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Biocompatibility and Performance
of Medical Devices
This page intentionally left blank
Woodhead Publishing Series in Biomaterials
Biocompatibility and
Performance of Medical
Devices
Edited by
An imprint of Elsevier
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The Officers’ Mess Business Centre, Royston Road, Duxford, CB22 4QH, United Kingdom
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
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© 2020 Elsevier Ltd. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
permission in writing from the publisher. Details on how to seek permission, further information about
the Publisher’s permissions policies and our arrangements with organizations such as the Copyright
Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/
permissions.
This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience
broaden our understanding, changes in research methods, professional practices, or medical treatment
may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating
and using any information, methods, compounds, or experiments described herein. In using such
information or methods they should be mindful of their own safety and the safety of others, including
parties for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume
any liability for any injury and/or damage to persons or property as a matter of products liability,
negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas
contained in the material herein.
Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library
ISBN: 978-0-08-102643-4 (print)
ISBN: 978-0-08-102644-1 (online)
If you want to build a ship, don’t drum up the men to gather wood, divide
the work, and give orders. Instead, teach them to yearn for the vast and
endless sea.
Antoine de Saint-Exupery
Contributors xv
Foreword xvii
Introduction xxiii
J.M. Anderson Case Western Reserve University, Cleveland, OH, United States
R.P. Brown Risk Science Consortium, LLC, Arnold, MD, United States
R.E. Geertsma National Institute for Public Health and the Environment (RIVM),
Bilthoven, The Netherlands
W.H. De Jong National Institute for Public Health and the Environment (RIVM),
Bilthoven, The Netherlands
followed, taking into account the principles of biological evaluation that have been
included in standards and guidance documents since 1979. These principles, which are
explained in Clause 4 of ISO 10993-1:2018, can be summarized as follows:
●
the importance of chemical characterization of a material;
●
the influence of components, residues, leachables and degradation products;
●
the need for good laboratory practice;
●
the need for evaluation by competent, informed people;
●
the need for full experimental data;
●
the need to evaluate any changes in chemical composition, processing, physical configura-
tion or intended use;
●
the need for the biological evaluation to be considered within the context of all relevant
information (e.g., bench and mechanical testing, preclinical performance studies, clinical
experience, postmarket surveillance data).
Annex E.3.c) of ISO DTR 24971:2019 (Guidance on the application of ISO 14971)
identifies the sort of data needed for a biological risk analysis, which comprise:
●
the physical and chemical characteristics of the materials;
●
the history of clinical use or data from human exposure;
●
existing toxicity data on components, and
●
biological safety data from test procedures carried out with materials and final products.
The way these types of data are used in the risk management process is explained
in Annex B of ISO 10993-1:2018, which provides guidance on the application of
ISO 14971 to the conduct of biological evaluation. The risk management process
starts with the identification of hazards; in this case, toxicological hazards arising
from the chemical constituents of a device and biological hazards arising from its
physical nature. The harm arising from such hazards can include adverse reactions
to materials, constituents or degradation products, or an inappropriate biological
response. A hazardous situation arises if a person is exposed to a toxicological or
physical hazard arising from the device. If a hazardous situation is identified, the
risk arising from the anticipated level, route and duration of exposure to the hazard
must be estimated and its acceptability assessed. However, if exposure to the hazard
is below a level that can cause harm to health, there is no risk and the process can
stop. So the quickest way to exit an evaluation can be to confirm that there is no haz-
ardous situation. Likewise, if risk control measures are needed, these are normally
targeted at preventing a hazardous situation arising, for example by eliminating a
source of toxicity or reducing exposure. Note that a hazardous situation only occurs
if the hazard is present at a level that can cause harm. A structured biological eval-
uation plan is a way of determining what additional datasets are needed to identify
hazards or estimate risks.
The reason material characterization is so important in a biological evaluation is
that it allows hazards to be identified, thus initiating the biological risk management
process. Hazard identification is arguably the most critical of all the risk management
steps. Once a hazard has been recognized, a manufacturer will take action to control
the risk. Thankfully very few problems have arisen as a result of toxicity arising from
a device but, where field safety action has been taken in response to toxic hazards,
Forewordxix
for example with toxic degradation products from soybean-filled breast implants or
aluminum leaching from IV fluid warmers, the situation occurred because the toxic
hazard had not been appreciated. On the other hand, risks tend to be controlled rou-
tinely with respect to compounds whose hazardous nature is well known, such as
ethylene oxide or nickel.
A flowchart in ISO 10993-18:2019 illustrates how chemical characterization data
drive the risk management process. The initial stage of the process, required in all
cases by ISO 10993-1:2018, is the gathering of physical and chemical information.
Combined with other available data addressing the biological endpoints relevant to the
device, this can be sufficient to estimate the risk. The risk estimate is a measure of the
likelihood and severity of harm arising as a result of exposure to a hazard that can give
rise to an adverse reaction during the interaction between the device and the body. The
term “biocompatible” corresponds to a region on the risk estimate scale where the risk
of an inappropriate biological response is negligible.
Annex B of ISO 10993-1:2018 itemizes this process as follows:
●
define and characterize each material, including suitable alternative materials;
●
identify hazards in materials, additives, processing aids, etc.;
●
identify the potential effect of downstream processing (e.g., chemical interactions between
material components, or final product sterilization) on chemicals present in final product;
●
identify the chemicals that could be released during product use (e.g., intermediate or final
degradation products from a degradable implant);
●
estimate exposure (total or clinically available amounts);
●
review toxicology and other biological safety data (published/available);
●
evaluate the risks posed by the identified hazards; and
●
determine whether there is an undue toxicological risk from the material.
The scope of this risk management process can be widened by considering perfor-
mance issues as potential hazards.
The final stage of the risk management process is the determination of risk accept-
ability. If a biological or performance-related risk is identified, it must be established
that it cannot be eliminated or reduced, for example by choosing another material or
process, and the residual risk must be outweighed by the benefit of the device. An im-
portant component of the risk estimate is the level of uncertainty in the risk analysis.
No biological evaluation can eliminate all unknowns so uncertainty always needs to
be factored into the residual risk estimate. Although the level of uncertainty is a crit-
ical factor in a biological evaluation, its impact on the overall risk assessment should
not be overplayed. The data simply need to be robust enough to allow the benefit-risk
balance to be established with confidence.
Part I of this book develops the above model and explores the challenges it throws
up in the planning and execution of a biological evaluation within a risk management
process. It shows that the use of a risk-based approach can justify an abbreviated eval-
uation program for clinically established materials, but novel, bioactive or biorespon-
sive materials need a more rigorous, bespoke investigation. As our expectations of
biomaterials and the claims we make of them become more demanding, we face new
challenges in testing and evaluation. This requires a carefully constructed biological
evaluation plan to define the information needed to characterize the risk.
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