industrial personnel onsuch subjects as sterilization processing, methods of collecting data toestablish safety and efficacy, human engineering, and otherprocessing or evaluation techniques; such guidelines may be useful tohealth care professionals in understanding industrial practices.

In determining whether an AAMI standard or recommendedpractice is relevant to the specific needs of a potential user of thedocument, several important concepts must be recognized:

All AAMI standards and recommended practices are voluntary(unless, of course, they are adopted by government regulatory orprocurement authorities). The application of a standard or recom-mended practice is solely within the discretion and professionaljudgment of the user of the document.

Each AAMI standard or recommended practice reflects thecollective expertise of a committee of health care professionals andindustrial representatives, whose work has been reviewed nationally(and sometimes internationally). As such, the consensusrecommendations embodied in a standard or recommended practiceare intended to respond to clinical needs and, ultimately, to helpensure patient safety. A standard or recommended practice is limited,however, in the sense that it responds generally to perceived risks andconditions that may not always be relevant to specific situations. Astandard or recommended practice is an important reference inresponsible decision-making, but it should never replace responsibledecision-making.

Despite periodic review and revision (at least once every fiveyears), a standard or recommended practice is necessarily a staticdocument applied to a dynamic technology. Therefore, a standardsuser must carefully review the reasons why the document wasinitially developed and the specific rationale for each of itsprovisions. This review will reveal whether the document remainsrelevant to the specific needs of the user.

Particular care should be taken in applying a product standard toexisting devices and equipment, and in applying a recommendedpractice to current procedures and practices. While observed orpotential risks with existing equipment typically form the basis for thesafety and performance criteria defined in a standard, professionaljudgment must be used in applying these criteria to existing equip-ment. No single source of information will serve to identify aparticular product as "unsafe". A voluntary standard can be used asone resource, but the ultimate decision as to product safety andefficacy must take into account the specifics of its utilization and, ofcourse, cost-benefit considerations. Similarly, a recommendedpractice should be analyzed in the context of the specific needs andresources of the individual institution or firm. Again, the rationaleaccompanying each AAMI standard and recommended practice is anexcellent guide to the reasoning and data underlying its provision.

In summary, a standard or recommended practice is truly usefulonly when it is used in conjunction with other sources of informationand policy guidance and in the context of professional experience andjudgment.

INTERPRETATIONS OF AAMI STANDARDSAND RECOMMENDED PRACTICES

Requests for interpretations of AAMI standards and recommendedpractices must be made in writing, to the Manager for TechnicalDevelopment. An official interpretation must be approved by letterballot of the originating committee and subsequently reviewed andapproved by the AAMI Standards Board. The interpretation willbecome official and representation of the Association only uponexhaustion of any appeals and upon publication of notice of interpre-tation in the "Standards Monitor" section of the AAMI News. TheAssociation for the Advancement of Medical Instrumentationdisclaims responsibility for any characterization or explanation of astandard or recommended practice which has not been developed andcommunicated in accordance with this procedure and which is notpublished, by appropriate notice, as an official interpretation in theAAMI News.

AAMI/ American National Standard ANSI/AAMI/ISO 10993-11:2006 (Revision of ANSI/AAMI 10993-11:1993)

Biological evaluation of medical devices—Part 11: Tests for systemic toxicity

Developed by Association for the Advancement of Medical Instrumentation Approved 19 October 2006 by American National Standards Institute Inc.

Abstract: Specifies requirements and gives guidance on the procedures to be followed in the evaluation of the potential for medical devices and their materials to cause adverse systemic reactions.

Keywords: biological evaluation, tests, systemic toxicity

AAMI 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 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 time. AAMI procedures require that action be taken to reaffirm, revise, or withdraw this standard no later than five years from the date of publication. Interested parties may obtain current information on all AAMI standards by calling or writing AAMI.

All 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 adopted 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 1110 N. Glebe Road, Suite 220 Arlington, VA 22201-4795

© 2006 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 prior written permission of AAMI. All requests pertaining to this draft 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 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, contact AAMI, 1110 N. Glebe Road, Suite 220, Arlington, VA 22201-4795. Phone: (703) 525-4890; Fax: (703) 525-1067.

Printed in the United States of America

ISBN 1–57020–276–1

Contents Page

Glossary of equivalent standards ................................................................................................................... iv

Committee representation................................................................................................................................ vi

Background of AAMI adoption of ISO 10993-11:2006 .................................................................................. vii

Foreword.......................................................................................................................................................... viii Introduction ........................................................................................................................................................ x 1 Scope...................................................................................................................................................... 1 2 Normative references ........................................................................................................................... 1 3 Terms and definitions........................................................................................................................... 1 4 General considerations ........................................................................................................................ 3 4.1 General................................................................................................................................................... 3 4.2 Selection of animal species ................................................................................................................. 3 4.3 Animal status......................................................................................................................................... 3 4.4 Animal care and husbandry................................................................................................................. 3 4.5 Size and number of groups.................................................................................................................. 4 4.6 Route of exposure................................................................................................................................. 5 4.7 Sample preparation............................................................................................................................... 5 4.8 Dosing .................................................................................................................................................... 5 4.9 Body weight and food/water consumption ........................................................................................ 6 4.10 Clinical observations............................................................................................................................ 6 4.11 Clinical pathology ................................................................................................................................. 7 4.12 Anatomic pathology.............................................................................................................................. 7 4.13 Study designs........................................................................................................................................ 8 4.14 Quality of investigation ........................................................................................................................ 8 5 Acute systemic toxicity ........................................................................................................................ 8 5.1 General................................................................................................................................................... 8 5.2 Study design.......................................................................................................................................... 8 5.3 Evaluation criteria ............................................................................................................................... 10 5.4 Final report .......................................................................................................................................... 11 6 Repeated exposure systemic toxicity (subacute, subchronic and chronic systemic

toxicity) ................................................................................................................................................ 12 6.1 General................................................................................................................................................. 12 6.2 Study design........................................................................................................................................ 13 6.3 Evaluation criteria ............................................................................................................................... 15 6.4 Final report .......................................................................................................................................... 16 Annex A (informative) Routes of administration............................................................................................ 17 Annex B (informative) Dosage volumes.......................................................................................................... 19 Annex C (informative) Common clinical signs and observations ................................................................ 20 Annex D (informative) Suggested haematology, clinical chemistry and urinalysis

measurements..................................................................................................................................... 21 Annex E (informative) Suggested organ list for histopathological evaluation ........................................... 23 Annex F (informative) Information on material-mediated pyrogens ............................................................ 25 Bibliography ..................................................................................................................................................... 27

Glossary of equivalent standards

International Standards adopted in the United States may include normative references to other International Standards. For each International 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.

Other normatively referenced International Standards may be under consideration for U.S. adoption by AAMI; therefore, this list should not be considered exhaustive.

International designation U.S. designation Equivalency IEC 60601-1:2005 ANSI/AAMI ES60601-1:2005 Major technical variations IEC 60601-1-2:2001 and Amendment 1:2004

ANSI/AAMI/IEC 60601-1-2:2001 and Amendment 1:2004

Identical

IEC 60601-2-2:2006 ANSI/AAMI/IEC 60601-2-2:2006 Identical IEC 60601-2-4:2002 ANSI/AAMI DF80:2003 Major technical variations IEC 60601-2-19:1990 and Amendment 1:1996

ANSI/AAMI II36:2004 Major technical variations

IEC 60601-2-20:1990 and Amendment 1:1996

ANSI/AAMI II51:2004 Major technical variations

IEC 60601-2-21:1994 and Amendment 1:1996

ANSI/AAMI/IEC 60601-2-21 and Amendment 1:2000 (consolidated texts)

Identical

IEC 60601-2-24:1998 ANSI/AAMI ID26:2004 Major technical variations IEC 60601-2-50:2001 ANSI/AAMI/IEC 60601-2-50:2006 Identical IEC/TR 60878:2003 ANSI/AAMI/IEC TIR60878:2003 Identical IEC/TR 62296:2003 ANSI/AAMI/IEC TIR62296:2003 Identical IEC 62304:2006 ANSI/AAMI/IEC 62304:2006 Identical IEC/TR 62348:2006 ANSI/AAMI/IEC TIR62348:2006 Identical ISO 5840:2005 ANSI/AAMI/ISO 5840:2005 Identical ISO 7198:1998 ANSI/AAMI/ISO 7198:1998/2001/(R)2004 Identical ISO 7199:1996 ANSI/AAMI/ISO 7199:1996/(R)2002 Identical ISO 10993-1:2003 ANSI/AAMI/ISO 10993-1:2003 Identical ISO 10993-2:2006 ANSI/AAMI/ISO 10993-2:2006 Identical ISO 10993-3:2003 ANSI/AAMI/ISO 10993-3:2003 Identical ISO 10993-4:2002 and Amendment 1:2006

ANSI/AAMI/ISO 10993-4:2002 and Amendment 1:2006

Identical

ISO 10993-5:1999 ANSI/AAMI/ISO 10993-5:1999 Identical ISO 10993-6:1994 ANSI/AAMI/ISO 10993-6:1995/(R)2001 Identical ISO 10993-7:1995 ANSI/AAMI/ISO 10993-7:1995/(R)2001 Identical ISO 10993-9:1999 ANSI/AAMI/ISO 10993-9:1999/(R)2005 Identical ISO 10993-10:2002 and Amendment 1:2006

ANSI/AAMI BE78:2002 ANSI/AAMI BE78:2002/A1:2006

Minor technical variations Identical

ISO 10993-11:2006 ANSI/AAMI/ISO 10993-11:2006 Identical ISO 10993-12:2002 ANSI/AAMI/ISO 10993-12:2002 Identical ISO 10993-13:1998 ANSI/AAMI/ISO 10993-13:1999/(R)2004 Identical ISO 10993-14:2001 ANSI/AAMI/ISO 10993-14:2001 Identical ISO 10993-15:2000 ANSI/AAMI/ISO 10993-15:2000 Identical ISO 10993-16:1997 ANSI/AAMI/ISO 10993-16:1997/(R)2003 Identical ISO 10993-17:2002 ANSI/AAMI/ISO 10993-17:2002 Identical

iv © 2006 Association for the Advancement of Medical Instrumentation ANSI/AAMI/ISO 10993-11:2006

International designation U.S. designation Equivalency ISO 10993-18:2005 ANSI/AAMI BE83:2006 Major technical variations ISO/TS 10993-19:2006 ANSI/AAMI/ISO TIR10993-19:2006 Identical ISO/TS 10993-20:2006 ANSI/AAMI/ISO TIR10993-20:2006 Identical ISO 11135:1994 ANSI/AAMI/ISO 11135:1994 Identical ISO 11137-1:2006 ANSI/AAMI/ISO 11137-1:2006 Identical ISO 11137-2:2006 (2006-08-01 corrected version)

ANSI/AAMI/ISO 11137-2:2006 Identical

ISO 11137-3:2006 ANSI/AAMI/ISO 11137-3:2006 Identical ISO 11138-1: 2006 ANSI/AAMI/ISO 11138-1:2006 Identical ISO 11138-2: 2006 ANSI/AAMI/ISO 11138-2:2006 Identical ISO 11138-3: 2006 ANSI/AAMI/ISO 11138-3:2006 Identical ISO 11138-4: 2006 ANSI/AAMI/ISO 11138-4:2006 Identical ISO 11138-5: 2006 ANSI/AAMI/ISO 11138-5:2006 Identical ISO/TS 11139:2006 ANSI/AAMI/ISO 11139:2006 Identical ISO 11140-1:2005 ANSI/AAMI/ISO 11140-1:2005 Identical ISO 11140-5:2000 ANSI/AAMI ST66:1999 Major technical variations ISO 11607-1:2006 ANSI/AAMI/ISO 11607-1:2006 Identical ISO 11607-2:2006 ANSI/AAMI/ISO 11607-2:2006 Identical ISO 11737-1: 2006 ANSI/AAMI/ISO 11737-1:2006 Identical ISO 11737-2:1998 ANSI/AAMI/ISO 11737-2:1998 Identical ISO 11737-3:2004 ANSI/AAMI/ISO 11737-3:2004 Identical ISO 13485:2003 ANSI/AAMI/ISO 13485:2003 Identical ISO 14155-1:2003 ANSI/AAMI/ISO 14155-1:2003 Identical ISO 14155-2:2003 ANSI/AAMI/ISO 14155-2:2003 Identical ISO 14160:1998 ANSI/AAMI/ISO 14160:1998 Identical ISO 14161:2000 ANSI/AAMI/ISO 14161:2000 Identical ISO 14937:2000 ANSI/AAMI/ISO 14937:2000 Identical ISO/TR 14969:2004 ANSI/AAMI/ISO TIR14969:2004 Identical ISO 14971:2000 and A1:2003 ANSI/AAMI/ISO 14971:2000 and A1:2003 Identical ISO 15223:2000, A1:2002, and A2:2004

ANSI/AAMI/ISO 15223:2000, A1:2001, and A2:2004

Identical

ISO 15225:2000 and A1:2004 ANSI/AAMI/ISO 15225:2000/(R)2006 and A1:2004/(R)2006

Identical

ISO 15674:2001 ANSI/AAMI/ISO 15674:2001 Identical ISO 15675:2001 ANSI/AAMI/ISO 15675:2001 Identical ISO/TS 15843:2000 ANSI/AAMI/ISO TIR15843:2000 Identical ISO 15882:2003 ANSI/AAMI/ISO 15882:2003 Identical ISO/TR 16142:2006 ANSI/AAMI/ISO TIR16142:2006 Identical ISO 17664:2004 ANSI/AAMI ST81:2004 Major technical variations ISO 17665-1:2006 ANSI/AAMI/ISO 17665-1:2006 Identical ISO 18472:2006 ANSI/AAMI/ISO 18472:2006 Identical ISO/TS 19218:2005 ANSI/AAMI/ISO 19218:2005 Identical ISO 25539-1:2003 and A1:2005 ANSI/AAMI/ISO 25539-1:2003 and

A1:2005 Identical

1In production Last updated 12/1/2006 2Final approval pending

© 2006 Association for the Advancement of Medical Instrumentation ANSI/AAMI/ISO 10993-11:2006 v

Committee representation

Association for the Advancement of Medical Instrumentation Biological Evaluation Committee

The adoption of ISO 10993-11:2006 as an AAMI Standard was initiated by the AAMI Biological Evaluation Committee, which also functions as a U.S. Technical Advisory Group to the relevant work in ISO/TC 194, Biological Evaluation of Medical Devices Committee, of the International Organization for Standardization (ISO). U.S. representatives from the AAMI Systemic Toxicity Working Group (U.S. sub-TAG for ISO/TC 194/WG 7), chaired by Daniel McLain, PhD, played an active part in developing the ISO standard.

At the time this document was published, the AAMI Biological Evaluation Committee had the following members: Cochairs: Donald E. Marlowe Peter William Urbanski Members: James M. Anderson, MD, PhD, Case Western Reserve University (Independent Expert) Lawrence H. Hecker, PhD, Hospira Inc John G. Miller, DVM, Association for Assessment and Accreditation of Laboratory Sharon Northup, PhD, US Pharmacopeia Convention Inc. Barry F.J. Page, (Independent Expert) Anita Y. Sawyer, Becton Dickinson & Company Melvin E. Stratmeyer, PhD, FDA/CDRH Paul J. Upman, PhD, NAMSA Peter William Urbanski, Medtronic Inc Alternates: Raju G. Kammula, DVM, PhD, FDA/CDRH Donald E. Marlowe, FDA/CDRH Michael F. Wolf, Medtronic Inc At the time this document was published the committee’s Systemic Toxicity Working Group had the following members:

Chair: Daniel Edward McLain, PhD CNS DABFE Members: Stephanie Board, St. Jude Medical Inc. Kimbrell Darnell, CR Bard John Dooley, PhD, DABT, Johnson & Johnson Gloria H. Frost, PhD, Cardinal Health (MP&S) Joel R. Gorski, PhD, NAMSA Lawrence H. Hecker, PhD, Hospira Inc William H. Houser, Abbott Laboratories Howard I. Maibach, MD, University of California At San Francisco (Independent Expert) Daniel Edward McLain, PhD, CNS, DABFE (Independent Expert) Lisa Olson, AppTec Barry F.J. Page, (Independent Expert) Edward Reverdy, PhD, Boston Scientific Corporation Anita Y. Sawyer, Becton Dickinson & Company Kenneth R. St John, PhD, University of Mississippi Medical Center (Independent Expert) Melvin E. Stratmeyer, PhD, FDA/CDRH Audrey Turley, RM (NRM), Nelson Laboratories Inc Alternates: Joseph Carraway, NAMSA Anthony J. DeMarinis, MS, CQA, CQM, CR Bard Jared Forsyth, Nelson Laboratories Inc Stacie Schulze, Kimberly-Clark Corporation William P. Tyler, Jr., RPh, Abbott Laboratories NOTE—Participation by federal agency representatives in the development of this standard does not constitute endorsement by the federal government or any of its agencies.

vi © 2006 Association for the Advancement of Medical Instrumentation ANSI/AAMI/ISO 10993-11:2006

Background of AAMI adoption of ISO 10993-11:2006

As indicated in the foreword to the main body of this document (page viii), the International Organization for Standardization (ISO) is a worldwide federation of national standards bodies. The United States is one of the ISO members that took an active role in the development of this standard.

U.S. participation in ISO/TC 194 is organized through the U.S. Technical Advisory Group for ISO/TC 194, administered by the Association for the Advancement of Medical Instrumentation (AAMI). The United States made a considerable contribution to this standard.

AAMI encourages its committees to harmonize their work with International Standards in the area of biological evaluation of medical devices as much as possible in order to help reduce unnecessary repetition of testing. Upon review of the final Draft International Standard, the AAMI Biological Evaluation Committee and the AAMI Systemic Toxicity Working Group decided to adopt ISO 10993-11:2006, Biological evaluation of medical devices – Part 11: Tests for systemic toxicity verbatim as a revision of ANSI/AAMI 10993-11:1993.

Major differences between this current edition and the first version are that the references to Organization for Economic Cooperation and Development (OECD) testing typically applied to chemicals have been replaced with medical device-specific test recommendations, and detailed discussion of specific test protocols and their reporting requirements have been added.

AAMI and ANSI procedures require that American National Standards be reviewed periodically and, if necessary, revised to reflect technological advances that may have occurred since publication.

AAMI and (ANSI) have adopted other ISO standards. See the Glossary of Equivalent Standards for a list of ISO standards adopted by AAMI, which gives the corresponding U.S. designation and the level of equivalency with the ISO standard.

The concepts incorporated in this standard should not be considered inflexible or static. This standard, like any other, must be reviewed and updated periodically to assimilate progressive technological developments. To remain current, it must be modified as technological advances are made and as new data comes to light.

Suggestions for improving this standard are invited. Comments and suggested revisions should be sent to Standards Department, AAMI, 1110 N. Glebe Rd., Ste. 220, Arlington, VA 22201-4795.

NOTE—Beginning with the ISO foreword on page viii, this American National Standard is identical to ISO 10993-11:2006.

© 2006 Association for the Advancement of Medical Instrumentation ANSI/AAMI/ISO 10993-11:2006 vii

Foreword

ISO (the International Organization 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 established 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.

International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.

The main task of technical committees is to prepare International Standards. Draft International Standards adopted 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 document may be the subject of patent rights. ISO shall not be held responsible for identifying any or all such patent rights.

ISO 10993-11 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices.

This second edition cancels and replaces the first edition (ISO 10993-11:1993) which has been technically revised.

ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices:

⎯ Part 1: Evaluation and testing

⎯ Part 2: Animal 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: Framework for identification and quantification of potential degradation products

⎯ Part 10: Tests for irritation and delayed-type hypersensitivity

⎯ Part 11: Tests for systemic toxicity

⎯ Part 12: Sample preparation and reference materials

viii © 2006 Association for the Advancement of Medical Instrumentation ANSI/AAMI/ISO 10993-11:2006

⎯ Part 13: Identification and quantification of degradation products from polymeric 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 allowable limits for leachable substances

⎯ Part 18: Chemical characterization of materials

⎯ Part 19: Physico-chemical, morphological and topographical characterization

⎯ Part 20: Principles and methods for immunotoxicology testing of medical devices

© 2006 Association for the Advancement of Medical Instrumentation ANSI/AAMI/ISO 10993-11:2006 ix

Introduction

Systemic toxicity is a potential adverse effect of the use of medical devices. Generalized effects, as well as organ and organ system effects can result from absorption, distribution, and metabolism of leachates from the device or its materials to parts of the body with which they are not in direct contact. This part of ISO 10993 addresses the evaluation of generalized systemic toxicity, not specific target organ or organ system toxicity, even though these effects may result from the systemic absorption and distribution of toxicants.

Because of the broad range of medical devices, and their materials and intended uses, this part of ISO 10993 is not overly prescriptive. Whilst it addresses specific methodological aspects to be considered in the design of systemic toxicity tests, proper study design must be uniquely tailored to the nature of the device’s materials and its intended clinical application.

Other elements of this part of ISO 10993 are prescriptive in nature, including those aspects that address compliance with good laboratory practices and elements for inclusion in reporting.

While some systemic toxicity tests (e.g. long term implantation or dermal toxicity studies) can be designed to study systemic effects as well as local, carcinogenic or reproductive effects, this document focuses only on those aspects of such studies, which are intended to address systemic effects. Studies which are intended to address other toxicological endpoints are addressed in ISO 10993-3, ISO 10993-6, ISO 10993-10, and ISO/TS 10993-20.

Pyrogenicity (see Annex F) represents an additional systemic effect which has historically been included in this part of ISO 10993. However, efforts are being taken to address pyrogenicity in a dedicated, stand-alone standard.

Finally, toxicology is an imperfect science. The outcome of any single test should not be the sole basis for making a determination of whether a device is safe for its intended use.

x © 2006 Association for the Advancement of Medical Instrumentation ANSI/AAMI/ISO 10993-11:2006

American National Standard ANSI/AAMI/ISO 10993-11:2006

Biological evaluation of medical devices — Part 11: Tests for systemic toxicity

1 Scope

This part of ISO 10993 specifies requirements and gives guidance on procedures to be followed in the evaluation of the potential for medical device materials to cause adverse systemic reactions.

2 Normative references

The following referenced documents are indispensable for the application of this document. For undated references, the latest edition of the referenced document (including any amendments) applies.

ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing

ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements

ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference materials

3 Terms and definitions

For the purposes of this document, the terms and definitions given in ISO 10993-1 and the following apply.

3.1 dose dosage amount of test sample administered (e.g. mass, volume) expressed per unit of body weight or surface area

3.2 dose-effect relationship between the dosage and the magnitude of a defined biological effect either in an individual or in a population sample

3.3 dose-response relationship of dosage to the spectrum of effects related to the exposure

NOTE There are two types of dose-response relationships. The first type is the response of an individual to a range of doses. The second type is the distribution of responses of a population of individuals to a range of doses.

3.4 leachable substance chemical removed from a device or material by the action of water or other liquids related to the use of the device

© 2006 Association for the Advancement of Medical Instrumentation - ANSI/AAMI/ISO 10993-11:2006 1

NOTE Examples of leachable substances are additives, sterilant residues, process residues, degradation products, solvents, plasticizers, lubricants, catalysts, stabilizers, anti-oxidants, coloring agents, fillers, and monomers.

3.5 limit test use of a single group treated at a suitable dosage of test sample in order to delineate the presence or absence of a toxic hazard

3.6 systemic toxicity toxicity that is not limited to adverse effects at the site of contact between the body and the device

NOTE Systemic toxicity requires absorption and distribution of a toxicant from its entry point to a distant site at which deleterious effects are produced.

3.7 acute systemic toxicity adverse effects occurring at any time after single, multiple or continuous exposures of a test sample within 24 h

3.8 subacute systemic toxicity adverse effects occurring after multiple or continuous exposure between 24 h and 28 d

NOTE Since this term is semantically incorrect, the adverse effects occurring within the specified time period may also be described as a short-term repeated exposure systemic toxicity study. The selection of time intervals between 14 d and 28 d is consistent with most international regulatory guidelines and considered a reasonable approach. Subacute intravenous studies are generally defined as treatment durations of > 24 h but < 14 d.

3.9 subchronic systemic toxicity adverse effects occurring after the repeated or continuous administration of a test sample for a part of the lifespan

NOTE Subchronic toxicity studies are usually 90 d in rodents but not exceeding 10 % of the lifespan of other species. Subchronic intravenous studies are generally defined as treatment durations of 14 d to 28 d.

3.10 chronic systemic toxicity adverse effects occurring after the repeated or continuous administration of a test sample for a major part of the life span

NOTE Chronic toxicity studies usually have a duration of 6 months to 12 months.

3.11 test sample material, device, device portion, component, extract, or portion thereof that is subjected to biological or chemical testing or evaluation

2 © 2006 Association for the Advancement of Medical Instrumentation - ANSI/AAMI/ISO 10993-11:2006