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Current practices in biocompatibility assessment of medical devices

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CURRENT PRACTICES IN BIOCOMPATIBILITY ASSESSMENT OF MEDICAL DEVICES

by

Michael A. Yartzoff

A Dissertation Presented to the
FACULTY OF THE USC SCHOOL OF PHARMACY
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF REGULATORY SCIENCE

August 2022

Copyright [April 25, 2022] Michael A. Yartzoff

ii
Dedication
I dedicate this dissertation to my family, especially to my wife Becki, my son Michael,
my daughter Christine, my father Andrew, and my mother Elizabeth. To Becki, Christine and
Michael, I am eternally grateful for the daily support, love, and encouragement that you have
always provided and your understanding of the time needed to complete this research work and
overall Doctorate program. Without the three of you, I would have never been able to complete
this difficult journey. To my mother and father, although you had both passed away before I
began my program at USC, it is your emphasis on the value of continuing education that has
been a constant driver and inspiration to challenge myself with higher education throughout my
life and ultimately towards completing my Doctoral degree.

iii
Acknowledgements
I would like to thank all of those who helped to encourage and support me along my
journey to complete my research and the Doctorate of Regulatory Science is program at USC. I
would like to thank Dr. Frances Richmond who has had a very significant contribution and
influence towards my success in this program. Dr. Richmond was present at every step of the
way during the six years that I was in the program. She was there for classroom studies, with our
cohort as we visited Asia and Europe and finally alongside me, step by step, as I worked to
complete my research project and thesis. Her dedication and support were invaluable to my
success. I would next like to thank Dr. Susan Bain who also helped to support my research
project and thesis. She was able to provide a unique perspective as a former industry colleague,
prior graduate of the program, and as a professor at the University. I would also acknowledge
and thank the professors and staff at the University of Southern California and my fellow cohorts
in the program. I would also like to acknowledge and thank my technical writer Carleen
Robideau, who provided the ongoing support and general encouragement as we worked through
each iteration of my thesis. I would also like to acknowledge and offer thanks to Dr. John P.
McGrath and Gary Sorsher from Edwards Lifesciences, who both provided support during my
studies at USC. The six years I participated in this program were the most challenging of my
lifelong educational journey, and I feel this program has given me the opportunity to acquire
practical knowledge that will allow me to succeed in my future career. Finally, and most
importantly, I thank my immediate family, including my wife Becki, my son Michael, and my
daughter Christine, for their ongoing love, support, and understanding of the time and sacrifice to
complete this program at USC. Each of them provided the unwavering support and
understanding that allowed me to dedicate time to complete the work needed for success, and I
am eternally grateful for this sacrifice and display of love. In closing, I acknowledge my late

iv
father Andrew Yartzoff, who was an immigrant to the USA, who placed a tremendous value on
education and earned a doctorate degree while working professionally. The value system he
instilled has been a force within me, driving towards final success in this program.

v
TABLE OF CONTENTS
Dedication .................................................................................................................................. ii
Acknowledgements ................................................................................................................... iii
List of Tables .......................................................................................................................... viii
Abstract ..................................................................................................................................... xi
Chapter 1. Overview ................................................................................................................. 12
1.1 Introduction ................................................................................................ 12
1.1.1 Medical Device Safety Testing ........................................................ 12
1.1.2 Regulation of Medical Devices in the United States and the
European Union .............................................................................. 14
1.1.2.1 United States........................................................................ 14
1.1.2.2 European Union ................................................................... 15
1.1.2.3 Regulation of Biocompatibility Testing for Medical
Devices ................................................................................ 16
1.2 Statement of the Problem ............................................................................ 17
1.3 Purpose of the Study ................................................................................... 20
1.4 Importance of the Study .............................................................................. 21
1.5 Limitation, Delimitations, Assumptions ...................................................... 22
1.6 Organization of Thesis ................................................................................ 22
1.7 Definitions Section ...................................................................................... 23
Chapter 2. Literature Review ..................................................................................................... 25
2.1 Literature Search ......................................................................................... 25
2.2 Evolution of Medical Device Regulation ..................................................... 26
2.3 Medical Device Regulation ......................................................................... 27
2.3.1 Defining and Classifying Medical Devices ...................................... 27
2.3.2 Regulation in the European Union (EU) .......................................... 28
2.3.3 Medical Device Regulations in the United States ............................. 30
2.4 Medical Device Safety Testing .................................................................... 32
2.5 Biocompatibility Safety Testing .................................................................. 34
2.5.1 Definition of Biocompatibility ......................................................... 34
2.5.2 Principles of Biocompatibility Testing............................................. 35
2.5.3 Biocompatibility and the Medical Device Lifecycle......................... 36
2.6 Biocompatibility Regulations and Guidelines in the United States ............... 37
2.7 Biocompatibility Regulations and Guidelines in the European Union .......... 39
2.8 Standards and Guidance Documents that Define Biocompatibility .............. 40

vi
2.8.1 ISO 10993 ....................................................................................... 40
2.8.2 FDA Guidance Document on the Use of ISO 10993-1 ..................... 44
2.8.3 Risk Management Standards ........................................................... 45
2.9 Stages of Biocompatibility Testing .............................................................. 46
2.9.1 Chemical Characterization............................................................... 47
2.9.2 Physical and Surface Characterization ............................................. 49
2.9.3 Biological Testing ........................................................................... 49
2.9.3.1 In vitro Tests ........................................................................ 50
2.9.3.2 In vivo Tests ........................................................................ 52
2.9.4 Toxicological Risk Assessment ....................................................... 58
2.10 Current Challenges with Biocompatibility Testing ...................................... 59
2.10.1 Biocompatibility Standards can be Difficult to Interpret .................. 61
2.10.2 Differences Between Local Regulations and International
Biocompatibility Standards ............................................................. 62
2.10.3 Design and Manufacturing Changes Complicate Biocompatibility
Safety Assessment and Testing........................................................ 63
2.10.4 Challenges with Material and Device Biocompatibility ................... 64
2.10.5 Challenges with Biocompatibility Testing and Test Methods ........... 65
2.10.6 Movement Away from Use of Animals in Biocompatibility
Testing ............................................................................................ 66
2.11 Framing Proposed Research ........................................................................ 68
2.11.1 Implementation Framework ............................................................. 69
2.11.2 Transparency Framework ................................................................ 72
2.11.3 Blended Framework for Present Research ....................................... 72
Chapter 3. Methodology ............................................................................................................ 76
3.1 Introduction ................................................................................................ 76
3.1.1 Survey Participants .......................................................................... 76
3.1.2 Development and Validation of the Survey...................................... 76
3.1.3 Survey Delivery .............................................................................. 78
3.1.4 Survey Analysis .............................................................................. 78
Chapter 4. Results ..................................................................................................................... 79
4.1 Survey Participation .................................................................................... 79
4.2 Demographic Profiles of Respondents ......................................................... 79
4.2.1 Biocompatibility Experience and Expertise ..................................... 85
4.3 Exploring New Biocompatibility Standards and Guidance Documents ........ 87
4.4 Planning and Installing New Biocompatibility Requirements ...................... 98
4.5 Initial Implementation of New Biocompatibility Requirements ................. 114
4.6 Full Implementation of New Biocompatibility Requirements .................... 126

vii
Chapter 5. Discussion .............................................................................................................. 139
5.1 Overview of Research ............................................................................... 139
5.2 Methodological Considerations ................................................................. 139
5.2.1 Delimitations ................................................................................. 139
5.2.2 Limitations .................................................................................... 142
5.3 Consideration of Results ........................................................................... 145
5.3.1 Exploration Stage .......................................................................... 145
5.3.2 Installation Stage ........................................................................... 150
5.3.3 Initial Implementation Stage .......................................................... 154
5.3.4 Full Implementation Stage ............................................................. 157
5.4 Conclusions and Recommendations .......................................................... 161
References .............................................................................................................................. 164
Appendices ............................................................................................................................. 176
Appendix A. Current Trends in Biocompatibility – Yartzoff Survey .................. 176

viii
List of Tables
Table 1: Nature of Device Contact ........................................................................................ 41
Table 2: Duration of Device Contact .................................................................................... 41
Table 3: ISO 10993 Standard Listing .................................................................................... 43
Table 4: “Other” Functional Roles ........................................................................................ 80
Table 5: Summary of Responses regarding the Usefulness of Resources for
Planning Purposes .............................................................................................. 92
Table 6: Weighted Average Ranking of Statements .............................................................. 94
Table 7: Comments on Other Issues that Complicated Early Exploration .............................. 97
Table 8: Other Pre-planning Activities Before EU MDRs Became Active ............................ 99
Table 9: Summary of Ranking of Changes Based Upon Importance –
ISO 10993-1 .................................................................................................... 106
Table 10: Summary of Ranking of Changes Based Upon Importance –
ISO 10993-18 .................................................................................................. 109
Table 11: Level of Participation when Planning for the Implementation of Revisions
to Biocompatibility Standards .......................................................................... 112
Table 12: Responses to Question, “In retrospect, would you have done something
differently to prepare your organization for implementation?” .......................... 113
Table 13: Summary of Responses: Difficulty of Implementing Pilot Approaches to
the New Biocompatibility Requirements for Participants’
Organizations ................................................................................................... 116
Table 14: “What were the principal challenges that respondent organizations faced
during the pilot phase?”.................................................................................... 116
Table 15: Ranking for Difficulty with Initial Implementation of ISO 10993 and the
FDA Guidance Document ................................................................................ 119
Table 16: Additional Issues Related To Initial Implementation of New ISO 10993-1
and FDA Guidance Document.......................................................................... 119
Table 17: Difficulty Level of First Attempts at ISO 10993-18 Implementation ..................... 121
Table 18: Additional Issues when First Implementing ISO 10993-18 ................................... 122
Table 19: Ranking of Challenge when Fully Implementing ISO 10993-1 Standard ............... 130
Table 20: “Other” Responses: Degree of Alignment of Current Biocompatibility
Strategies with the ISO 10993-18 Roadmap of Performing Physical
Characterization, Chemical Characterization, and a Toxicological Risk
Assessment, Prior to Conducting Biological Testing ........................................ 131
Table 21: Summary of Responses to Question “Do you have additional comments
to share on unexpected outcomes that your organization has
experienced as it has interacted with regulators following
implementation of changing biocompatibility standards?” ................................ 137

ix
Figure 1: Implementation framework ..................................................................................... 70
Figure 2: Blended framework constructed for use in this study .............................................. 74
Figure 3: Survey responses .................................................................................................... 79
Figure 4: Functional roles of respondents ............................................................................... 80
Figure 5: Current responsibilities of respondents.................................................................... 81
Figure 6: Length of time working in biocompatibility ............................................................ 82
Figure 7: Numbers of participants working for a medical device company ............................. 82
Figure 8: Description of organization with which participants worked ................................... 83
Figure 9: Size of organizations at which respondents worked ................................................. 83
Figure 10: Number of marketing submissions for new products that include
biocompatibility supported by respondent .......................................................... 84
Figure 11: Classes of medical devices sold or supported in the United States ........................... 84
Figure 12: Classes of medical devices sold or supported in Europe .......................................... 85
Figure 13: Level of expertise in medical device biocompatibility ............................................. 85
Figure 14: Experience implementing biocompatibility standards and guidance
document ........................................................................................................... 86
Figure 15: Implementation timeline for ISO 10993 .................................................................. 87
Figure 16: Activities used to get early understanding of biocompatibility documents ............... 89
Figure 17: Usefulness of resources when planning new approaches to biological
evaluation .......................................................................................................... 91
Figure 18: Agreement with statements of possible impediments to understanding the
new biocompatibility regulations and approaches ............................................... 94
Figure 19: Are the expectations in ISO and FDA documents sufficiently detailed? .................. 96
Figure 20: Pre-planning to anticipate changes related to new MDR biocompatibility
requirements ...................................................................................................... 99
Figure 21: Approaches to plan/ prepare for implementing revised standards .......................... 101
Figure 22: Parts of organization involved in planning to implement new standards ................ 102
Figure 23: Responses to question “How early did your organization start preparing
for changes to biocompatibility standards and guidance document?” ................ 103
Figure 24: Satisfaction with company’s preparation to transition to new
biocompatibility requirements .......................................................................... 104
Figure 25: Changes to be ready to implement ISO 10993-1 and FDA guidance
document on ISO 10993-1 ............................................................................... 106
Figure 26: Ranking of changes made to prepare for implementation of
ISO 10993-18:2020 .......................................................................................... 108
Figure 27: Frequency of early-stage meetings with regulators before implementing
new biocompatibility strategies ........................................................................ 110
Figure 28: Stage where organization held early-stage meetings with regulators...................... 111
Figure 29: Level of participation of listed stakeholders when planning for the
implementation of revisions to biocompatibility standards ............................... 112

x
Figure 30: Difficulty implementing pilot approaches to new biocompatibility
requirements .................................................................................................... 115
Figure 31: Ranking for difficulty with initial implementation of revised ISO 10993-1
biocompatibility standard and FDA guidance document on
ISO 10993-1 .................................................................................................... 118
Figure 32: Difficulty of implementing the revised ISO 10993-18 standard ............................. 121
Figure 33: Usefulness of activities during initial implementation of changes.......................... 123
Figure 34: Was FDA consistent, transparent and accessible? ................................................. 124
Figure 35: Were Notified Bodies consistent, transparent and accessible? ............................... 126
Figure 36: Degree of implementation of key biocompatibility standards ................................ 127
Figure 37: Organization’s understanding of key biocompatibility standards ........................... 128
Figure 38: How challenging were the following elements when fully implementing
ISO 10993-1 standard? ..................................................................................... 129
Figure 39: Alignment of biocompatibility strategies with ISO 10993-18 roadmap of
performing physical characterization, chemical characterization, and a
toxicological risk assessment, prior to conducting biological testing................. 131
Figure 40: Areas where organization struggled with FDA guidance document on
10993-1............................................................................................................ 132
Figure 41: Difficulty to get sufficient information for biocompatibility safety
assessments ...................................................................................................... 134
Figure 42: How frequently does your organization struggle with the use of chemical
characterization followed by a toxicological risk assessment to justify
limiting the amount of biological testing performed? ........................................ 135
Figure 43: What unexpected outcomes has your organization experienced as you
have interacted with regulators following implementation of changing
biocompatibility standards? .............................................................................. 136

xi
Abstract
New or changed medical devices that contact human tissue are subject to safety testing
for biocompatibility. International harmonized standards such as ISO 10993-1, the European
Medical Device Regulations, and FDA guidance documents guide this testing. Traditionally they
suggested a checklist approach to specify biological tests, but revisions introduced within the last
five years all recommend a different roadmap that starts with chemical and materials
characterization. This information bases the development of a targeted toxicological risk profile
that helps to determine what, if any, additional biological testing to perform. The available
literature suggests that this change in paradigm has been challenging for industry and the
regulators to understand and implement. Here, a survey tool based on a hybrid
implementation/transparency framework was developed to explore how companies in the US and
EU are negotiating the challenges related to the changed international standards and regionally
based regulatory expectations. Eighty-seven respondents experienced in biocompatibility
management were recruited from medical device manufacturers, contract research organizations,
consultancies and regulatory bodies. Their feedback shows that the industry has been challenged
to interpret and apply the new standards and regulations. Difficulties were common in at least
four areas: aligning internal strategies with evolving regulatory expectations, obtaining the
needed resources and support, training and retaining staff, and revising procedures and test
methods. Efforts were handicapped because the standards lacked detail, and the notified bodies
and FDA frequently provided inconsistent advice and expectations. Results point to the
importance of expanding detailed guidance, improving training opportunities and materials, and
clarifying regulatory expectations to ensure that biocompatibility programs transition effectively
to requirements of the new standards and regulations.

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Chapter 1. Overview
1.1 Introduction
The medical device industry designs, develops, manufactures, and markets a wide range
of medical devices, from everyday items like bandages and stethoscopes, to highly complex
devices, such as pacemakers and heart valves. Today, about 15,000 global manufacturers
currently exist (RAPS, 2014), and more than 5,000 types of medical devices are on the market or
under development (Boutrand, 2012). The medical device industry is expected to reach about
540 billion dollars in annual sales by 2024 (EvaluateMedTech, 2018). Considering the number of
people who will use one or more medical devices during their lifetime, device safety is critical. It
is therefore not surprising that developers must perform extensive safety testing before a medical
device is used in or on patients.
1.1.1 Medical Device Safety Testing
There are numerous ways in which a medical device can be harmful, and this is reflected
in the diversity of tests used to address multiple aspects of product safety and quality. Areas
typically explored include the absence of toxic substances, biocompatibility safety, electrical
safety, mechanical safety, radiation safety, noise safety, thermal safety, sterility, packaging, and
transportation. One of the most challenging of these is the ability to assess biocompatibility,
defined as “the ability of material to perform with an appropriate host response in a specific
application” (Boutrand, 2012). This safety assessment is an integral part of determining overall
device safety and is required prior to obtaining approval from regulatory bodies for its use in
human beings, either during clinical trials or as a commercially sold and distributed medical
device.

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Biocompatibility concerns need not be addressed for every type of medical product but
instead are applicable to medical devices that come into contact with the human body. The type
of contact can include exposure of the device to diverse tissues such as skin, mucosal membrane,
blood, bone, and dentin. Thus, over time, testing strategies have been developed that consider the
specific nature of the risk that the device will pose according to the tissue that is contacted and
the duration of that contact. Biocompatibility safety testing may include chemical, physical, and
biological assays, as well as toxicological risk-based assessments. Testing is directed at
understanding the chemical composition and physical morphology of the device; additionally, in
vitro and in vivo biological tests examine whether the device will have cytotoxic or pyrogenic
effects or sensitize or irritate tissue after even short-term exposure. Testing may also be
performed to examine whether a device will damage tissues in the longer term by directing
additional focus at understanding systemic or tissue toxicity, hemocompatibility, genotoxicity,
carcinogenicity, and reproductive and developmental toxicity.
Many of the tests used to understand biocompatibility have been collated in an
international standard, ISO 10993 [ISO10993-1, Annex A, Table A.1; (International
Organization for Standardization, 2018)]. This important standard has for many years directed
medical device companies to select a testing strategy based upon a number of considerations,
including the nature and duration of contact with the body, materials of construction, chemical
composition, sterilization process, surface characteristics, prior experience from non-clinical or
clinical studies, and additional considerations identified as part of risk management process
[FDA Guidance Document on Use of ISO 10993-1, 2020; (International Organization for
Standardization, 2018, US FDA, 2020)]. To assist the document’s users, testing requirements
were consolidated into a matrix by categorizing devices into different groups on the basis of

14
three criteria: the nature of the contacted tissue, the type of contact, and the duration of that
contact. A specific battery of tests was then suggested for each category of device. More
recently, however, requirements have put more emphasis on a toxicological risk-based approach,
coupled with an understanding of the chemical characterization of the device and consideration
of prior testing of the device or its materials of construction [ISO 10993-1 (International
Organization for Standardization, 2018)]. Device testing strategy then involves more targeted
selection of in vitro and in vivo tests, in order to fill gaps of information needed for a
comprehensive understanding of its biocompatibility risks.
An international standard is voluntary unless it becomes required by some form of
legislation. The reason why ISO 10993 is so central to the thinking about biocompatibility is that
it has been recognized by regulators in most important commercial markets, such as the United
States (US) and the European Union (EU). These agencies have incorporated ISO 10993 in
whole or part into national rules for device testing. Medical device manufacturers that comply
with these standards and guidance documents are fulfilling regulatory expectations for
biocompatibility in both the US and the EU.
1.1.2 Regulation of Medical Devices in the United States and the European Union
1.1.2.1 United States
In the US, the regulation of medical devices traces its early roots to the Federal Drug and
Cosmetics Act (FD&C Act) of 1938. However, it was not until 1976 with passage of the Medical
Device Amendments that specific and comprehensive regulation of medical devices was put into
place to address the safety and effectiveness of medical devices. The Medical Device
Amendments established key requirements, such as registration of device manufacturers, listing
of devices, good manufacturing practices (GMPs), premarket requirements, and reporting of

15
adverse events. They also established regulatory pathways that defined how to obtain registration
or approval to sell medical devices. Reviews by the FDA are based on classifying medical
devices as specified in 21 CFR 862-892; establishing premarket notification procedures for
medium-risk devices under 21 CFR 807, part E (21CFR§807 Subpart E, 1977); investigational
device exemptions for investigational devices under 21 CFR 812 (21CFR§812, 1980); modified
approaches to humanitarian use devices under 21 CFR 814, Subpart H (21CFR§814, 1986b); and
premarket approval of high-risk and novel medical devices under 21 CFR 814 (21CFR§814,
1986a). Each of these regulatory pathways for device registration or approval has requirements
for biocompatibility safety testing. The requirements for that testing have evolved to keep pace
with changes in technological advances and scientific experience, in order to improve confidence
that medical devices will be safe and effective without compromising the speed and access of
medical devices for patients. As part of this evolution, the US has adopted the philosophy and
approaches of ISO 10993-1 for biocompatibility safety testing.
1.1.2.2 European Union
The regulation of medical devices within the EU was first established in 1965 with
Council Directive 65/65/EEC (Council Directive 65/65/EEC, 1965). This directive laid an initial
foundation for regulatory oversight over medicinal products, including medical devices, in order
to safeguard the health and safety of the public. However, it would take almost three decades for
specific medical device regulations to be introduced in the EU, beginning in 1993 with Council
Directive 93/42/EEC concerning medical devices (Council Directive 93/42/EEC, 1993), and
progressing further with the addition in 2001 of the 2007 Council Directive 2007/47/EC relating
to active implantable medical devices (Council Directive 2007/47/EC, 2007), and soon
thereafter, the In Vitro Diagnostic Devices Directive 98/79/EC (Directive 98/79/EC, 1998) and

16
Directives 2003/12/EC, 2003/32/EC (replaced in 2013 with 722/2012) covering breast implants
and medical devices manufactured using tissues of animal origin (Commission Directive
2003/12/EC, 2003, Commission Directive 2003/32/EC, 2003).
Until recently, medical devices sold within the EU were required to meet the health and
safety requirements set forth in the medical device directives (MDD). Starting in 2017,
oversight of medical devices was greatly modified by the introduction of the new and stricter
medical device regulations (MDR), Regulation (EU) 2017/745 of the European Parliament and
of the Council of 5 April 2017 on medical devices (RAPS, 2019, Regulation (EU) 2017/745,
2017). However, under both the old and new rules, medical devices that comply with the
applicable requirements following a conformity assessment procedure (CAP) can bear a “CE”
mark that allows the marketing of the device in all of the member states of the EU. Device
manufacturers with higher risk products must work with a third party, called a Notified Body, to
assess and assure conformity prior to and while marketing the device. As in the US, approval of
medical devices in the EU also requires biocompatibility testing and refers to the approaches
advocated in ISO 10993-1.
1.1.2.3 Regulation of Biocompatibility Testing for Medical Devices
Today, biocompatibility testing is an important part of medical device safety assessment.
It is defined for regulatory purposes by a duality of instruments. First is the most recent revision
of the international standard, ISO 10993-1, “Biological evaluation of medical devices – Part 1:
Evaluation and testing within a risk management process” and its accompanying normative and
informative reference standards, documented in ISO 10993-2 through 20 (International
Organization for Standardization, 2018). This revision changes the recommended strategy to
biocompatibility testing from a “checklist approach to one that is grounded in risk assessment.

17
Second are the specific regulations and guidance documents developed by the relevant
regulatory agencies in different constituencies. For example, the US FDA has published a
specific guidance document on the use of ISO 10993-1. The guidance document entitled “Use of
International Standard ISO 10993-1, Biological evaluation of medical devices – Part 1:
Evaluation and testing within a risk management process” provides the current thinking of the
FDA in a way that is more granular than the regulations themselves (US FDA, 2020). Further,
both the US and EU add additional aspects to the strategy and logistics of biocompatibility
testing by requiring conformance to Good Laboratory Practices (GLP), defined in 21 CFR Part
58 Good Laboratory Practice for Nonclinical Laboratory Studies, and by the Principles of Good
Laboratory Practice published by the Organization for Economic Co-operation and Development
(OECD) (21CFR§58, 1978, OECD, 1998). Risk management also plays a key role in decisions
about biocompatibility testing as promoted by ISO 10993, so both the US and the EU identify
the need to follow a second ISO standard, ISO 14971, “Medical Devices. Application of Risk
Management to Medical Devices” (International Organization for Standardization, 2019d).
1.2 Statement of the Problem
The changes that have been introduced to ISO 10993 and the related regional regulatory
requirements add new challenges to the already complex task of biocompatibility testing and
evaluation. The new ISO 10993-1 standard and its associated normative and informative
standards do not describe a proscriptive approach, but instead a risk-based framework for
biocompatibility safety testing and assessment. The appropriate use of the tables and annexes in
the ISO standard depends on the guidance of subject matter experts, who can use their
experience and expertise to tailor an evaluation strategy for the specific needs and risks of a
specific product under development.

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However, the assessment of medical devices for biocompatibility is challenging because
only a few international standards and regulatory guidance documents are available to assist
teams that are responsible for biocompatibility testing. This presents difficulties, particularly
because the recent 2018 update to the ISO 10993-1 standard proposes a significant change in the
approach to biocompatibility strategy. Whereas the previous paradigm was to primarily rely on
biological testing to assure biocompatibility safety, the current standard recommends that
assessments start with first characterizing the chemical profile of the device and applying a
toxicological risk evaluation. Only then should the strategy proceed to fill the gaps in
understanding uncharacterized risks using in vitro and in vivo biological testing.
In this changing environment, it is important to have guidance that can help with
strategy-setting. However, the ISO 10993 series is necessarily quite general in its attempts to
encompass the wide range of medical devices with biocompatibility testing needs. Thus, the
practical application of the standard to any one device type is poorly specified and open to
individual interpretation. Regulatory agencies and reviewers then apply their own interpretations
and local requirements. As a result, subject matter experts must deal with inconsistencies and
lack of clarity in the reference documents, made worse by differing opinions expressed in
regional regulatory policies and views of individual reviewers when marketing applications are
submitted to the regulatory agencies. They are further challenged by variations in
biocompatibility strategies amongst medical device manufacturers. The thinking on this topic by
regulators, scientists, and engineers responsible for this area varies based upon their experience
and approach to meeting biocompatibility testing requirements in the past. All of this takes place
against a backdrop of pressures internal to the company that place a premium on expediting new
product development by reducing the number, duration, and cost of biocompatibility tests.

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Adequate biocompatibility safety testing is often on the critical path in the new product
development process. It is not unusual for the biocompatibility testing to take up to 6 - 9 months
to complete.
The result of these competing changes and demands is some uncertainty about the recipe
for a successful comprehensive strategy to fulfill regulatory testing expectations. Incorrect or
incomplete testing may result in an application deficiency or non-approval. Additionally, if
biocompatibility testing is incorrect or insufficient, safety issues may be missed and only
discovered after human use, potentially resulting in recalls, patient injury, liability claims, and
regulatory penalties. The impact of these problems is apparent in a history of unfortunate case
studies. These include compatibility problems of metal-on-metal hip replacement implants in the
UK, where corrosion due to surface wear required that almost 10% of implants be replaced; or
suspected genotoxic concerns in breast implants, when degradation products of the soybean oil
used as filler required that implants be removed from about 80% of total implant recipients; or
the opacification of intraocular lenses when silicone components migrated requiring that they be
explanted in about 27% of the recipients (Boutrand, 2012).
Therefore, when deciding upon a biocompatibility testing strategy, it is important to “get
it right” the first time. “Getting it right” means performing biocompatibility safety testing with
all endpoints and considerations that fully meet the expectations for regulatory approval.
However, it is not an easy task to develop a regulatory strategy, especially in world that depends
on global commerce. Differences in interpretation can occur between regulators even in the two
constituencies of the EU and US. Differences in biocompatibility expectations can be magnified
further as additional regions are added to the global marketing map (Reeve and Baldrick, 2017,
Crawford, 2020).

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Because the changes in biocompatibility standards and guidances are so new, we know
relatively little about how these changes are being addressed by industry. We know that
companies must modify their biocompatibility approaches to address the new standards and
guidances. What we do not know is how this is being done and how these changes have affected
the developmental activities related to biocompatibility safety testing. We have an incomplete
understanding of where biocompatibility experts are finding educational sources that help them
to implement changes and whether they have sufficient trained people, money, management
support, and regulatory access to ensure success in this process.
1.3 Purpose of the Study
The research study used a mixed methods approach to gain insight into views and
experiences of companies dealing with the uneasy convergence of international standards with
nationally based regulatory expectations and traditional biocompatibility testing approaches. It
further explored how medical device companies negotiate the challenges that changes in
biocompatibility testing standards have posed for medical devices planned for sale in the US and
the EU. The research begins with a literature review to examine the history, current trends, and
industry best practices in biocompatibility safety testing and assessment that can be gained from
standards, guidance documents, industry and academic publications, textbooks, and
communications from subject matter experts in industry and regulatory agencies.
However, literature review alone may not give a complete and accurate portrayal of the
views of subject matter experts regarding the current practices of biocompatibility safety testing
and assessment. A novel survey was constructed by reference to an implementation framework
from Bertram, Blasé and Fixsen that is elaborated using a secondary transparency framework
first used by Solberg and Richmond (Solberg and Richmond, 2012). The survey tool was

21
critiqued by a focus group that provided some measure of content validation. The survey was
then be sent to biocompatibility experts in medical device companies, contract laboratories, and
consulting firms to derive further information about what they consider to be current and best
practices for the development of testing strategies and regulatory interactions.
1.4 Importance of the Study
Biocompatibility safety testing and assessment is one of many requirements for obtaining
approval for new or modified medical devices used in clinical studies and for commercial
distribution. Biocompatibility can be a particularly time-consuming and expensive activity at a
state of development when resources are often limited. It can even be the rate-limiting step prior
to submitting a device application for permission to perform clinical trials or to take a product to
market. Thus, it is important to develop an efficient and comprehensive strategy, to prevent
application deficiencies that could result in long approval delays. Delays can be costly in terms
of dollars lost in sales, loss of first-to-market position, and most importantly, delay in approval of
novel devices that may be the only therapeutic option for otherwise untreatable life-threatening
disease conditions.
This study may be helpful to more than one stakeholder in the medical device sector.
First, it may help the medical device industry to better understand the expectations and current
and best practices for biocompatibility safety assessment and testing. This knowledge might
streamline the development of appropriate testing strategy to avoid costly mistakes and do-overs,
with the end-goal of meeting the expectations of US and EU regulators. It may also help to
identify areas of challenge for regulators, so that efforts to educate and assist the applicants can
be targeted to meet those needs more effectively. More generally, it can help stakeholders who

22
are on the fringe of this process to understand where to anticipate bottlenecks and uncertainties,
so that these can be incorporated in planning or funding decisions.
1.5 Limitation, Delimitations, Assumptions
This study is delimited to respondents employed in or providing support to companies
that make medical devices destined for sale within the US and the EU. This study is also
delimited to regulations used within the US and the EU medical device market, primarily 21
CFR Part 820, 21 CFR Part 58, OECD GLP Guidelines, ISO 13485 quality systems, ISO 10993-
1 and associated normative and informative standards, FDA Guidance Document on use of ISO
10993-1, and ISO 14971 (21CFR§820, 1996, 21CFR§58, 1978, OECD, 1998, International
Organization for Standardization, 2016b, International Organization for Standardization, 2018,
US FDA, 2020, International Organization for Standardization, 2019d). The study was also
subject to a number of potential limitations. Its reach was restricted to a finite group of
respondents and the responses can be limited by the knowledge and experience of the survey
participants. This could be additionally problematic if survey respondents were cautious about
sharing information because they might fear the disclosure of company information. Because the
target participant group is composed of busy professionals, many may choose not to respond, so
response rates may be relatively low. This is further addressed in Chapter 5.
1.6 Organization of Thesis
This dissertation contains five chapters. Chapter 1 presents an overview of the research
problem, background of biocompatibility safety testing, and high-level introduction to
regulations and device approval pathways. Chapter 1 also discusses reasons why the topic was
selected. Chapter 2 outlines the literature relevant to the research topic and sets up a framework
through which the research questions of interest are studied and examined. Chapter 3 defines and

23
explains the methods that were used as part of this research study. Chapter 4 is focused on
reviewing and evaluating the results of this study. Finally, Chapter 5 discusses the study results,
their validity and significance, findings, conclusions and recommendations. Chapter 5 also
contains suggestions based on my survey for follow-on research.
1.7 Definitions Section
Antigenic: Stimulates an unwanted immune response.
Biomaterials: Synthetic materials designed for use in a specific biological
activity (Basu and Nath, 2009)
Biomechanically
compatible:
Compatible with the mechanics of a part or function of a living
body, such as of the heart. (For the American Heritage
Dictionary definition: biomechanically. (n.d.) American
Heritage® Dictionary of the English Language, Fifth Edition.
(2011). Retrieved June 27, 2020 from
https://www.thefreedictionary.com/biomechanically)
Carcinogenic: Leads to cancer development
GCMS: Gas chromatography mass spectroscopy. An analytical
chemistry instrumental testing process that couples the power of
chemical separation (chromatography) with powerful
identification (mass spectroscopy) techniques. In
Biocompatibility testing, this analytical technique is used for
identification and quantification of volatile and semi-volatile
organic leachables and extractables and for laboratory based
chemical characterization efforts.
ICPMS: Inductively coupled plasma mass spectroscopy. An analytical
chemistry instrumental testing process that couples the power of
plasma metals excitation source with powerful identification
(mass spectroscopy) techniques. In Biocompatibility testing, this
analytical technique is used for identification and quantification
of inorganic or metal leachables and extractables and for
laboratory based chemical characterization efforts
In vitro Outside of a living orgasm. This refers to a test that is not
performed using an animal.
In vivo: Within a living organism. This refers to a test performed using
an animal.

24
LCMS: Liquid chromatography mass spectroscopy. An analytical
chemistry instrumental testing process that couples the power of
chemical separation (chromatography) with powerful
identification (mass spectroscopy) techniques. In
Biocompatibility testing, this analytical technique is used for
identification and quantification of non- volatile organic
leachables and extractables and for laboratory based chemical
characterization efforts.
Mutagenic: Changes or mutates from a desired to undesired characteristic
Normative
reference
documents:
A referenced document that is indispensable to the application of
the international recognized standard. Without it, the subject
technical standard cannot be fully and properly utilized.
Risk: The combination of the probability of occurrence of harm and
the severity of that harm (Wu et al., 2019)
Thrombogenic: Causes a blood clot formation
Toxic: Contains noxious or undesired materials

25
Chapter 2. Literature Review
2.1 Literature Search
A review of the literature was performed to understand current research and opinions
related to biocompatibility testing strategies for medical devices in the US and the EU. The USC
library search tool was the primary means of search. The search terms included biocompatibility,
ISO 10993-1, biocompatibility of medical devices, medical device biocompatibility,
biocompatibility in vivo testing, biocompatibility in vitro testing, medical device pre-clinical
safety testing, and medical device non-clinical safety testing. Search parameters were focused on
articles that contained the keywords within the title of the articles. This initial search generated
more than 495,000 articles and books. Further refinement of the search focused on isolating
articles, published within the recent decade. This culling activity yielded approximately 8,000
articles. Article titles were then evaluated to identify those that were relevant to the topic of the
dissertation, with particular emphasis on current trends in the biocompatibility safety testing of
medical devices in the US and the EU. Article titles were also evaluated to identify those
providing insight into views and experiences of companies dealing with the uneasy convergence
of international standards with nationally based regulatory expectations and traditional
biocompatibility testing approaches. The articles excluded by this filtering process mostly
focused on scientific discovery and evaluation of assay methods, materials, and medical devices.
This culling activity yielded approximately 80 articles. The references used by these articles
were also searched for additional references relevant to the topic.
Additional materials were sourced from industry trade publications, government
documents, and seminar and conference presentations. Further, reference books and textbooks
already present in the thesis author’s personal library were supplemented with additional books
found during the search. Additionally, a small, focused search was also performed to identify

26
articles and textbooks to use in the research framework selection process. At the conclusion of
the comprehensive search and associated refinement steps as has been previously described,
approximately 91 articles and 14 textbooks were used as the primary foundational material
presented in this chapter.
2.2 Evolution of Medical Device Regulation
Medical devices have been in use for millennia in many different cultures. Some of the
first medical devices included implants of gold and ivory, which were used by the Egyptians and
Romans to repair defects in bone (Siswomihardjo, 2016). However, medical devices have since
become much more sophisticated. Medical devices now vary in complexity and use, from simple
products such as adhesive bandages, wheelchairs and syringes, to technologically advanced
products such as heart pacemakers and valves. They have also become the basis for a
wide-ranging commercial enterprise. In 2017, the global medical device market was estimated to
be approximately 400 billion dollars in sales, with about 40% of this activity taking place in the
US (US International Trade Administration, 2017).
Medical device development can be quite demanding. Some analysts have attempted to
estimate the cost to take a medical device product from concept to commercialization in the US.
In 2010, a survey of over 200 medical technology companies was conducted to understand the
impact of US regulations on medical technology innovation. As part of the analysis, results
suggested that, on average, it cost $31 million to bring a low- to moderate-risk product from
concept to clearance and approximately $94 million for a higher-risk product (Makower et al.,
2010). However, this number can be misleading because it does not reflect the highly varying
costs associated with different types of devices; these typically increase in direct proportion to
the complexity of the device. For example, a simple device such as an adhesive bandage would

27
have minimal development costs, whereas a state-of-the-art heart valve may have development
costs of hundreds of millions of dollars. A significant amount of the cost associated with the
development of medical devices is earmarked for safety testing and compliance, which includes
biocompatibility safety testing (Reifschneider, 2017), the topic of this dissertation.
Medical devices may be constructed from a wide variety of materials, including metals,
ceramics, polymers, animal-sourced tissues, and plant-based materials. These materials, and the
final devices from which they are constructed, have the potential to damage the biological tissues
with which they come into contact. Additionally, these materials may also be intended to induce
some type of biological response, such as wound healing or fracture repair, to treat the patient’s
disease or disability. It is therefore important that medical devices and their materials can remain
in a biological environment without causing harm, and that they remain effective for their
intended use. These expectations for safety and effectiveness underlie the need to perform
biocompatibility safety testing (Basu and Nath, 2009). Because these considerations are so
important for assuring patient health, regulations have been developed to ensure that these
potential risks and benefits are understood and managed. The discussion below will focus on
devices that contact the patient’s body in some way and thus require testing to assure
biocompatibility.
2.3 Medical Device Regulation
2.3.1 Defining and Classifying Medical Devices
Many global governmental and industry organizations are involved in medical device
regulation, and each has its own set of definitions for medical devices. For example, the US
definition of a medical device is stated in the United States Food Drug & Cosmetic (FD&C) Act
and the EU definition is found in the Medical Device Regulations (MDRs). However, a more

28
harmonized point of reference to use when defining a medical device is that provided by the
International Medical Device Regulators Forum (IMDRF), a voluntary group of medical device
regulators from around the world who are focused on accelerating international medical device
regulatory harmonization and convergence. The group began in 2011, building on the work
previously done by a similar, but now disbanded Global Harmonization Task Force (GHTF).
Both organizations have published multiple documents to encourage harmonization of the
technical standards and methods to facilitate their mission. Among those documents is “Essential
Principles of Safety and Performance of Medical Devices and IVD Devices.” This document
contains comprehensive definition of a medical device:
Any instrument, apparatus, implement, appliance, implant, reagent for in vitro
use, software, material or other similar related article, intended by the
manufacturer to be used, alone or in combination, for human beings, for one or
more of the specific medical purpose(s) of: Diagnosis, prevention, monitoring,
treatment or alleviation of disease, Diagnosis, monitoring, treatment, alleviation
of, or compensation for, an injury, Investigation, replacement, modification, or
support of the anatomy, or physiological process, Supporting or sustaining life,
Control of conception, Cleaning, disinfection or sterilization of medical device,
Providing information by means of an in vitro examination of specimens derived
from the human body; And does not achieve its primary intended action by
pharmacological, immunological, or metabolic means, in or on the human body,
but which may be assisted in its intended function by such means (IMDRF Good
Regulatory Review Practices Group, 2018).

2.3.2 Regulation in the European Union (EU)
The regulation of medical devices in both the EU and the US is built upon a tiered system
of device classification. The placement of a device in this system depends on its complexity and
the degree of risk presented by exposure to the device (Rados, 2006). However, the two
economies have different methods to manage medical products within a particular class. In the
EU, the system governing devices has changed markedly over the last half century. Prior to the
1990s, each member state had its own method of regulating medical devices and its own range of

29
nationally based requirements to achieve this task. This fragmented approach changed
dramatically after the passage of the Medical Device Directives (MDD), the first of which was
published in 1965, Council Directive 65/65/EEC. This Directive was associated with a
requirement that devices marketed in the EU have conformity assessment (CE) marking.
Manufacturers of low-risk (Class 1 non-sterile) devices can self-certify that they comply with the
related Directive (RAPS, 2014). However, manufacturers of higher-risk devices must work with
a third party, called a Notified Body, authorized to conduct an assessment that the Directives
have been followed. Notified bodies are private organizations which operate under a mandate
from EU member states and are responsible to assess medical device manufacturers’ compliance
with requirements of EU medical device law. The Notified Bodies grant certificates of
compliance to the medical device manufacturers and monitor that compliance through on-going
audits and reviews (RAPS, 2014). Medical devices that comply with the MDD/MDR can then
apply a “CE” mark to their labeling, indicating that they meet approval of the essential
requirements of applicable directives. Compliance with the CE marking requirements will then
open the whole of the EU market to the medical devices (Kramer et al., 2012, RAPS, 2014).
The first MDD was followed by additional directives that consolidate requirements under
one system and include:
• The 1993 Council Directive 93/42/EEC concerning medical devices, which was further
amended in 2001 (Council Directive 93/42/EEC, 1993).
• The 2007 Council Directive 2007/47/EC relating to active implantable medical devices
(Council Directive 2007/47/EC, 2007).
• The In Vitro Diagnostic Devices Directive 98/79/EC (Directive 98/79/EC, 1998).
• Directives 2003/12/EC, 2003/32/EC (replaced in 2013 with 722/2012), covering breast
implants and medical devices manufactured using tissues of animal origin (Commission
Directive 2003/12/EC, 2003, Commission Directive 2003/32/EC, 2003).

30
There are additional directives that cover areas such as clinical trials, personal protective
equipment, and updates to directives on breast implants, medical device using animal tissues, and
active implantable medical devices (RAPS, Global Medical Device Regulation, 2014). These
Medical Device Directives (MDD) have for several decades been the basis for approval of
medical devices within the EU (Council Directive 93/42/EEC, 1993). Recently, however, the EU
has enacted new Medical Device Regulations (MDR) to replace the Medical Device Directives.
These regulations, which became effective in May 2017 and transitioned to final implementation
in May 2021, now define the requirements to achieve conformity for CE marking (Regulation
(EU) 2017/745, 2017). A full description of this evolution from MDD to MDR is beyond the
scope of this dissertation. The text, Fundamentals of Medical Device Regulations that has been
published by the Regulatory Affairs Professionals Society (RAPS, 2019), provides a good
reference describing the general evolution of the EU regulatory system. However, the specific
aspects of the Directives and Regulations related to biocompatibility are described below in more
detail.
2.3.3 Medical Device Regulations in the United States
In the US, the Food and Drug Administration (FDA) is the primary organization
responsible for medical device oversight. The initial act giving to the FDA the responsibility to
regulate medical products was the 1938 Federal, Food, Drug, and Cosmetic Act (FD&C Act)
(P.L. 75-717, 1938, Termini, 2012). As a result of its passage, the FDA was able to bring charges
against a device manufacturer for adulteration or misbranding, but lacked the authority to require
pre-market testing, review and approval (Van Norman, 2016, Munsey, 1995, Rados, 2006). To
expand the FDA’s authority over medical devices, Congress passed the Medical Device
Amendments to the Federal FD&C Act in 1976 (21USC§§301-392, 1976, Termini, 2012). These

31
amendments established a three-class system to categorize medical devices based upon risk and
gave FDA authority to develop rules for device listing, registration of medical device
manufacturers and use of good manufacturing practices (GMPs) (RAPS, 2014).
Following the 1976 Medical Device Amendments, US medical device regulations and
laws have continued to evolve to assure the quality, safety and effectiveness of devices, and also
to increase the speed and access of medical devices for patients. These included but were not
limited to regulations defining the Investigational Device Exemption (IDE) in 1980 [Medical
Devices; Procedures for Investigational Device Exemptions, 45 Fed. Reg. 3732, 3738 Jan. 18,
1980 (US FDA, 1980)], which required FDA approval prior to initiation of clinical trials;
regulations in 1984 that required reporting of adverse events [MDR Regulations, 49 Fed. Reg.
36326, September 14, 1984 (US FDA, 1984)]; with passage of the Safe Medical Devices Act
[Safe Medical Devices Act of 1990, P.L. 101-629, H.R.3095, 101
st
Cong. (1990) (H.R.3095 -
101st Congress, 1990)] in 1990; and passage of the Medical Device User Fee and Modernization
Act in 2002 [Medical Device User Fee and Modernization Act of 2002 (MDUFMA), P.L. 107-
250, H.R. 3580, 107
th
Cong. (2002) (Public Law 107-250, 2002)].
The FDA operationalizes all of its relevant legislation through regulations that are legally
enforceable. Importantly, however, it also assists the device manufacturers in the use of these
regulations by publishing guidance documents that describe the FDA’s current thinking on
specific topics and interpretation of the regulations. These guidance documents, while not
binding, do help companies to recognize an acceptable way to fulfill the requirements of the
regulations, based upon FDA’s interpretation. Additionally, the FDA will recognize standards
(for example ISO, ICH, ASTM) that describe an internationally based consensus about
approaches to fulfill specific requirements for device development. Some examples of key

32
standards used during the development of medical devices and particularly relevant to this
research are ISO 14971, which addresses the application of risk management, and ISO 10993-1,
which addresses the biological evaluation of medical devices to evaluate safety issues
(International Organization for Standardization, 2019d, International Organization for
Standardization, 2018). These will be discussed in more detail below.
2.4 Medical Device Safety Testing
Medical devices are designed to improve a disease or disability; however, they are not
risk free and most have the capacity to compromise the safety of the patients and users if
designed, manufactured, or used incorrectly. Thus, a wide range of tests are used to evaluate
critical aspects of product safety and quality. These tests evaluate safety in areas such as the
absence of toxic substances, biocompatibility safety, electrical safety, mechanical safety,
radiation safety, noise safety, thermal safety, sterility, packaging and transportation (Boutrand,
2012). The safety testing includes biocompatibility testing, applicable for products that contact
the patient. Biocompatibility safety testing examines potential chemical or biological hazards for
devices that have direct or indirect contact with the patient. Medical devices that do not have
physical contact with the patient do not require biocompatibility testing or assessment.
Biocompatibility testing adds to the data from various sources that are used to evaluate the safety
risk profile of a medical device and to understand its potential adverse effects (Myers et al.,
2017, Geckler, 2017). Important to that consideration is the management of risk, guided by the
international standard ISO 14971, “Application of Risk Management to Medical Devices”
(International Organization for Standardization, 2019d). This standard describes the need to
consider a range of potential hazards, including energy related, biological, chemical,

33
informational, and operational hazards, as part of risk management and design control activities
during new product development. (Holzer et al., 2017).
The life cycle may be short for many medical devices, so industry may have minimal
time to recover costs associated with design, development and testing of a device. Thus,
development decisions must consider the delicate balance between innovation, patient safety,
and financial constraints. Regulators play an important role, facilitating a swift process for
design, development, and safety testing, while scrutinizing patient safety and risk reduction
(Holzer et al., 2017). Thus, they must exercise careful oversight, achieved in part by requiring
the manufacturer to provide comprehensive data on pre-clinical safety testing before allowing it
to go forward into human clinical trials and later into commercialization.
In the US, regulations covering preclinical safety testing include Section 515 of the
FD&C Act, which requires “reasonable assurances that a device is safe and effective under
conditions of use,” before pre-market approval. This may include clinical testing. Prior to
engaging in such testing, an IDE application must be submitted and approved by the FDA. The
IDE application includes reports of safety testing, including biocompatibility and toxicology
testing, to assure the regulators that the devices have a strongly positive benefit-risk profile
(Holzer et al., 2017). In the EU, the notified bodies oversee this process and are responsible to
assess the manufacturers’ compliance with requirements of EU medical device laws and
directives. The notified bodies grant certificates of compliance to the medical device
manufacturers and monitor compliance through on-going audits and reviews (RAPS, 2014). The
notified bodies also review device applications that include safety testing in much the same way
as FDA reviewers do in the US, to ensure that medical devices have a strongly positive benefit-
risk profile.

34
2.5 Biocompatibility Safety Testing
2.5.1 Definition of Biocompatibility
Biocompatibility is a broad term that covers a variety of interactions between a medical
device and the host tissues that contact it (Fiedler, 2017). Biocompatibility considers
characteristics of the device including materials of construction, surface morphology, location of
contact, duration of contact, and type of contact. It also examines the biological consequences of
the manufacturing and sterilization processes that have been used. In 1986, the consensus
definition of biocompatibility was “the ability of a material to perform with an appropriate host
response in a specific application” [Chester Consensus Conference on Definitions in
Biomaterials, 1986 (Williams, 1987)]. Since that time technology has become more
sophisticated, and its evolution is reflected in a wider definition:
Biocompatibility is the ability of a biomaterial to perform it’s desired function
with respect to a medical therapy, without eliciting any undesirable local or
systemic effects in the recipient or beneficiary of that therapy, but generating the
most appropriate cellular or tissue response in that specific situation, and
optimizing the clinical relevant performance of that therapy (Williams, 2008).

The terms “biological safety” and “biocompatibility” are often used interchangeably.
They are in fact different; biological safety implies that risk is not present, whereas
biocompatibility implies that an active equilibrium exists between the device and surrounding
tissues such that it addresses the therapeutic intent (Bernard et al., 2018). Biocompatibility is a
property influenced by the chemical composition and physical and surface characteristics of a
medical device. It is influenced by the nature of chemicals that the device can leach and the
actions that it will exert or will be exerted on it. Biocompatibility can also depend on the length
of time that the device will be in contact with the body and the tissue location that it occupies.
(Siswomihardjo, 2016).

35
2.5.2 Principles of Biocompatibility Testing
An understanding of biocompatibility of medical devices and their associated materials of
construction has evolved over time. Prior to 1950, many implants were poorly tolerated by the
body because the designers of these devices had an insufficient understanding of
biocompatibility, which can affect performance and reliability throughout the lifetime of a device
(Siswomihardjo, 2016). Today, we demand that implanted devices or materials of construction
will not be toxic, antigenic, thrombogenic, carcinogenic, or mutagenic (Fiedler, 2017). They
should be compatible biomechanically with the surrounding tissues, and where expected, should
be able to establish an appropriate bio-adhesive interface with them (Basu and Nath, 2009). If a
host response is expected, such as might be expected from devices coated with drugs, those
responses should be predictable and safe (Basu and Nath, 2009). In addition to ensuring safety of
the medical device user, biocompatibility safety testing is also performed to evaluate potential
safety impact to healthcare practitioners, caregivers, service providers, and other persons who
interact with the device (Wu et al., 2019).
Implanting a medical device into the human body elicits typical biological responses that
depend on size, geometry, material properties, and surface characteristics. As previously
discussed, a medical device should not produce adverse local, systemic, carcinogenic,
reproductive, or developmental effects, either directly or through the release of constituents from
materials of construction (Mohanan, 2014). When a medical device is not biocompatible,
untoward reactions may be limited locally to tissues contacting the device, or they may be
systemic. Examples of local tissue reaction include irritation and formation of thrombus; those of
systemic reactions include toxic or allergic responses. Much of what decides whether a patient-
contacting device or material will be biocompatible is its intended physical and clinical purpose.
A material may be biocompatible for some applications, yet completely unacceptable for others

36
(Siswomihardjo, 2016). Biocompatibility safety testing must address all of these types of
interactions as described by the international standard ISO 10993-1.
2.5.3 Biocompatibility and the Medical Device Lifecycle
Biocompatibility is a factor that must be considered throughout the lifecycle of a product.
It begins with the initial screening of new materials, and continues with risk assessments based
on physical, chemical, and biological testing prior to clinical trials or device commercialization.
As part of life cycle management, changes to a commercialized device must also be evaluated to
understand whether the changes introduce any new or elevated risks (Vidal and Granjeiro, 2017).
Examples of changes to a device for which additional biocompatibility testing may be required
include changes in indications or conditions of use, sterilization, cleaning, or manufacturing
processes, or changes of raw materials, components or packaging materials in contact with the
device (Reifschneider, 2017, Bernard et al., 2018).
The biocompatibility of a device may change over time even if its design is not altered. It
can be affected by factors such as conditions of use, wear, inherent degradation of the materials
of construction, and device interaction with the body. For example, hip implants have been
known to deteriorate over time; in some cases that wear has caused the release of toxic levels of
metals, ions and particulate matter into the body (Boutrand, 2019). The dental filling material,
amalgam, was used for almost 200 years before science made clear that the mercury in the filler
posed risks; this has caused the dental community to shift away from materials with high
mercury content toward the use of polymers (Siswomihardjo, 2016).
Biocompatibility safety assessment has become more complex and challenging as
biotechnology yields novel biomaterials and bioproducts that are used in innovative medical
devices. Examples include medical devices designed to support the repair of body tissues and

37
products that combine the device with drugs or biologics to facilitate the controlled release of
drugs into the body. These biomaterials and “combination” products challenge the existing
standards and associated testing regimes in place to evaluate the biocompatibility of medical
devices (Vidal and Granjeiro, 2017). They also present challenges for the regulator, as
recognized in the way that each regulatory agency organizes its rules and requirements.
2.6 Biocompatibility Regulations and Guidelines in the United States
Prior to 1987, medical device manufacturers had little guidance from regulators regarding
the expectations for biocompatibility testing. Each company and product would utilize what
seemed to be the most appropriate reference to guide safety testing, including applicable chapters
of the United States Pharmacopeia (USP) (Reifschneider, 2017). To improve consistency, in
1986, the Toxicology Subgroup of the Tripartite Subcommittee on Medical Devices developed
the “Tripartite Biocompatibility Guidance for Medical Devices,” for use by Canada, the United
Kingdom, and the US, to evaluate the toxicological risks of medical devices. This guidance
document was used as the primary biocompatibility guidance by the FDA from 1987 until 1995
and is discussed in April 1987 FDA General Program Memorandum # G87-1 “Tripartite
Biocompatibility Guidance” (Toxicology Subgroup Tripartite Subcommittee on Medical
Devices, 1988).
The principles laid out by this document are a foundation for the guidance documents and
regulations that have evolved and are in effect today. They direct manufactures to consider a full
understanding of the materials of construction, all associated processes, leachables and
degradation products in the toxicological safety evaluation of a device. The selected testing
strategy should consider the nature, degree, frequency, and duration of bodily contact with the
device and materials. Good Laboratory Practices (GLP) should be followed for biological testing

38
used to support regulatory submissions, and whenever the device or materials undergo changes
(chemical composition, sterilization, etc.), manufacturers should identify whether to re-evaluate
device biocompatibility. The overall biocompatibility safety assessment should also consider
other relevant sources of information such as clinical studies and post-market information.
Additionally, the guidance document discusses the selection of in vitro and in vivo testing based
upon the nature and duration of device contact with the human body (Toxicology Subgroup
Tripartite Subcommittee on Medical Devices, 1988).
The Tripartite Biocompatibility Guidance was the key standard followed in the US until
1995 when FDA published the G95 Memorandum. This new document incorporated ISO
Standard 10993-1 “Biological Evaluation of Medical Devices” and adopted the ISO 10993
testing matrix to which it added its own modifications [G95 memorandum, “Use of International
Standard ISO-10993, ‘Biological Evaluation of Medical Devices Part 1: Evaluation and Testing,’
May 1, 1995” (US FDA, 1995)]. This revision was consistent with an evolving view amongst
regulators that international standards could be used as delegated legislation to reduce nationally
developed rules and increase regulatory harmonization. The content of this important standard is
detailed below in Section 2.8.1. To align with updates to ISO 10993-1, in 2013, the FDA
released a draft guidance document on the use of the ISO 10993-1 standard, titled “Use of
International Standard ISO-10993, ‘Biological Evaluation of Medical Devices Part 1: Evaluation
and Testing within a Risk Management Process’ ”. In 2016, this document officially superseded
the 1995 Blue Book Memorandum #G95-1. The new guidance document provides updated
information on use of the current International Standard ISO 10993-1, "Biological evaluation of
medical devices - Part 1: Evaluation and testing within a risk management process.” It supported
an important new policy shift away from the relatively inflexible and proscriptive matrix-based

39
approach suggested in the G95 Memorandum to a risk-based approach to determine whether and
how much biocompatibility testing is needed. It also provides recommendations on use of
chemical and materials characterization that was not previously addressed in the G95-1 memo
(US FDA, 2020). This FDA guidance document was updated in late 2020 to take account of
these changes. However, most modifications to this document were editorial and did not alter the
new approach to biocompatibility testing.
2.7 Biocompatibility Regulations and Guidelines in the European Union
To become approved in the EU, a medical device manufacturer also must address
biocompatibility and biological safety. First, the company must identify the risks and hazards
associated with the use of the device and how these have been addressed. For those devices that
make physical contact with a patient, biocompatibility testing must be conducted prior to affixing
a CE mark (MDD 93/42/EEC, amended Directive 2007/47/EC, and Directive 90/385/EEC
(Council Directive 93/42/EEC, 1993, Council Directive 2007/47/EC, 2007, Council Directive
90/385/EEC, 2007). As is in the US, biocompatibility safety assessments are guided by the ISO
10993-1. The EU member states presume compliance with the essential requirements when the
device manufacturers conform with other relevant harmonized national standards that have been
adopted as well. These include standards that address chemical, physical, and biological
properties of medical devices. The technical dossier that will be reviewed by the Notified Body
must include a biocompatibility report that complies with ISO 10993-1. The biocompatibility
report summarizes the rationale and testing used to demonstrate and assure the safety of the
device and/or material (RAPS, 2014).

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2.8 Standards and Guidance Documents that Define Biocompatibility
Biocompatibility safety evaluation of a device is initiated before the device is used in
humans; it is therefore often classified as “preclinical testing” (Mohanan, 2014). The standards
and guidance documents that define biocompatibility are described in the following sections.
Evaluations generally take place in stages during the new product development process, with
increasing rigor prior to clinical trials. Biocompatibility testing will often continue and intensify
as clinical trials proceed, because the potential risks that such testing might uncover will have a
more widespread consequence as larger clinical study populations are exposed to the product.
Prior to a small clinical study at the stage of early feasibility (EFS) or feasibility, preliminary
biocompatibility assessment may therefore be limited to laboratory chemical and biological
testing and may leverage testing from a predicate device and literature safety assessments.
However, a more comprehensive panel of biological and chemical laboratory testing is typically
needed before proceeding to pivotal clinical studies for higher risk devices such as implants.
2.8.1 ISO 10993
As identified above, ISO 10993-1 has become the international “gold” standard that is
used in the US and the EU to guide the evaluation of biocompatibility safety for medical devices
and materials of construction. This harmonized international standard, along with the standards
in the series (identified as ISO 10993-2 to 20), is intended to assess the biological response of
materials and medical devices through physical, chemical, biological, and toxicological testing
and risk assessments. The extent of testing and assessment of a device depends on the nature and
duration of its contact with the body. Section 5.2 of the ISO 10993-1 Standard defines the nature
of device contact and is summarized here in Table 1. Section 5.3 of the Standard describes the
duration of contact and is summarized in Table 2.

41
Table 1: Nature of Device Contact
Type of Patient Contact Description of Contact
Non-contact The device does not contact a patient’s body (either directly or
indirectly)
Surface contact The device is in contact with the skin, mucosal membranes,
breached or compromised surfaces (such as an ulcer)
Externally communicating The device is in contact with indirect blood path or circulating blood
(such as a blood administration set or intravascular catheter), tissue,
bone, or dentin contact (such as dental filling materials)
Implant The device is implanted within the body and is contacting bone or
blood

Table 2: Duration of Device Contact
Duration of Device Contact Description of Duration
Limited exposure A device with single or combined multiple uses that do not exceed a
total of 24 hours
Prolonged exposure A device with a single or combined multiple uses that are more than
24 hours, but do not exceed 30 days
Long-term exposure A device with a single or combined multiple uses that exceed
30 days

The nature and duration of contact will dictate the extent of chemical and biological
testing that should be considered and/or performed. Testing regimens become more
comprehensive as the degree of invasiveness and duration of the device contact increase. A
variety of testing methods are available, and include in vivo, in vitro, chemical, and physical
testing, as described in Table A.1 of the 10993-1 standard (International Organization for
Standardization, 2018). In vitro tests are usually intended for screening purposes. They mostly
use single cell lines and may not reflect all of the tissue interactions that might be experienced
when the device is in contact with intact physiological systems. In vivo tests are performed using
animal models and may better approximate the human environment. These replicate the effects
of contact with various cell types of the body and can be affected by hormones and other
environmental changes (Basu and Nath, 2009). Chemical and physical testing can reduce the

42
need for some types of in vitro and in vivo tests and will be discussed later in Section 2.9 of this
chapter.
Regulatory agencies appreciate that biocompatibility strategy can require multiple tests
and attempt to communicate their views on such testing in multiple ways. First is through
regulations, which are made clearer with more specific “guidance documents.” Second is by
reference to “technical standards” developed by expert organizations attempting to develop
consensus on best practices. International bodies such as ISO often count on the regulators in
different countries to adopt their consensus standards in order to harmonize practices across
different jurisdictions. Both standards and guidance documents are intended to be applied and
used by subject matter experts with appropriate knowledge and experience, expecting that they
will apply judgement in their practical application (Bernard et al., 2018).
As noted above, one standard, ISO 10993-1:2018, is by far the most comprehensive and
influential biocompatibility standard. The standard is divided into several parts. Part 1 is an
overview that discusses the overall strategy for biocompatibility evaluation. According to the
International Standard ISO 10993-1, a device developer should first understand the nature and
duration of contact of the device. Information should then be gathered about the device’s
materials of construction, its manufacturing, cleaning, and sterilization processes. A Biological
Safety Evaluation Plan based on this collected information should then be developed during the
early stages of the biocompatibility safety assessment using a risk management approach
(Cambiaghi, 2018). Once hazards are identified, the device manufacturer should carry out a risk
assessment and identify gaps of information that might prevent good risk estimation and
evaluation. Physical and chemical testing may be performed at this point to fill in the gaps, using
targeted or screening tests as described in subsequent parts of the standard. The preliminary risk

43
assessment can then be used to determine whether further biological testing is necessary. After
chemical and biological testing is complete, a final risk assessment may be written to describe
the comprehensive approach that it used to base its conclusions about the biocompatibility of the
device (Przygoda, 2017). The requirements set forth in the primary part of this international
standard are rather specific, yet leave some room for interpretation (Hampshire and Gilbert,
2018).
The bulk of ISO 10993 comes from 17 additional normative reference documents whose
individual relevance to a biocompatibility program will depend on the characteristics of the
device and its tissue environment. These ISO normative reference documents are shown in Table
3 and are discussed in Section 2.9 below. The reader is also referred to each document for more
detailed information.
Table 3: ISO 10993 Standard Listing
ISO Standard Number Brief Description
10993-2 This standard discusses animal welfare requirements.
10993-3 This standard discusses testing for genotoxicity, carcinogenicity and
reproductive toxicity.
10993-4 This standard discusses the selection of tests for interactions with blood.
10993-5 This standard discusses the tests for in vitro cytotoxicity.
10993-6 This standard discusses the tests for local effects after implantation.
10993-7 This standard discusses ethylene oxide sterilization residuals.
10993-9 This standard discusses the framework for identification and quantification
of potential degradation products.
10993-10 This standard discusses tests for skin sensitization.
10993-11 This standard discusses tests for systemic toxicity.
10993-12 This standard discusses sample preparation and reference materials.
10993-13 This standard discusses identification and quantification of degradation
products from polymeric medical devices.
10993-14 This standard discusses identification and quantification of degradation
products from ceramics.
10993-15 This standard discusses identification and quantification of degradation
products from metals and alloys.

44
Table 3: ISO 10993 Standard Listing
ISO Standard Number Brief Description
10993-16 This standard discusses toxicokinetic study design for degradation products
and leachables.
10993-17 This standard discusses the establishment of allowable limits for leachable
substances.
10993-18 This standard discusses the chemical characterization of materials.
10993-20 This standard discusses principles and methods for immunotoxicology
testing of medical devices.
10993-23 This standard discusses tests for irritation

2.8.2 FDA Guidance Document on the Use of ISO 10993-1
The FDA can incorporate by reference some or all the recommendations of the ISO
10993 standards. However, it may also identify areas in which its interpretation might differ. The
FDA guidance document, titled “Use of International Standard ISO 10993-1, Biological
evaluation of medical devices – Part 1: Evaluation and testing within a risk management
process,” was promulgated to provide insight into the FDA’s thinking. It offers a few options
when evaluating appropriate testing for a medical device that are consistent with a foundational
risk-based classification and approval scheme but are tailored to the specifics of the US
classification and approval schema. These include the ability to establish biocompatibility by
comparison to an already cleared and marketed medical device and the use of a risk assessment
to establish the extent to which more limited testing may be needed. Additionally, the FDA
guidance advocates the use of a toxicological and biological safety risk assessment to guide the
strategy for physical and chemical characterization, followed by additional biological testing as
needed to establish comprehensive biocompatibility safety (Reifschneider, 2017). In this respect,
it provides a roadmap for biocompatibility testing like that described in ISO 10993-1. The
guidance document recommends the testing of a device, if feasible, in the final finished form in

45
which it would be provided to the patient or end user. Further, it advocates the use of chemical
characterization in conjunction with a toxicological risk assessment, in order to understand what,
if any, biological testing to perform. The biological testing should consider the nature, duration,
and conditions of exposure of the device to the human body. The guidance document also
discusses that potential impact on biocompatibility should be evaluated when changes are made
to an approved device in areas such as sterilization, materials, processing, intended use, and
physical configuration. Finally, it identifies that the overall biocompatibility safety assessment of
a device should consider other relevant non-clinical testing and post market safety and
experience, if available and applicable. (Reifschneider, 2017)
Biological tests that support safety assessments must be performed following Good
Laboratory Practices (GLP) as defined by 21 CFR Part 58 (21CFR§58, 1978). This requirement
is also defined in the ISO 10993-1 international standard. The GLP quality system requires a
more rigorous level of discipline and oversight to assure the quality and integrity of the data on
which decisions about safety for humans will be based. It typically is required for in vitro and in
vivo studies but not for chemical or physical testing. The intent of the GLP quality system is to
assure that results from biological studies are valid, reliable, and can be reproduceable (Bernard
et al., 2018).
2.8.3 Risk Management Standards
Risk management is a relatively new but significant approach to shape strategies for
biocompatibility testing. It emphasizes the need to identify risks, that can be categorized as high,
medium or low, and then balancing those risks against the benefits of the device (Wu et al.,
2019). Most device developers now place substantial focus on use of the risk management
process as a foundational framework for the design and development of devices (Wu et al.,

46
2019). Unsurprising, then, is the expanded use of risk-based approaches to assess
biocompatibility. Information from many sources, including chemical and material knowledge,
laboratory testing, clinical history, and performance of similar devices are all considered to
understand the level of risk associated with biocompatibility concerns of a medical device under
consideration.
The primary standards that provide guidance when using a risk-based approach for
biocompatibility evaluation apart from ISO 10993-1 include ISO 13485 and ISO 14971
(International Organization for Standardization, 2016b, International Organization for
Standardization, 2019d). ISO 13485 is the international standard that defines the quality
management system used for medical devices. This standard states:
…when the term risk is used, the application of the term within the scope of this
international standard pertains to safety or performance requirements of the
medical device or meeting applicable regulatory requirements.
The safety requirements include biocompatibility safety assessment using a risk-based
approach as described in ISO 10993-1.
The international standard 10993-1 also describes how biocompatibility testing interfaces
with the more specific standard on risk management, ISO 14971 (Wu et al., 2019). ISO 14971 is
the principal standard used as a reference for medical device companies to develop their risk
management systems.
2.9 Stages of Biocompatibility Testing
ISO 10993-1 defines a series of stages to assess biocompatibility. First are risk
assessments to determine gaps in existing safety information and to identify the testing required
to fill them. This risk assessment includes understanding the chemical characterization of all
device components and materials of construction, materials interactions, manufacturing methods,
and sterilization processes. It may also include prior in vivo and in vitro testing performed on the

47
same or similar device or materials, information from the literature, and any clinical or post-
market data that might be available (Reifschneider, 2017). Only then should physical, chemical,
and biological testing be performed, and should, where possible, be carried out on the final
finished form of the device. Once sufficient analysis has been conducted, the data are evaluated
to determine if the risks that have been identified in the testing are low enough to justify human
use.
2.9.1 Chemical Characterization
Chemical characterization is an early activity described in ISO 10993-18 as a process
whereby all materials and component chemicals are identified and assessed according to the
degree to which they may leach toxic materials into the human body during the use of the
medical device. Those identified chemicals can come from materials of construction as well as
residual chemicals that might remain on the device from manufacturing, cleaning, and other
relevant processes. Laboratory testing may include identification of device and material
components, leachable and extractable testing, and targeted chemical testing (International
Organization for Standardization, 2020a). The collated information is then evaluated by a
toxicologist to understand whether any of the leached chemicals might pose a safety risk to
patients at the anticipated level and duration of exposure (Myers et al., 2017). Data obtained at
this stage are important not only to understand toxicological risk and potential biological effects,
but may also be used when needed to demonstrate equivalence of a device or material to one
previously characterized and commercially available (Bernard et al., 2018).
Testing for leachables and extractables is described in detail in ISO 10993-12 (sample
preparation) and ISO 10993-18. Leachables are compounds that migrate under normal conditions
of physiological pH and temperature and are a subset of extractables. Extractables include

48
additional compounds that migrate from a medical device under aggressive environmental
conditions such as high sample extraction temperature, extended sample extraction time, or
aggressive solvent systems used during sample extraction. Leachables and extractables may
come from the residual presence of materials that were used in device manufacturing and the
materials and components that make up the device itself. For example, polymeric components
may contain additives such as processing aids, monomers, and oligomers that may be freed
through dissolution (Bernard et al., 2018). Leachable and extractable testing is typically
performed by fully immersing and mixing (i.e., extracting) the device or materials in different
solvents and then evaluating the chemical components of the extracts using laboratory
instruments such as gas chromatography mass spectrometer (GCMS), liquid chromatography
mass spectrometer (LCMS), and inductively coupled plasma mass spectrometer (ICPMS) to
identify and semi-quantitate or quantitate the chemicals and metals found.
Leachables and extractables testing can be challenging, especially when it comes to the
interpretation of the results. The sample extraction process may also degrade materials such as
polymers, when performed under extreme conditions such as exposure to harsh solvents and high
temperatures. Further, degradation chemicals can form when the materials of construction
interact during certain manufacturing processes such as sterilization. Sterilization using gamma
radiation or ethylene oxide may degrade polymeric materials used to construct medical devices.
Degradation chemicals may be reported as “tentatively identified” or “unknown” compounds.
They are often reactive and unstudied compounds for which little to no historical information is
available and are therefore difficult to manage using conventional approaches to toxicological
risk assessment (Li, 2017). This is further discussed in Section 2.9.4 of this chapter.

49
2.9.2 Physical and Surface Characterization
The surfaces and materials of construction of a medical device may also affect tissue
compatibility and thus impact the performance of the device and affect tissue compatibility.
Biological reactions may be caused or increased by certain features of the device’s surface or
materials of construction (Bernard et al., 2018). For example, pore size and surface chemistry
can affect the ability of the device to bind proteins and other tissue components (Reifschneider,
2017). They may also activate the immune system through the presence of immunoreactive
chemical functional groups (Sokolov, 2012). Thus, such attributes are germane to the evaluation
of potential biocompatibility risks, and can be the basis of further biological testing, as outlined
below.
2.9.3 Biological Testing
Information collated from chemical and physical data is evaluated by a toxicologist to
estimate whether any of the chemical or physical features might pose a safety risk to patients at
the anticipated level and duration of exposure. (Myers et al., 2017). Data obtained at this stage
are important not only to understand toxicological risk and potential biological effects, but also
equivalence to a commercially available device or material that had been characterized
previously (Bernard et al., 2018). If there is a question about the risk at this stage, biological
testing is typically warranted.
A range of in vivo and in vitro biological tests is available to extend the information
needed to understand the biocompatibility of a device. These tests have been developed to
evaluate specific types of hazards, ranging from short term effects such as cytotoxicity and
irritation to long term effects such as carcinogenicity or teratogenicity (Anderson, 2016). Only a
subset of the available tests may be needed based on the nature of the device. Typically,

50
biological tests are structured according to strict protocols that have predefined acceptance
criteria. In some cases, they also require that the test results be compared to those of a positive or
negative control or a comparator device with a similar use that has already been approved for
sale and shown to be safe, to provide clinical context for test results. Such use is described in the
current FDA guidance document on use of ISO 10993-1. Examples of testing where the use of a
comparator device would be appropriate include cytotoxicity and hemocompatibility assays
(Reeve and Baldrick, 2017).
When performing in vivo or in vitro testing, the use of well-accepted assays is essential to
assure proper sensitivity, reproducibility, and comparability, especially given the wide variety of
devices and materials tested (Bernard et al., 2018). ISO standards are useful in this regard
because they are well-respected and acceptable in most jurisdictions. Nonetheless, the methods
must be validated or verified by the testing group, and that group should also apply quality
controls and use validated reference controls to demonstrate that the methods are in control at the
time of use. ISO 10993-1 and the FDA Guidance Document on the use of 10993-1 both
recommend conducting the biocompatibility tests using the medical device in its final finished
form. Any changes made to the device after biocompatibility testing must therefore be evaluated
in order to determine if further testing is required (International Organization for
Standardization, 2018, US FDA, 2020).
2.9.3.1 In vitro Tests
In vitro tests are performed outside of a living animal, typically in test tubes or culture
dishes. Standardized in vitro tests have the advantages of being quick, inexpensive, and easy to
control. They are commonly used to screen for potential hazards that originate from materials
and chemicals used in the construction of medical devices. However, their predictive capabilities

51
are limited, because the biological responses and interactions take place in an environment quite
different from that in which the device will be used. This makes it difficult to establish the
relevance of in vitro testing to the in vivo environment (Siswomihardjo, 2016, Boutrand, 2019).
The primary in vitro tests used for medical device biocompatibility include cytotoxicity, in vitro
genotoxicity, and in vitro hemocompatibility assays.
2.9.3.1.1 In vitro Cytotoxicity Testing
In vitro cytotoxicity assays are intended to detect the potential of a device, its materials of
construction, or device extracts to exert sublethal to lethal effects on cultured cells. These tests
can show changes in cellular endpoints such as growth, replication, and morphology after the
cells have been exposed directly to the medical device, material, or extract. The selection of the
specific type of assay depends on the device or material being evaluated [ISO 10993-5:2009,
Biological evaluation of medical devices – Tests for in vitro cytotoxicity International
Organization for Standardization, 2009 (International Organization for Standardization, 2009)]
(Liu et al., 2018b). According to ISO 10993-1, cytotoxicity is one of the three tests that must be
considered, along with sensitization and irritation, for all device categories. Because of its low
cost, cytotoxicity tests are often used as the first screening tool when evaluating new materials
for potential use in medical devices (Bernard et al., 2018), in addition to being used during
biocompatibility safety assessments and ongoing raw material testing (Liu et al., 2018b).
However, cytotoxicity tests have certain limitations. The short testing duration, generally up to 7
days, may not predict the reaction kinetics over an extended period, as may be relevant for
devices with long term use. The tumor-derived cell lines, usually fibroblasts, may not represent
well the types of cells and tissues that the device will contact when placed in the body
(Anderson, 2016).

52
2.9.3.1.2 In vitro Hemocompatibility Testing
In vitro tests to evaluate possible interactions with blood including hemolysis and
thrombosis are described in ISO 10993-4. Some tests examine what happens when the blood
makes contact with the material surface; others examine the effect of extractable chemicals or
non-physiological or mechanically induced stresses that might cause cell lysis. To evaluate
thrombosis, clinical chemistry assays evaluate coagulation, platelet, leukocyte, complement, and
hematology effects [ISO 10993-4:2017, Biological evaluation of medical devices – Selection of
tests for interactions with blood (International Organization for Standardization, 2017a)].
2.9.3.1.3 In vitro Genotoxicity Testing
Genotoxicity assays that evaluate the potential for a device, material, or extract to cause
gene mutations, chromosomal damage and other DNA or gene toxicities are described in ISO
10993-3. Genotoxicity assays include both in vitro and in vivo options. (ISO 10993-3:2014,
Biological evaluation of medical devices – Tests for genotoxicity, carcinogenicity and
reproductive toxicity). The primary in vitro assays include 1) the Ames test which evaluates the
ability of the extract to induce gene mutations in Salmonella typhimurium; 2) the Chromosomal
Aberration assay, which uses mammalian cells to evaluate chromosomal mutations or
aberrations; 3) the Mouse Lymphoma assay, which evaluates the potential for DNA damage at
the gene and chromosomal level; and 4) the Mouse Micronucleus assay, which looks for
chromosomal aberrations such as breakage and instability [ISO 10993-3:2014, Biological
evaluation of medical devices – Tests for genotoxicity, carcinogenicity and reproductive toxicity
(International Organization for Standardization, 2014)].
2.9.3.2 In vivo Tests
Tests that use live animals are described in Annex A of ISO 10993-1. They include an
extensive battery of options directed at specific areas of concern: sensitization, irritation, material

53
mediated pyrogenicity, acute systemic toxicity, subacute toxicity, sub-chronic toxicity, chronic
toxicity, implantation effects, in vivo hemocompatibility, in vivo genotoxicity, in vivo
carcinogenicity, and in vivo reproductive and developmental toxicity. These types of tests can
provide better insight into the complex interactions that can occur between the device’s materials
of construction and a living system. However, many are time consuming and expensive to
conduct. Further, they often cannot predict accurately the effects that might eventually occur in
the human biological system. While similarities in anatomy and physiology between humans and
animals make in vivo testing a powerful tool to use prior to human clinical trials, devices that
present a safe profile during in vivo testing sometimes provoke an unexpected reaction during
clinical trials (Holzer et al., 2017). Thus, the test results may have to be interpreted
conservatively by experts with a knowledge of the device and its context of use. Additionally,
ethical concerns are driving the replacement of in vivo testing with alternative testing that does
not involve the use of animals in testing (Siswomihardjo, 2016).
2.9.3.2.1 Sensitization Tests
Sensitization tests, described in ISO 10993-10, are intended to detect the potential of a
device, its materials of construction, and/or extracts, to produce a sensitization response in an
animal following repeated exposure to the extracted materials from the device [ISO 10993-10:
2021, Biological evaluation of medical devices - Tests for skin sensitization (International
Organization for Standardization, 2021a)]. The definition of a sensitizer, as stated in ISO 10993-
10, is a “substance or material that is capable of inducing a specific hypersensitivity reaction
upon repeated contact with that substance or material.” Sensitization testing is carried out most
commonly as a screening procedure in guinea pigs exposed to the mixture of extractables
obtained from the device of concern. A more specific test in mice may be used to examine
effects of single chemicals. The currently used sensitization procedures include the guinea pig

54
maximization test, the guinea pig occluded patch test, and the local lymph node assay in mice, all
described in detail elsewhere (Gad and Gad-McDonald, 2016); [ISO 10993-10:2010, Biological
evaluation of medical devices - Tests for irritation and sensitization (International Organization
for Standardization, 2021a)].
2.9.3.2.2 Irritation Tests
Irritation or intracutaneous reactivity tests evaluate whether the device, materials, or
extracts have the potential to irritate tissue. Irritation is defined in ISO 10993-23 as “localized
non-specific inflammatory response to single, repeated or continuous application of a
substance/material. Skin irritation is a reversible reaction that is mainly characterized by local
erythema (redness) and swelling (edema) of the skin.” The tests described in ISO 10993-23
consider the different susceptibilities of specific body tissues to this type of insult.
The 2021 edition of the ISO 10993-23 standard introduced the use of alternative in vitro
assay methods to evaluate irritation. In vivo irritation testing is typically evaluated using rabbit
models. The ISO standard references two different rabbit tests, one that applies extracts or
materials to skin for specified periods of time, and another in which device extracts are injected
intradermally. In both, skin reactivity is examined at specified time points for signs of erythema
and edema [ISO 10993-23:2021, Biological evaluation of medical devices - Tests for irritation
(International Organization for Standardization, 2021c)]. However, in vitro irritation testing can
also be conducted by exposing other tissues such as mucosal or ocular tissue to device extracts;
for example, ocular irritation testing is used when the device is intended to be put in the eye (Gad
and Gad-McDonald, 2016).
2.9.3.2.3 Systemic Toxicity Testing
Systemic toxicity tests, described in ISO 10993-11, evaluate the potential of leachates
from a medical device to elicit effects in organs or physiological systems [ISO 10993-11, 2017,

55
Biological evaluation of medical devices - Tests for systemic toxicity (International Organization
for Standardization, 2017b)]. They have four levels, according to the length of exposure. Acute
systemic toxicity tests usually cover a time period of 72 hours; subacute tests, up to 28 days;
subchronic tests, up to 90 days; and chronic tests, 6 – 12 months. The device is administered or
implanted as appropriate for the context of use, for example, dermal, intramuscular, or
intravenous exposure. Most tests are performed in mouse or rat, but the rabbit is preferred for
dermal and implantation studies. Animals are observed for changes in clinical signs, food intake,
and weight loss. Depending on the length of study, follow up clinical and gross pathological
evaluations, organ weights, and histopathology can provide further data (International
Organization for Standardization, 2017b).
2.9.3.2.4 Pyrogenicity
As described in ISO 10993-11, Annex G, pyrogenicity tests evaluate the likelihood of
febrile reaction from exposure to chemical pyrogens, which are chemical substances leaching
from devices that are known to or have the potential for material-mediated pyrogenicity
(International Organization for Standardization, 2017b). Traditionally, rabbits are injected
intravenously with extracts and evaluated for a rise in temperature. The ISO standard
recommends following a compendial method for use in testing, such as the <151> pyrogen test
in the United States Pharmacopeia (USP, 2009).
2.9.3.2.5 Hemocompatibility
Hemocompatibility tests, described in ISO 10993-4, include options for in vivo assays, as
well as the in vitro assays described above, to evaluate whether the device or its materials of
construction could adversely interact with the blood. Typically, the tested device is implanted
into the blood path of larger animals such as dogs, pigs or sheep, and then monitored over time to
simulate use in patients. The formation of thrombus would typically be evaluated during a well-

56
designed in vivo study. Additionally, the collected data give insight into multiple aspects of
pathophysiology through clinical measurements, blood chemistry testing, necropsy, and
histopathology [(ISO 10993-4:2017, Biological evaluation of medical devices – Selection of tests
for interactions with blood (International Organization for Standardization, 2017a)].
2.9.3.2.6 Implantation Tests
Implantation tests, described in ISO 10993-6, evaluate local effects during short and
long-term studies by assessing the reaction of muscle or subcutaneous tissue to the implanted
device or materials of construction. Test protocols and species selection depend on the site of
eventual use and size of implant. Clinical, chemical, and histopathological evaluations are
performed, as necessary, at specified timepoints. Short-term responses are assessed in 1–4-week
studies, whereas long-term studies may exceed 12 weeks. Comprehensive implantation studies
may at times be combined with acute, sub-acute, sub-chronic and/or chronic toxicity studies
when an appropriate number of animals and timepoints are included in the studies [(ISO 10993-
6:2016, Biological evaluation of medical devices – Test for local effects after implantation and
ISO 10993-1: 2018, Biological evaluation of medical devices – Evaluation and testing within a
risk management process (International Organization for Standardization, 2016a, International
Organization for Standardization, 2018)].
2.9.3.2.7 Genotoxicity Tests
Genotoxicity tests, described in ISO 10993-3, evaluate the potential for a device,
material, or extract to cause gene mutations, changes in chromosome structure, and other DNA
or gene toxicities. The primary starting assays used for medical devices are conducted in vitro as
described previously in section 2.9.3.1.3. Those include the Ames test (bacterial reverse mutation
assay), mouse lymphoma, chromosomal aberration, and mammalian cell micronucleus assay.
The ISO standard and FDA guidance document both require use of the Ames test and one of the

57
three mammalian cell test assays. In the event of failure of an in vitro test, the origin of the
failure must be investigated further by evaluation of in vitro assay validity, chemical
characterization, and toxicological risk assessment. A follow-on assay using an in vivo test may
be recommended. In vivo tests can include a micronucleus test in rodents, metaphase analysis in
rodent bone marrow, and transgenic rodent mutagenicity tests. The test selection depends on
what is most appropriate to understand the nature of potential device genotoxicity risks [(ISO
10993-3:2014, Biological evaluation of medical devices – Tests for genotoxicity, carcinogenicity
and reproductive toxicity (International Organization for Standardization, 2014)].
2.9.3.2.8 Carcinogenicity Testing
Carcinogenicity testing, described in ISO 10993-3, is seldom performed for medical
devices unless required to investigate a positive response to a genotoxicity assay. Such testing
may also be needed if the device contains a known genotoxic/ carcinogenic material or a
degradable material with a degradation or absorption time in excess of 30 days with no history of
safe in-human use. The standard indicates that “carcinogenicity testing shall not be performed
when risks can be assessed or managed without generating new carcinogenicity data.” The
avenues to assess risks include rigorous chemical characterization and toxicological risk
assessment. If testing is necessary, the standard provides guidance on the in vivo test strategies
and test methods [ISO 10993-3:2014, Biological evaluation of medical devices – Tests for
genotoxicity, carcinogenicity and reproductive toxicity (International Organization for
Standardization, 2014)].
2.9.3.2.9 Reproductive and Developmental Toxicity Testing
Reproductive and developmental toxicity tests, described in ISO 10993-3, are also
seldom required for medical devices. This testing evaluates the potential effects of devices on the
reproductive function of device recipients. However, no such testing is needed if a toxicological

58
risk assessment concludes that the risk of reproductive and developmental toxicity has been
reduced sufficiently. If testing is necessary, the standard provides guidance on the in vivo test
strategy and method that may be needed. [ISO 10993-3:2014, Biological evaluation of medical
devices – Tests for genotoxicity, carcinogenicity and reproductive toxicity (International
Organization for Standardization, 2014)].
2.9.4 Toxicological Risk Assessment
The previously discussed tests have been established and used for more than three
decades according to a relatively rigid set of expectations recommended in earlier iterations of
the ISO 10993 standards. However, as mentioned earlier, thinking has changed. Today, the most
updated standards recommend a focus on risk analysis and chemical characterization to
understand from first principles, the degree of human exposure and associated safety risks for a
specific device. The international standard ISO 10993-17, “Toxicological Assessment of Medical
Device Components,” describes approaches to establish safe limits for leached chemicals, in part
determined by estimates of human daily exposure (Bernard et al., 2018). In such an approach, the
levels of chemicals identified through chemical characterization and laboratory testing, such as
leachables and extractables testing (Albert and Hoffmann, 2008), are used as the input into a 4-
step process that starts with the identification of the hazard, and proceeds to a dose response
assessment, an exposure assessment, and finally a risk characterization. These analyses then
guide the selection of follow-on in vitro and in vivo testing, that now can be seen as an
adjunctive approach to understand further the safety risk profile of the medical device (Brown,
2015, Myers et al., 2017). ISO 14971, used alongside ISO 10993, can guide the evaluation of
toxicological risks (Albert and Hoffmann, 2008).

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When compounds used in a device or material have been well characterized previously,
the approach is relatively straightforward. However, if a leachate cannot be identified from the
chemical characterization, an alternative approach to assessing toxicological risk is needed.
Without knowing chemical identity or structural information, the traditional route of looking for
experimental or derived toxicological values to assess a compound is not available. The approach
currently advocated by FDA and ISO is now based on the concept of “Threshold of
Toxicological Concern” (TTC) [ISO/TS 21726:2019 Biological evaluation of medical devices -
Application of the threshold of toxicological concern (TTC) (International Organization for
Standardization, 2019a)]. In this approach, a level of safe exposure would be identified for a
majority of all chemicals associated with the device. Below that threshold, significant risk to
health is not considered to be present (Brown, 2015). This approach can be useful in reducing the
need for biological testing. However, the TTC level is set at an extremely low concentration.
Many times, unidentified chemical compounds, while at low levels, will be above the TTC level,
and therefore require that devices be tested further using more demanding tests to evaluate
unresolved safety questions.
2.10 Current Challenges with Biocompatibility Testing
Biocompatibility testing and safety assessments face many challenges, which in part may
arise because the regulations related to safety testing must balance competing goals. On one
hand, they must facilitate the rapid introduction of new and innovative devices, but on the other,
they must assure device safety and effectiveness (Van Norman, 2016). Thus, any strategy that
reduces the time required for preclinical testing must be balanced by considering its potential
impact on risk. Recent approvals of high-risk devices without enough safety testing have shown
how important this balance can be for public health. For example, the CoSTAR drug eluting

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stent was approved in the EU with minimal testing but had to be recalled a year later after an
increased number of adverse cardiovascular events was identified in a US clinical trial. The
company making the stent then discontinued the US clinical trials and withdrew the device from
markets in which it was already approved. In Europe, the Poly Implant Prothese silicone breast
implant was commercialized but later recalled because hazards arising from high rupture rates
and use of nonmedical grade silicone caused many patient injuries (Janetos et al., 2018). These
two examples highlight the consequences of introducing a medical device without sufficient
safety testing to understand and minimize risk to the public.
Much has been written about the need for governments to reduce regulation, however,
little evidence supports the premise that fewer regulatory requirements will benefit the patients
using medical devices. Instead, many voice concerns that some economies have insufficient
control over medical device safety. For example, criticisms have been directed at the European
system that had a less rigorous system of regulations whose oversight was largely in the hands of
notified bodies, which many thought to put patients at greater risk. These concerns were then in
large part responsible for recent implementation of more stringent EU medical device
regulations, which introduce a higher safety testing bar for some high-risk devices, set higher
standards for clinical evidence, and elevate regulatory oversight of medical devices (Janetos et
al., 2018). In the past, the more stringent regulatory system of the US was seen to be responsible
for undesirable delays in getting product to market (Fiedler, 2017). However, many are now
predicting that the new EU regulations, designed for patient protection, will also slow new
product introduction in that region.
The changing regulatory landscape also affects the strategies that are used to evaluate
biocompatibility. Industry professionals have suggested anecdotally that these changes can pose

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challenges for the development and implementation of biocompatibility strategy and testing.
These include: 1) lack of detail in the biocompatibility standards leading to differences in
interpretation; 2) differences between local regulations and international biocompatibility
requirements; 3) confusion associated with the possible need to retest devices after design and
manufacturing changes; 4) lack of clarity about how to test new types of materials; 5) challenges
with conducting the test methods themselves; and 6) societal movement away from the use of
animals in testing.
2.10.1 Biocompatibility Standards can be Difficult to Interpret
International standards such as ISO 10993-1 are general in nature and thus may lack
sufficient detail for some users. ISO 10993-1 recommends a risk-based approach that proceeds
from chemical characterization to toxicological risk assessment, to in vitro tests, and then to in
vivo tests. As a high-level process map, it attempts to provide sufficient flexibility to deal with a
variety of products that may have few risks or many. The lack of detail is not surprising, because
no general standard can provide detailed guidance on appropriate safety testing methods for
every type of device and material of construction (Bernard et al., 2018). However, this adaptive
approach does not align well with the mindset of its users, that have a history of following a
specified, stereotypic set of tests. The absence of detailed instruction leaves open the option for
different companies to construct their biocompatibility testing strategies in various ways, some
stronger than others. Biocompatibility strategies in medical device companies are often built on a
history of previously accepted actions that may include now obsolete paradigms and
biocompatibility testing methods. They may even favor the earlier checklist approaches, which
they view as simpler and more predictable. Additionally, some manufacturers may harbor the
incorrect assumption that a material historically used extensively in medical device manufacture

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will be safe and should not require biocompatibility testing. This assumption would only be valid
when the material has the same base chemistry and minor components, and when it has been
subjected to the same manufacturing, cleaning and sterilization process used in an approved
device with the same or higher level of patient contact (Reifschneider, 2017).
The risk-based approaches may also pose challenges for regulatory reviewers who had
become accustomed to expecting that devices will follow a common, comprehensive battery of
in vivo and in vitro testing. Thus, company experts and regulatory reviewers can differ in their
views regarding the adequacy of the biocompatibility safety studies needed for marketing or
clinical trial approvals (Hampshire and Gilbert, 2018, Reeve and Baldrick, 2017). The lack of
consensus can delay the approval of the device submission, as the company addresses confusion
and corrects gaps in what they had thought was an appropriate biocompatibility strategy.
2.10.2 Differences Between Local Regulations and International Biocompatibility Standards
ISO 10993-1 was developed to be used globally. However, the regulations of different
countries may specify dissonant or additional requirements for biocompatibility assessments and
test methods. This can complicate the biocompatibility testing strategy for developers who seek
medical device registrations in different parts of the world (Reeve and Baldrick, 2017, Myers et
al., 2017) . The FDA recognizes most of the elements in ISO 10993-1, and further describes the
agency’s thinking on the use of ISO 10993-1 in a guidance document but as described above,
leaves many areas open to interpretation. Thus, manufacturers can struggle as they try to capture
the US expectations into a global strategy. Challenges are amplified when reviewers in different
countries also vary in their expectations (Wu et al., 2019, Myers et al., 2017). Senior officials at
such regulatory agencies may express their willingness to be flexible or to accept alternative
approaches to those suggested by ISO 10993. In practice, however, many biocompatibility

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experts report that reviewers dealing with a specific submission may not seem so flexible.
Medical device manufacturers may therefore find it difficult to identify the constellation of
biocompatibility safety studies that will meet the needs of all of the countries in which they wish
to market (Hampshire and Gilbert, 2018, Reeve and Baldrick, 2017).
2.10.3 Design and Manufacturing Changes Complicate Biocompatibility Safety Assessment
and Testing
Fulfilling biocompatibility safety requirements with on-going device design and
manufacturing changes is a challenge. Change is a part of product development to improve the
safety and performance of medical products. However, when some aspect of a product is
changed, its impact must be evaluated to understand whether the change could affect the safety
profile. For example, changes in the specifications or suppliers of raw materials and components
have the potential to impact the types and amounts of residual chemicals. Even something as
seemingly innocuous as a change to a mold release agent as part of the manufacturing process
can alter the surface coating of the finished device and therefore impact its biocompatibility. For
this reason, the ISO 10993-1 international standard and the FDA guidance document both
recommend retesting the biocompatibility of the final finished device if its externally facing
components have been affected by the change. However, such testing is expensive and time-
consuming (Reifschneider, 2017). To speed the biocompatibility testing process, device
manufacturers will sometimes perform all of the chemical and biological testing concurrently
(Myers et al., 2017). This approach can defeat the purpose of a risk-based approach in which the
testing begins with chemical characterization and in vitro testing prior to selection and
performance of in vivo testing and can result in performing more testing than needed.

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2.10.4 Challenges with Material and Device Biocompatibility
Early biocompatibility rules were in no position to predict the kinds of materials that
technology has recently developed. However, some of these novel materials, such as synthetic
polymers or nanomaterials, have undesirable biocompatibility features that could cause
inflammatory reactions or the elaboration of fibrous encapsulation (Bernard et al., 2018). Thus,
when developers specify the materials on which their devices are based, they could be assisted
by having comprehensive information on a range of materials and components whose
appropriateness could be judged in the context of proposed manufacturing processes and
performance requirements for the new or modified devices (Bernard et al., 2018). Such a library
of information could prevent costly missteps associated with the selection of an undesirable or
contaminated material (Myers et al., 2017). Nonetheless, comprehensive toxicity data does not
exist for many chemical compounds. Toxicological assessment for such materials then would
require a TTC approach, followed where appropriate by additional in vivo and in vitro testing
(Brown, 2015), as previously discussed in Section 2.9.4. It is not clear, however, how often this
kind of challenge occurs amongst device manufacturers and how it is avoided or mitigated. It is
also unclear whether the philosophy and application of the TTC approach is seen as a way to set
a default level for safe exposure or as a benchmark to indicate the need for additional testing
(Brown, 2015).
The methods to assess biocompatibility have traditionally come from the study of
materials that are non-biologically reactive or inert (Anderson, 2016). Assuring a good
knowledge of material biocompatibility is key to the efficient development of certain disruptive
technologies with much clinical promise. However, some novel biomaterials, such as
nanomaterials and tissue engineering scaffolds pose novel challenges, and some devices will be
made with materials chosen deliberately because they are bioactive. Current in vivo and in vitro

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test methods are primarily engineered to demonstrate that a material used in a medical device is
non-biologically reactive or inert (Anderson, 2016). The testing strategies for such novel
materials are therefore still in evolution (Schmalz and Galler, 2017). Although ISO 10993-1 is
widely accepted for the biological evaluation of medical devices, some researchers question
whether it is appropriate for some cutting-edge medical devices such as tissue engineered
devices, thus potentially leaving a gap in our approaches for some cutting-edge medical devices
and structural biologics (Fiedler, 2017).
2.10.5 Challenges with Biocompatibility Testing and Test Methods
Many practical challenges exist when trying to apply certain biocompatibility strategies
and associated test methods. For example, several biological tests, such as that for complement
activation, have no established pass/fail criteria. Thus, it is a recommended practice to include a
comparator device as a reference alongside the device under test (US FDA, 2020). This approach
can be difficult if an appropriate comparator device is not available. Even if such a comparator
device can be found, the manufacturer, whether internal or a competitor, may be reluctant to
provide this product for further testing, especially if the testing goes beyond that used as part of
the marketing application.
Other tests depend on extractions to free substances that might be toxic, using a highly
specified protocol and a variety of solvents or media, defined in detail in ISO 10993-12 [ISO
10993-12, Biological evaluation of medical devices – Part 12: Sample preparation and reference
materials (International Organization for Standardization, 2021b)]. However, these standardized
methodologies may be hard to apply. For example, many larger devices cannot be completely
submerged in the solvent so must be cut into pieces. This procedure may allow the solvent to
extract internal non-contacting materials that would not normally contact the patient. These

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methods also pose problems for small devices; to extract sufficient material, large numbers of
devices may have to be produced at considerable expense and effort and then sacrificed (Myers
et al., 2017).
Challenges also arise if compounds are extracted whose identity is uncertain. For
example, unfamiliar compounds may form when polymers react with gamma, steam, or ethylene
oxide sterilization. When such chemicals are found, toxicologists must assume a worst-case
approach by using very low safety limits, as directed by international standards that define
toxicological risk assessments. These evaluations may complicate the way that such materials
can be used (Li, 2017).
Animal studies also can pose logistical challenges. Properly designed large animal studies
are often needed for certain types of systemic toxicity, implantation, and thrombogenicity
testing. However, they require significant specialized protocol design and planning that often
must be discussed with regulators to obtain preclearance (Hampshire and Gilbert, 2018). It may
take time and effort to come to an agreement because biological and scaling differences may
exist between the proposed and normally tested species, and relevance to humans may also be of
concern (Hampshire and Gilbert, 2018).
2.10.6 Movement Away from Use of Animals in Biocompatibility Testing
Biocompatibility testing, traditionally done using animals, has come under scrutiny in the
last few decades, as public and scientific sentiment turns against the use of animals for testing
purposes (Hampshire and Gilbert, 2018). Thus most experimental approaches are under scrutiny,
in an attempt to implement the “3R” principles- the replacement of animal-based tests with non-
animal alternatives, the reduction of animals used for in vivo testing and the refinement of
animal based tests to minimize distress for the animals (Chapman et al., 2013). Directives,

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regulations, and international standards have been updated to reflect the need to minimize the use
of animals in preclinical testing. EU directives in particular emphasize the need for measures
based on the 3Rs, to promote alternative approaches (Lazzarin, n.d.).
Additional benefits may accrue from alternative testing initiatives in addition to
protecting animals. In vitro testing, computer models, and imaging methods often can reduce
time and costs. However, the medical device industry is conservative about changes that could
delay or compromise regulatory approvals. As identified above, only a few in vitro tests are
accepted by the regulatory community. Much testing instead relies on in vivo tests using animal
models (Myers et al., 2017). The use of in vitro methods as called out by the International
Standard ISO 10993-1 allows for the use of in vitro methods for tests such as sensitization and
irritation testing, although negative test results (no response) demonstrated by such in vitro tests
must be confirmed using an in vivo method. This is counterproductive, because most in vitro
tests will be negative, and therefore require duplicate testing by in vitro and in vivo methods
(Myers et al., 2017).
To improve regulatory acceptance of more in vitro testing, more safety data needs to be
generated, the risks to human safety better understood, and this information must be shared with
the regulatory agencies. To this end, development of new in vitro assays has gained momentum.
EU legislation banning animal-based assays for most chemical and cosmetic testing has been
influential in driving those efforts, and scientific advances offer better alternatives that are now
undergoing validation and qualification for regulatory acceptance (Chapman et al., 2013). The
current FDA guidance document on use of ISO 10993-1 also describes how data from large
animal studies that are needed as part of the new product development may be used in place of
additional rodent studies, as long as valid scientific principles, endpoints, and methods are

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applied (Hampshire and Gilbert, 2018). This approach reduces the need to conduct both the large
and small animal studies. The 2018 update to ISO 10993-1 also promotes the application of
alternative approaches to animal-based tests (Myers et al., 2017). However, those methods can
only be adopted if they are reproducible, validated and readily available for use throughout the
medical device industry (Lazzarin, n.d.). A lead time of eight to nine years is typical to qualify a
new test method, such as the replacement of an in vitro method with an updated method. The
FDA supports the qualification of new test methods to support device commercialization through
its Medical Device Development Tools (MDDT) program. Included in this effort can be test
methods for use as alternatives to in vivo biocompatibility testing (Lazzarin, n.d.).
2.11 Framing Proposed Research
The foregoing descriptions make it clear that much has changed in the philosophy and
expectations for biocompatibility testing for medical devices. Whenever changes like these are
introduced into complex operations, some degree of challenge can be expected as teams
“unfreeze” from previous approaches and then “refreeze” in a way that allows alignment with
new strategies (Lewin, 1943). However, the literature review provides little insight into the
pragmatic and logistical approaches that industry has taken to deal with their biocompatibility
needs as they adjust to new policies. Thus, in this research, I seek to understand the views and
experiences of companies dealing with the principal change underlying biocompatibility testing;
the convergence of international standards emphasizing a risk-based and toxicological approach
with traditional and nationally based regulatory expectations for biocompatibility testing across
the US and EU. To this end, I used a survey that was systematized by using two conceptual
frameworks to guide the development of survey questions and focus subsequent analyses of
survey responses.

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Approximately 35 conceptual frameworks were reviewed to find appropriate candidate
frameworks for use in this research. From this set two conceptual frameworks described below
were selected, one focused on implementation and the other on transparency. The selections
were chosen to align two themes arising from the literature. First are the challenges of
developing a testing strategy that meets both company and regulatory needs as ideas change on
how best to test biocompatibility. The implementation framework, described in more detail
below, describes a roadmap with stages and key activities for implementing program and policy
changes successfully (Gilliland and Manning, 2002). It has been used extensively in the past to
identify activities and experiences at different stages of the implementation process.
Within the implementation of biocompatibility testing resides a specific set of challenges
related to the necessary interactions between manufacturer and regulator. Given the centrality of
consensus to the success of implementing an effective strategy, a transparency framework was
embedded within the implementation approach. Such a framework was used previously to
understand transparency in the drug submission process of three Asian countries (Solberg and
Richmond, 2012). Its tenets, described below, appeared to be useful more generally to study
transparency in regulatory consultation and decision-making related to biocompatibility.
2.11.1 Implementation Framework
Implementation frameworks are relatively new, with roots in work by Fixsen et al. in
2005 (Fixsen et al., 2005). His early implementation framework has been modified over the last
decade. In a research article entitled “Improving Programs and Outcomes: Implementation
Frameworks and Organization Change,” Bertram, Blasé and Fixsen describe a more recent
iteration promoted through the National Implementation Research Network (Bertram et al.,

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2015). This framework describes the implementation as a process with a linear roadmap whose
multiple stages take place typically over the course of 2-4 years (see Figure 1).
Figure 1: Implementation framework

As shown in Figure 1, the implementation framework has four stages. The first stage is
“exploration”. This stage includes a range of early planning activities, such as evaluating the
stakeholders that would be involved and impacted by the planned changes, assessing
organizational resources that are available, and determining what will be needed to initiate the
implementation or change. Information gathered is used to support an effective decision-making
process to determine if the project should proceed. The second stage is “installation.” At this
stage, implementation teams begin to obtain the additional resources needed for the project,
prepare the organization and staff for the use of the new approach, and plan the logistical steps
for implementation. A third stage is typically defined as “initial implementation.” This stage is
characterized by pilot or initial efforts to act on the installation plan. It requires that personnel
begin to transition from an old to a new way of doing things, and in so doing challenge their

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behaviors and work processes. Critical to success in this stage is to learn from mistakes and to
make necessary systematic improvements to the plan and processes. This is also the stage where
organizations and their staff may feel uncomfortable with the shift from old methods to the new.
In the fourth, “full implementation” phase, organizations operate within the new program with a
strong degree of capability and comfort. Organization, leadership, and competency are
considered by implementation practitioners as key drivers that will affect the success of
subsequent implementation.
Implementation frameworks often vary a little in their terminology and level of detail.
Nonetheless, in most, the four stages of implementation described above are similar. However, in
early iterations of implementation frameworks, a fifth, final stage identified as “sustainability”
was present. This stage referred to the need to assure that the new process or program would be
embedded effectively in the organizational structure and ethos. In more recent iterations, like the
one adopted for the purposes of this research, sustainability was no longer represented as a
separate final stage but instead was refined to include activities in each of the other
implementation stages, geared towards sustaining the improvements that have been made during
each phase of implementation (Gilliland and Manning, 2002).
Implementation frameworks may be used for a wide variety of policy and program
initiatives, which can vary in size, scope, and complexity. An example of a major initiative that
was put in place using an implementation roadmap is that in which evidence-based practices
were introduced into a multisite medical setting (Pollastri et al., 2020). In my research, the
implementation framework was used to examine how medical device manufacturers have
changed their approaches to biocompatibility safety testing. Of particular interest are the
difficulties and lessons learned at each stage of the implementation process.

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2.11.2 Transparency Framework
Confusion about regulatory requirements may impede the ability of even a motivated
company to conform to expectations. In part the confusion may be caused when regulatory
agencies have difficulty communicating expectations and outcomes. A study performed by
Solberg and Richmond drew attention to the importance of transparency with regard to
regulatory expectations (Solberg and Richmond, 2012). That study was directed at a different
topic - drug registration in emerging markets - but used a framework with elements that would be
helpful in exploring the challenges faced in understanding regulatory views and actions in other
activities, including biocompatibility testing.
In this study, I used the definition of transparency by Finkelstein (2000) as “policies that
are easily understood, where information about the policy is available, where accountability is
clear, and where citizens know what role that they play in the implementation of policy”
(Finkelstein, 2000). Within this definition are embedded three elements of a transparent system:
clarity, accessibility, and accountability. The term clarity implies that policies and procedures are
easy to understand and follow; accessibility is the ease of opportunity to participate or engage
with the process or program, and accountability implies that the decision-making process is
following a pre-defined and documented procedure. These three elements appear to be
foundational to regulatory change in general, because “transparency in government affects the
ability of stakeholders to work efficiently through a complex maze of regulations” (Solberg and
Richmond, 2012).
2.11.3 Blended Framework for Present Research
The two frameworks described above provide complementary approaches to capture
certain key challenges facing industry as it tries to understand and comply with expectations of

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regulators around biocompatibility programs. Each of the frameworks offers important elements
for use in constructing a comprehensive and organized survey. Transparency elements suggest
that the survey should include questions related to the clarity, accountability, and accessibility of
regulatory agencies that communicate those expectations. The implementation framework
suggests that the survey should include questions to understand the roadmap, stages, and key
activities needed for successful implementation of a major change. A modified framework was
therefore constructed by blending the two frameworks (Figure 2). Within this implementation
framework were embedded certain questions reflective of transparency. Some of these questions
are suggested in Figure 2; however, these may have changed as the survey tool was developed.

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Figure 2: Blended framework constructed for use in this study

Example questions about transparency throughout the implementation process
Attribute of
Transparency:
Stages of Implementation:
Exploration Installation Implementation
Clarity Were standards
and guidance
documents
sufficiently clear?
Was it easy to identify a
strategy using the ISO 10993-1
standard and FDA guidance
document?
Did the ISO 1093-1 standard and FDA
guidance document provide enough
detail and roadmap to allow an easy
implementation from old to the new
Biocompatibility requirements?
Accountability Was it clear who
will be responsible
for answering
questions?
Did all stakeholders both
internal and external share
accountability for success of
the planning for
implementation?
Did all stakeholders both internal and
external share accountability for
success of the implementation?

Did they all make changes to their
systems and processes to allow for
success of the implementation?
Accessibility Were FDA
regulators and
Notified Body
Auditors
accessible?
Were FDA regulators and
Notified Body Auditors
accessible to communicate on-
going changes and evolving
expectations?
Were internal and external subject
matter experts available to support the
implementation?

Were internal and external subject
matter experts available make long-
term improvements to drive
sustainability of the change?

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The modified framework incorporates transparency to examine communication of
biocompatibility expectations between industry and the regulatory authorities. It also
incorporates implementation to examine the challenges are being experienced relative to key
activities in each of the stages of implementation. This modified framework was used to guide
the development of survey questions, identify participants in the survey, and guide subsequent
analyses of the survey responses to formulate meaningful learnings.

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Chapter 3. Methodology
3.1 Introduction
The purpose of this study was to understand the views, experiences, and challenges of
companies dealing with the convergence of international standards with nationally based
regulatory expectations and traditional biocompatibility testing approaches across the US and
EU. A survey was used to explore the approaches that medical device manufacturers,
consultants, and contract testing organizations are taking to manage their biocompatibility
programs in the face of these changes. The survey was developed and organized using applicable
parts from two frameworks (implementation and transparency), as previously described in
Chapter 2. The research was done in four stages: a literature review and selection of conceptual
frameworks for the research, development of a survey instrument, distribution of the survey, and
analysis of the survey results, including written conclusions and recommendations.
3.1.1 Survey Participants
The survey was conducted with professionals employed by medical device
manufacturers, consulting companies that support the medical device industry, and contract
laboratory and research organizations performing medical device biocompatibility safety testing
and/or toxicological risk assessments. A majority of the study participants had at least five years
of recent experience performing work in support of medical device safety biocompatibility safety
testing for US and EU markets.
3.1.2 Development and Validation of the Survey
A fit-for-purpose survey was developed using the online survey and analytics platform,
Qualtrics (www.Qualtrics.com). This online survey application is relatively easy for survey

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participants to use, yet provides powerful tools for survey distribution, respondent participation
and analysis of results.
The survey first requested background information about each survey participant.
Questions were then constructed to probe their views, experiences, and suggestions to improve
the current approaches to biocompatibility safety testing. In addition, they probed how the
participants and their organizations were strategizing their development programs as
international standards merge with regulatory expectations of regulatory authorities in the US
and EU. Questions included in the survey had a variety of formats, including both suggested-
choice questions (i.e., multiple-choice options or preference ratings) and open-ended questions
that allow survey participants to provide free text responses. The number of survey questions
was restricted to assure that the survey could be completed in about 15 minutes, to reduce the
likelihood that the participants would tire of the exercise and leave the survey before finishing.
Once the draft survey instrument was constructed, a focus group convened to provide
feedback on the effectiveness and validity of the survey design and survey questions. The use of
focus groups and expert advice is a good way to benchmark if the survey questions are “clearly
worded and specific enough to produce reliable and valid results” (Ouimet et al., 2004). Prior to
sending out the survey, a focus group comprised of six industry and academic subject matter
experts was identified. The members of the focus group included medical device
Biocompatibility and Toxicology experts: Justin Stoehr, M.S.; Thor Rollins, B.S.; and Grantley
Charles, Ph.D., DABT. The members of the focus group also included three USC academic
experts: Frances Richmond, Ph.D., Professor USC; Benson Kuo, Ph.D., Assistant Professor
USC; and Susan Bain, DRSc, Assistant Professor USC. The focus group convened on July 8,
2021, for an approximately 90-minute review of the proposed survey. The group reviewed and

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provided feedback on the content and design of the survey questions. The focus group
considered what information was intended to be obtained from each of the questions, and
recommended improvements. In addition, it reviewed and discussed the survey as a whole and
provided feedback to improve the ability of the survey to gather as much useful information as
possible related to the research topic. This feedback was used to revise the survey into a final
finished form.
Prior to disseminating the survey to all participants, and to ensure the final survey tool in
the Qualtrics system works properly, the survey was sent to a minimum of three participants to
verify that the survey was received, responses could be logged as intended, branches in the
question tree performed appropriately, and the completed survey could be returned successfully.
3.1.3 Survey Delivery
Participants were contacted prior to the survey by email or personal contact to gauge their
willingness to participate in the survey. No financial compensation was offered to encourage
participation. Follow up reminders were provided every two weeks after receipt to participants
who have not completed the survey.
3.1.4 Survey Analysis
The results of the survey were collected and stored in the Qualtrics survey application.
Where possible, results from respondents who completed more than 50% of the survey were
included in the final survey analysis. The survey data presented in Chapter 4 were appropriately
cross tabulated, graphed, and analyzed to understand and describe the results.

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Chapter 4. Results
4.1 Survey Participation
The survey was disseminated between August 18, 2021, and September 27, 2021, to 253
subject matter experts (Figure 3). Ninety-five participants completed at least one question, for a
response rate of 38% (95/253). Of the 95 participants who completed at least one question, 87
completed the survey, for a completion rate of 92% (87/95).
Figure 3: Survey responses

4.2 Demographic Profiles of Respondents
The first set of questions collected demographic information about the survey
participants. First, they were asked to identify their functional role (Figure 4). About half of the
respondents reported that they worked in biocompatibility strategy development (47%, 40/85).
The next two most common roles were “Toxicologist” (29%, 25/85) and “Regulatory Affairs”
(28%, 24/85). Other roles included Biocompatibility Testing (22%, 19/85), R&D/ Product
Development (19%, 16/85), Quality Assurance/ Risk Management (15%, 13/85) and Study

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Director (7%, 6/85). Twelve participants identified their roles as “Other”; these roles are listed in
Table 4.
Figure 4: Functional roles of respondents

Table 4: “Other” Functional Roles

number of respondents

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The levels of responsibility for the participants were characterized as Scientist (26%,
22/86), Specialist (24%, 21/86), Director (22%, 19/86), Manager (17%, 15/86), and Vice
President (9%, 8/86). One survey participant reported his/her current responsibility as “Other”
described as Consultant (1%, 1/86) (Figure 5).
Figure 5: Current responsibilities of respondents

The survey participants were asked to report how long they have worked in some aspect
of biocompatibility (Figure 6). Times varied from under two years (8%, 7/86) and two to ten
years (48%, 41/86), to more than ten years (43%, 37/86). One participant had no familiarity with
biocompatibility and did not complete the survey beyond this point.

82
Figure 6: Length of time working in biocompatibility

Almost 90% of participants (89%, 58/65) worked for a company that was conducting or
supporting biocompatibility studies on medical devices; the remaining respondents were not
currently working with such a company (11%, 7/65) (Figure 7).
Figure 7: Numbers of participants working for a medical device company

Many reported that they worked for a medical device manufacturer (68%, 44/65). The
others reported working for a contract research organization or laboratory (15%, 10/65), a
number of respondents

83
consultancy to the medical device industry (11%, 7/65), or a regulatory agency or Notified Body
(6%, 4/65) (Figure 8).
Figure 8: Description of organization with which participants worked

Fewer participants reported working for small or medium-sized companies with 1-500
employees (20%, 13/65) or 501-2000 employees (22%, 14/65) than for companies with more
than 2001 employees (58%, 38/65) (Figure 9).
Figure 9: Size of organizations at which respondents worked

number of respondents
number of respondents

84
Participants had experience with differing numbers of new product marketing
submissions that included biocompatibility assessments [less than 5 (29%, 19/65); 5-25 (34%,
22/65); 26-50 (12%, 8/65); and greater than 50 (25%, 16/65)] (Figure 10).
Figure 10: Number of marketing submissions for new products that include
biocompatibility supported by respondent

Most survey respondents reported that their organizations sold or supported class II or III
medical devices in the United States (91%, 59/65). However, many also reported that the product
mix included class I devices (57%, 37/65) and in vitro diagnostics (25%, 16/65). A few did not
sell or support medical devices in the United States (9%, 6/65) (Figure 11).
Figure 11: Classes of medical devices sold or supported in the United States

number of respondents

85
Most survey respondents reported that their organizations were selling or supporting class
I, IIa, IIb and/or III medical devices in Europe: [class I, (60%, 39/65); class IIa, (75%, 49/65);
class IIb and III, (83%, 51/65)]. A smaller number sold or supported in vitro diagnostics in
Europe (18%, 11/65). Only a few worked for organizations that did not sell or support medical
devices into Europe (15%, 10/65) (Figure 12).
Figure 12: Classes of medical devices sold or supported in Europe

4.2.1 Biocompatibility Experience and Expertise
Survey participants were asked to rate their levels of expertise related to medical device
biocompatibility (Figure 13). Most rated themselves as experts (58%, 38/65), or as
“intermediate” (38%, 25/65), while two participants rated themselves as “novice” (3%, 2/65).
Figure 13: Level of expertise in medical device biocompatibility

number of respondents
number of respondents

86

Participants were then queried about their levels of experience related to implementing
ISO 10993-1:2018 and ISO 10993-18:2020 biocompatibility standards as well as the FDA
guidance document on the use of ISO 10993-1 (Figure 14). Most commonly, respondents rated
their experience at the expert level for all documents. Most of the remaining respondents self-
identified at the intermediate level, and only a few at novice level. The levels of experience were
broadly similar across the documents. They rated their expertise with ISO 10993-1:2018 as
expert (58%, 38/65), intermediate (34%, 22/65), novice (8%, 5/65), and unfamiliar (0%, 0/65);
experience with ISO 10993-18:2020 was rated as expert (48%, 31/65); intermediate (38%,
25/65); novice (14%, 9/65); and unfamiliar (0%, 0/65). Experience related to the FDA guidance
document on the use of ISO 10993-1 was rated as expert (58%, 38/65); intermediate (35%,
23/65); novice (3%, 2/65); and unfamiliar (2%, 1/65).
Figure 14: Experience implementing biocompatibility standards and guidance document

The survey participants were asked about the state of implementation of these standards
and guidance document in their companies (Figure 15). Most respondents reported that their
companies had already fully implemented the two standards and guidance document. More
number of respondents

87
specifically, for ISO 10993-1:2018, participants reported full implementation (71%, 46/65); in-
process (20%, 13/65); still planning implementation (8%, 5/65). None of the respondents
reported that their organization had not started implementation (0%, 0/65). For ISO 10993-
18:2020, responses were: fully implemented (55%, 36/65); in-process (35%, 23/65); still
planning implementation (8%, 5/65); and had not begun implementation (2%, 1/65). The FDA
guidance document on the use of ISO 10993-1 was reported to be: fully implemented (72%,
47/65); in-process (23%, 15/65); still planning implementation (5%, 3/65), with no respondents
reporting that their organization and had not started implementation (0%, 0/65).
Figure 15: Implementation timeline for ISO 10993

4.3 Exploring New Biocompatibility Standards and Guidance Documents
Four questions were posed to understand the activities, resources, and impediments
associated with the early exploration of the new biocompatibility standards and guidance
documents.

88
First, the participants were asked to choose activities that their organizations took at early
stages of exploration and installation of ISO 10993-1:18, ISO 10993-18:20, and the FDA
guidance document from a list of seven choices (Figure 16). Most participants reported that they
had read the early and final versions of the three documents. Many were involved in working
groups to draft the ISO standards and/or had attended biocompatibility conferences. More
specifically, for ISO 10993-1:2018, the participants reported that they had read the final
document (90%; 58/64); read early drafts (67%; 43/64); attended biocompatibility conferences
(66%; 42/64); participated in working groups (50%; 32/64); sought help from outside labs (40%;
25/64) or consultants (30%; 19/64); did not do anything (0%, 0/64); and “other” (3%; 2/64). For
ISO 10993-18:2020, they had read final document (90%; 58/64); read early drafts (73%; 47/64);
attended biocompatibility conferences (67%; 43/64); participated in working groups (56%;
36/64); sought help from outside labs (52%; 33/64) or consultants (36%; 23/64); did not do
anything (3%; 2/64); and “other” (3%; 2/64). For the FDA guidance document on the use of ISO
10993-1, they had read the final document (80%; 51/64); read early drafts (47%; 30/64);
attended biocompatibility conferences (53%; 34/64); participated in working groups (23%;
15/64); sought the help of outside labs (30%; 19/64) or consultants (25%; 16/64); did not do
anything (0%, 0/64); and other (6%; 4/64). The “other” approaches included: consulting with
FDA experts, presenting at conferences on FDA guidance, having direct conversations with FDA
and notified bodies, and conducting detailed gap assessments and comparisons.

89
Figure 16: Activities used to get early understanding of biocompatibility documents

The survey participants were then asked to rate the usefulness of eight common resources
used when planning to implement the new systematic approach to biological evaluation, where
an initial toxicological risk assessment precedes biological testing (Figure 17). Using a weighted
average, the resources are ranked from the most preferred resource to a resource that was not
useful (Table 5). Most of the respondents found ISO 10993-1 and the FDA guidance document
useful resources; these documents were ranked first and second, respectively. The specifics for
the FDA guidance document are most preferred source (31%, 20/64), very useful (23%, 15/64),
somewhat useful (36%, 23/64), not useful (3%, 2/64); did not use (3%, 2/64); and do not know
(3%, 2/64). For ISO 10993-1:2018, responses were most preferred source (31%, 20/64); very
number of respondents

90
useful (38%, 24/64); somewhat useful (25%, 16/64); not useful (0%, 0/64); did not use (2%,
1/64); and do not know (2%, 1/64).
Respondents gained information about the ISO 10993 standards and FDA guidance
document using other methods in addition to reading the documents. The respondents ranked
information learned from their colleagues third in usefulness [most preferred source (20%,
13/64); very useful (45%, 29/64); somewhat useful (25%, 16/64); not useful (3%, 2/64); did not
use (2%, 1/64); do not know (2%, 1/64)]. Ranked lower were attendance at conferences/training
sessions (4
th
), information on FDA/EMA websites (5
th
), and review of white papers (6
th
).
Specifically, distributions for attendance at conferences/training sessions were most preferred
source (5%, 3/64); very useful (34%, 22/64); somewhat useful (42%, 27/64); not useful (5%,
3/64); did not use (11%, 7/64); and do not know (2%, 1/64). Distributions related to the
FDA/EMA website were most preferred source (5%, 3/64); very useful (28%, 18/64); somewhat
useful (41%, 26/64); not useful (12%, 7/64); did not use (12%, 8/64); and do not know (2%,
1/64). Distributions for the review of white papers or articles were most preferred source (3%,
2/64); very useful (25%, 16/64); somewhat useful (52%, 33/64); not useful (3%, 2/64); did not
use (12%, 7/64); and do not know (3%, 2/64).
Other sources of information were ranked and rated lower. For internet search, rated 7
th
,
rankings were most preferred source (2%, 1/64); very useful (23%, 15/64); somewhat useful
(31%, 20/64); not useful (16%, 10/64); did not use (20%, 13/64); do not know (3%, 2/64). For
consultants, rated 8
th
, rankings were most preferred (5%, 3/64); very useful (19%, 12/64);
somewhat useful (30%, 19/64); not useful (5%, 3/64); did not use (36%, 23/64); do not know
(5%, 3/64).

91
The participants reported as part of the “other” category: ISO 10993-17, ISO 10993-18,
meeting with FDA via trade organizations, and ISO TC 194 working groups as other resources
used. “Other” was reported occasionally as most preferred source (5%, 3/64) but was ranked as
somewhat to not useful or not used by none.
Figure 17: Usefulness of resources when planning new approaches to biological evaluation

number of respondents

92
Table 5: Summary of Responses regarding the Usefulness of Resources for
Planning Purposes
Field
Most
Preferred
Source
Very
Useful
Somewhat
Useful
Not
Useful
Final
Value
Weighted
Average Rank Value: 4 3 2 1
FDA guidance
document on 10993-1
31%;
20/64;
value is
20x4 = 80
23%;
15/64; 45
36%;
23/64; 46
3%;
2/64; 2
173 43 2
ISO 10993-1:18
31%;
20/64; 80
38%;
24/64; 72
25%;
16/64; 32
0 184 46 1
Conferences/
trainings
5%;
3/64; 12
34%;
22/64; 66
42%;
27/64; 54
5%;
3/64; 3
135 34 4
White papers/articles
3%;
2/64; 8
25%;
16/64; 48
52%;
33/64; 66
3%;
2/64; 2
124 31 6
Information on
FDA/EMA website
5%,
3/64; 12
28%,
18/64; 54
41%,
26/64; 52
12%,
7/64; 7
125 31 5
Consultants
5%,
3/64; 12
19%,
12/64; 36
30%,
19/64; 38
5%,
3/64; 3
89 22 8
Colleagues
20%,
13/64; 52
45%,
29/64; 87
25%;
16/64; 32
3%;
2/64; 2
173 43 3
Internet search
2%;
1/64; 4
23%,
15/64; 45
31%,
20/64; 40
16%,
10/64; 10
99 25 7

Respondents were asked about their agreement with six statements suggested by others as
possible impediments to understanding the new biocompatibility regulations and approaches
(Figure 18; Table 6). Only a small minority of the respondents agreed that “did not see a need to
implement the new standards quickly” [agreement with this statement was: strongly agree (6%,
4/65); somewhat agree (11%, 7/65); neither agreed nor disagreed (9%, 6/65); somewhat disagree
(20%, 13/65); strongly disagree (46%, 30/65); and a small number did not know (5%, 3/65)].
Instead, other impediments to understanding the new biocompatibility regulations and
approaches were identified more commonly. The statement that the company’s senior
management could not provide sufficient resources was ranked 1
st
overall: strongly agree (9%,
6/65); somewhat agree (28%, 18/65); neither agree nor disagree: (25%, 16/65); somewhat
disagree (15%, 10/65); strongly disagree (15%, 10/65); and do not know: (6%, 4/65). Ranked 2
nd

93
was the statement that speakers at conferences were unclear about regulatory expectations:
strongly agree (3%, 2/65); somewhat agree (34%, 22/65); neither agree nor disagree: (23%,
15/65); somewhat disagree (26%, 17/65); strongly disagree (2%, 1/65); and do not know: (12%,
8/65). Being unclear where to go with questions about the revised biocompatibility standards or
guidance documents was ranked 3
rd
: strongly agree (9%, 6/65); somewhat agree (20%, 13/65);
neither agree nor disagree: (20%, 13/65); somewhat disagree (23%, 15/65); disagree (25%,
16/65); and do not know: (2%, 1/65).
Only a few reported that their companies were unable to find consultants who understood
the requirements (ranked 5
th
): strongly agree (9%, 6/65); somewhat agree (9%, 6/65); neither
agree nor disagree: (15%, 10/65); somewhat disagree (20%, 13/65); strongly disagree (14%,
9/65); and do not know: (29%, 19/65). Responses suggesting that companies were unaware of
the new changes was ranked 6
th
: strongly agree with the statement that an impediment was “not
being aware of the changes” (2%, 1/65); somewhat agree (14%, 9/65); neither agreed nor
disagreed (5%, 3/65); somewhat disagree (9%, 6/65); strongly disagree (66%, 43/65); and do not
know (2%, 1/65).
A few individuals had “other” comments relating to impediments at this early stage,
including not understanding regulatory expectations or how to interpret the guidance document;
finding that the rate of disseminating changes / new requirements from biocompatibility SMEs to
cross-functions was too slow or inefficient; or finding that guidance and feedback from
regulators was too slow.

94
Figure 18: Agreement with statements of possible impediments to understanding the new
biocompatibility regulations and approaches

Table 6: Weighted Average Ranking of Statements
Field
Strongly
Agree
Somewhat
Agree
Neither
Agree nor
Disagree
Somewhat
Disagree
Strongly
Disagree
Weighted
Average Rank Value: 5 4 3 2 1
We were unclear where to go
with questions about the
revised biocompatibility
standards or guidance
documents.
9%, 6/65;
30
20%,
13/65; 52
20%,
13/65; 39
23%, 15/65;
30
25%,
16/65; 16
167/5 = 33 3
Speakers at conferences were
unclear about regulatory
expectations.
3%, 2/65;
10
34%,
22/65; 88
23%,
15/65; 45
26%, 17/65;
34
2%,
1/65; 1
178/5 = 36 2
We could not find consultants
who understood the
requirements.
9%, 6/65;
30
9%,
6/65; 24
15%,
10/65; 30
20%, 13/65;
26
14%,
9/65; 9
119/5 = 24 5
number of respondents

95
Field
Strongly
Agree
Somewhat
Agree
Neither
Agree nor
Disagree
Somewhat
Disagree
Strongly
Disagree
Weighted
Average Rank Value: 5 4 3 2 1
Senior management could not
provide sufficient resources.
9%, 6/65;
30
28%,
18/65; 72
25%,
16/65; 48
15%, 10/65;
20
15%,
10/65; 10
180/5 = 36 1
We did not see a need to
implement the new standards
quickly.
6%, 4/65;
20
11%,
7/65; 28
9%,
6/65; 18
20%, 13/65;
26
46%,
30/65; 30
122/5 = 24 4
We were not aware of changes
to the standards/guidance
documents.
2%, 1/65;
5
14%,
9/65; 36
5%,
3/65; 9
9%,
6/65; 12
66%,
43/65; 43
105/5 = 21 6

The participants were asked if the level of detail and expectations provided by the ISO
standards and the FDA guidance document were possible impediments to understanding the new
biocompatibility approaches (Figure 19). Views were mixed. For ISO 10993-1:18, nearly one-
third agreed [strongly (6%, 4/64); somewhat (23%, 15/64)] whereas about 40% disagreed
[somewhat (31%, 20/64); strongly, (9%, 6/64)]. Almost a third neither agreed nor disagreed
(27%, 17/64) or did not know (3%, 2/64).
For ISO 10993-18:2020, about a third agreed [strongly (9%, 6/64); somewhat (25%,
16/64)] and a little more than a third disagreed [somewhat (22%, 14/64); strongly (14%, 9/64)].
Nearly a third neither agreed nor disagreed (28%, 18/64) or did not know (2%, 1/64).
Similarly, for the FDA guidance document, about a third agreed [strongly (6%, 4/64);
somewhat (30%, 19/64)], whereas slightly fewer disagreed [somewhat (20%, 13/64); strongly
(11%, 7/64)]. A similar proportion neither agreed nor disagreed (28%, 18/64) or did not know:
(5%, 3/64).

96
Figure 19: Are the expectations in ISO and FDA documents sufficiently detailed?

The survey participants were also asked to provide comments on other issues that
complicated their early exploration of the changing biocompatibility standards and guidance
documents. Table 7 lists the comments categorized by theme.
number of respondents

97
Table 7: Comments on Other Issues that Complicated Early Exploration
Comments Related to FDA and Notified Bodies:
To do the tox before biological testing is not realistic for a med device company and regulators seem
to know this
FDA not accepting published standards and requiring their own, unpublished, requirements around
test methods, sensitivities, calibrations and solvents.
FDA, both CDRH and CBER, are extremely inconsistent with their chemistry testing and TRA
expectations. Even when we submit biocompatibility and chemistry testing plans via pre-sub, we get
hammer with biocompatibility and chemistry deficiency questions.
Interpretation of the standards varies based on the country/notified body.
We were not even compliant yet to ISO 10993-1:2009 - Uncertainty around how the FDA and EU
Notified Bodies would enforce the new standard(s)
Differing views between FDA and industry
Expectations on compliance to changing standards were not clearly communicated by regulatory
agencies. Level of compliance often varies by agency and seems to be reactive to public scrutiny of
medical implants
The revised expectations are interpreted by various notified bodies in different manner. Submission
methodology/strategy changes as per the NB that is supposed to review the file.
Disparity between ISO requirements and FDA requirements
Guidelines do not properly justify a sufficient number of use cases which do not fit into the standard
mold of medical devices. Guidelines do not represent regulatory expectations for 20-30% of use
cases in some aspect or another. Regulators from the same agency do not appear to have a globally
harmonized opinion on technical matters, confounding compliance.
FDA's interpretation and current thinking of the standard
FDA expectations change much faster than guidance documents are updated. Reading the documents
is not a replacement for experience.
Different regulators have different interpretation.
General Comments:
Too many opinions, not enough science-based decisions
Comments Related to Regulatory Standards:
Responding to regulatory feedback/questions centered on topics not outlined in standards/guidance
documents, in particular for chemical characterization and in several cases before standards had been
published/recognized. For example: 1) how to demonstrate exhaustive extraction (how sensitive must
the NVR gravimetric technique be and how to interpret gravimetric results
Due to the vast array of different medical devices out there, it is clear that the guidance should be
taken as a framework for risk assessment. But this can lead to different interpretations and
approaches either in testing plan (ISO 10993-1 and FDA guidance) or the specific test setup (per ISO
10993-18). this creates a scenario where we propose one way that we see fit and the regulatory
bodies see a different approach.
All three documents: FDA 10993-1 guidance, ISO 10993-1:2018, and ISO 10993-18:2020 provide
only high-level information. If biocompatibility evaluations are conducted, device-specific
information on how to conduct these evaluations are not found in these guidance’s or standards,
which can be very challenging from an implementation perspective.

98
Table 7: Comments on Other Issues that Complicated Early Exploration
Global harmonization is still out of reach. Updating and adaptation of Pt 1 has flipped the previous
submission cadence in first approaching EU market. MDR is still uncertain as to what legacy data
can be leveraged when sufficient clinical data is available (e.g., are we still looking at endpoint
testing “gaps”).
The biological endpoints to consider are very clear and Annex A provides a great table and summary
in ISO 10993-1:18. However, the same is not clear for the physicochemical testing that needs to
come prior to biological testing. It would be helpful if examples of toxicological risk assessments
and physchem testing were provided.
Standards are outdated and do not support the emerging shift from in vivo to in vitro methods
Feedback from various regulatory agencies worldwide is not consistent with the chemistry testing
approach first followed by biological endpoint testing. Additionally, a number of the tests are for
local endpoints, which chemical characterization cannot address and that is not very clearly defined
for people who are not familiar with the testing/expectation from reg agencies
Global expectations regarding actual recognition of guidance is far from harmonized, greatly
impeding a ‘once for the world’ approach to biocompatibility strategy
Comments Related to Medical Device Industry:
Management was reluctant to provide budget for implementation activities right away.
There was a disconnect between what NEEDED to be assessed / what testing NEEDED to be
performed for to ensure patient safety versus what the ask may or may not be from a regulatory body.
E.g., the biocomp SMEs might recommend different test strategies depending on submission
strategy, when in fact, there was a testing gap per the standards/guidance’s that should be addressed
regardless of regulatory submission strategy.
When new ISO standards are released, there is always a time period of uncertainty when no one is
sure how global regulatory bodies are going to accept/interpret new versions of the standards. I feel
like that is only discovered through time and interactions.
Industry needs to rely more on experienced professionals and less on media.

4.4 Planning and Installing New Biocompatibility Requirements
Survey participants were asked about the pre-planning done by their organizations to
prepare for changes before the new biocompatibility requirements became active from nine
options (Figure 20). Most identified that they had read early drafts of the regulation (67%,
43/64), and many attended conferences and workshops on the new EU MDR (61%, 39/64). More
than half had worked with their notified bodies (56%, 36/64), nearly half had made changes to
their organization (44%, 28/64) and more than a third sought help from external consultants
(38%, 24/64). Only a small number reported that they did not know (9%, 6/64) or that the

99
question was not relevant to their organization (8%, 5/64). One respondent reported that his/her
organization did nothing (2%, 1/64) and three provided “other” activities (Table 8).
Figure 20: Pre-planning to anticipate changes related to new MDR biocompatibility
requirements

Table 8: Other Pre-planning Activities Before EU MDRs Became Active

Participants were then asked to choose from ten options to identify how their
organizations had prepared to implement the newly revised biocompatibility standards (Figure
21). Most had personnel who attended conferences and workshops (70%, 45/64) or had internal
number of respondents

100
communication meetings (67%, 43/64). Two-thirds also researched the upcoming changes (66%,
42/64). Half participated in ISO working groups (53%, 34/64); reached out to regulatory
agencies (52%, 33/64); expanded relationships with outside laboratories (45%, 29/64); and/or
made organizational changes (42%, 27/64). Less commonly, they employed expert consultants
(38%, 24/64); hired new staff with expertise (30%, 19/64); and/or built or expanded the internal
laboratories in their organizations (22%, 14/64). Two survey participants reported “other” ways.
One reported that their organization made many of the changes listed as options, but as a reactive
and not a planned response and another was unaware of any changes that the organization had
made.

101
Figure 21: Approaches to plan/ prepare for implementing revised standards

Survey participants were asked to report on the parts of their organization involved in
preparing for upcoming changes to the biocompatibility standards (Figure 22). Most reported
that biocompatibility and pre-clinical affairs were involved (80%, 51/64), but half or more also
involved Regulatory Affairs (67%, 43/64), Quality (58%, 37/64) and/or Research and
Development (50%, 32/64). Less commonly involved was Operations (19%, 12/64). Five
participants reported that “other” departments were involved; these included Toxicology, Sales,
Manufacturing, Human Resources, Facilities, and the Legal department.
number of respondents

102
Figure 22: Parts of organization involved in planning to implement new standards

The survey participants were asked how early their organizations had started to prepare
for changes related to ISO 10993-1:2018, ISO 10993-18:2020, the FDA guidance document on
use of ISO 10993-1, and EU medical device regulations (MDR) (Figure 23). For ISO 10993-
1:2018, nearly half started 1-3 years in advance (44%, 27/62) and about a third began at the time
that the new revision was implemented (37%, 23/62). Less commonly, they started at least one
year after the new revision was implemented (12%, 7/62). For a few, implementation was still
incomplete (8%, 5/62).
For ISO 10993-18:2020, more began 1-3 years in advance of the revision (56%, 35/62),
and fewer at the time that the new revision was implemented (19%, 12/62). A minority began at
least one year after the new revision was implemented (10%, 6/62) and activities were still
incomplete for a few (15%, 9/62). For the FDA 2020 guidance document on use of ISO 10993-1,
only about a quarter began 1-3 years in advance (27%, 17/62), and half began at the time that the
new revision was implemented (50%, 31/62). An equal percentage reported waiting at least one
number of respondents

103
year after the new revision was implemented (10%, 6/62), or that implementation was still
incomplete (10%, 6/62). For MDR biocompatibility requirements, nearly half began 1-3 years in
advance (45%, 28/62) and a quarter began when the new revision was implemented (23%,
14/62). A few identified that they began preparation at least one year after the new revision was
implemented (10%, 6/62) and that implementation was still incomplete for a few (15%, 9/62).
Figure 23: Responses to question “How early did your organization start preparing for
changes to biocompatibility standards and guidance document?”

Respondents varied in their level of satisfaction with their company’s transition to the
new biocompatibility standards (Figure 24). Most commonly they were somewhat satisfied

104
(38%, 24/63). Smaller numbers were somewhat dissatisfied (19%, 12/63); neither satisfied or
dissatisfied (17%, 11/65); extremely satisfied (17%, 11/65); or extremely dissatisfied (8%, 5/63).
Figure 24: Satisfaction with company’s preparation to transition to new biocompatibility
requirements

The respondents were asked to rank the importance of changes made to be ready to
implement ISO 10993-1:2018 and the FDA guidance document on use of ISO 10993-1 (Figure
25). Using a weighted average, the ranking of changes based upon level of importance are
summarized in Table 9. The change receiving highest ranking was procedure and document
changes: most important (33%, 20/60); very important (45%, 27/60); slightly important (12%,
7/60); and not at all important (7%, 4/60). Second was developing a budget for implementation:
most important (17%, 10/60); very important (40%, 24/60); slightly important (22%, 13/60); and
not at all important (18%, 11/60). The ranking was lower for hiring new staff (3
rd
): most
important (20%, 12/60); very important (25%, 15/60); slightly important (28%, 17/60); not at all
important (22%, 13/60) and setting up contracts or agreements with vendors (4th): most
important (8%, 5/60); very important (33%, 20/60); slightly important (32%, 19/60); and not at
all important (22%, 13/60). Changes associated with quality and laboratory systems ranked 5th
number of respondents

105
and 6th: [quality system: most important for (12%, 7/60), very important (30%; 18/60), slightly
important (32%, 19/60), and not at all important (22%, 13/60); expanding lab capabilities and
capacity, most important (13%, 8/60); very important (27%, 16/60), slightly important (25%,
15/60), and not at all important (28%, 17/60)]. Of least importance to most were the hiring of
consultants and modification of office space, ranking 7th and 8th [consultants; most important
(13%, 8/60), very important (22%, 13/60), slightly important (23%, 14/60); and not at all
important (33%, 20/60); office space: most important (0%, 0/60), very important (8%, 5/60);
slightly important (27%, 16/60); and not at all important (58%, 35/60)].
A few respondents offered “other” options, which included monitoring regulatory
enforcement, broader company awareness, internal process training for R&D and mechanical
engineers due to the increased amount of input needed for biological safety evaluations; and
sharing new information and requirements with cross functional teams.

106
Figure 25: Changes to be ready to implement ISO 10993-1 and FDA guidance document
on ISO 10993-1

Table 9: Summary of Ranking of Changes Based Upon Importance –
ISO 10993-1
Description of Changes
Most
Important
Very
Important
Slightly
Important
Not at all
Important
Weighted
Average Rank Value: 3 2 1 0
Changed procedures or
controlled documentation
33%,
20/60, 60
45%,
27/60, 54
12%,
7/60, 7
7%,
4/60, 0
121/4 = 30 1
Changed the quality
system
12%,
7/60, 21
30%,
18/60, 36
32%,
19/60, 19
22%,
13/60, 0
73/4 = 18 5
Added or changed office
space
0
8%,
5/60, 10
27%,
16/60, 16
58%,
35/60, 0
26/4 = 6.5 8
Set up contracts or
agreements with new
vendors
8%,
5/60, 15
33%,
20/60, 40
32%,
19/60, 19
22%,
13/60, 0
74/4 =
18.5
4
number of respondents

107
Table 9: Summary of Ranking of Changes Based Upon Importance –
ISO 10993-1
Description of Changes
Most
Important
Very
Important
Slightly
Important
Not at all
Important
Weighted
Average Rank Value: 3 2 1 0
Developed a budget for
implementation
17%,
10/60, 30
40%,
24/60, 48
22%,
13/60, 13
18%,
11/60, 0
91/4 = 23 2
Expanded lab capabilities
and capacity
13%,
8/60, 24
27%,
16/60, 32
25%,
15/60, 15
28%,
17/60, 0
71/4 = 18 6
Hired new staff 20%,
12/60, 36
25%,
15/60, 30
28%,
17/60, 17
22%,
13/60, 0
83/4 = 21 3
Hired consultant(s) 13%,
8/60, 24
22%,
13/60, 26
23%,
14/60, 14
33%,
20/60, 0
64/4 = 16 7

A similar distribution of rankings was seen when asked about changes made to prepare
for the implementation of ISO 10993-18:2020 (Figure 26). Using a weighted average, the
ranking of changes based upon level of importance is summarized in Table 10. Most highly
ranked was “changed procedures or controlled documentation” [most important (38%, 23/61);
very important (43%, 26/61); slightly important (13%, 8/61); and not at all important (3%,
2/61)]. Second and third, with similar distributions, were developing a budget for
implementation and hiring new staff [budget for implementation: most important (21%, 13/61),
very important (43%, 26/61), slightly important (13%, 8/61), not at all important (13%, 8/61);
hiring new staff: most important (23%, 14/61), very important (33%, 20/61), slightly important
(20%, 12/61), not at all important (16%, 10/61)]. Also similar were distributions associated with
setting up contracts or agreements with new vendors [most important (15%, 9/61); very
important (43%, 26/61); slightly important (10%, 6/61); not at all important (25%, 15/61)].
Changes to quality systems and lab capabilities were somewhat lower in rankings (5th
and 6th respectively) [changes to the quality system: most important (10%, 6/61), very important
(31%, 19/61), slightly important (30%, 18/61), and not at all important (23%, 14/61); laboratory
changes: most important (21%, 13/61), very important (28%, 17/61), slightly important (23%,

108
14/61), and not at all important (18%, 11/61)]. Lowest rankings were again associated with
hiring consultants and changing the office space [hiring consultants: most important (15%, 9/61),
very important (23%, 14/61), slightly important (18%, 11/61), not at all important (36%, 22/61);
changing office space: most important (2%, 1/61), very important (16%, 10/61), slightly
important (18%, 11/61), not at all important (56%, 34/61)].
Changes ranked as “other” were ranked most important (5%, 3/61); very important (2%,
1/61); slightly important (2%, 1/61); and not at all important (5%, 3/61). These “other” changes
included broader company awareness, expanded method development with external contract lab,
training staff on changes, and sharing new information with cross functional teams.
Figure 26: Ranking of changes made to prepare for implementation of ISO 10993-18:2020

number of respondents

109
Table 10: Summary of Ranking of Changes Based Upon Importance –
ISO 10993-18
Description of Changes:
Most
Important
Very
Important
Slightly
Important
Not at all
Important
Weighted
Average Rank Value: 3 2 1 0
Changed procedures or
controlled documentation
38%,
23/61, 69
43%,
26/61, 52
13%,
8/61, 8
3%,
2/61
129/4 = 32 1
Changed the quality system
10%,
6/61, 18
31%,
19/61, 38
30%,
18/61, 18
23%,
14/61
74/4 = 19 6
Added or changed office
space
2%,
1/61, 3
16%,
10/61, 20
18%,
11/61, 11
56%,
34/61
34/4 = 8 8
Set up contracts or
agreements with new vendors
15%,
9/61, 27
43%,
26/61, 52
10%,
6/61, 6
25%,
15/61
85/4 = 21 5
Developed a budget for
implementation
21%,
13/61, 39
43%,
26/61, 52
13%,
8/61, 8
13%,
8/61
99/4 = 25 2
Expanded lab capabilities and
capacity
21%,
13/61, 39
28%,
17/61, 34
23%,
14/61, 14
18%,
11/61
87/4 = 22 4
Hired new staff
23%,
14/61, 42
33%,
20/61, 40
20%,
12/61, 12
16%,
10/61
94/4 = 24 3
Hired consultant(s) 15%,
9/61, 27
23%,
14/61, 28
18%,
11/61, 11
36%,
22/61
66/4 = 16 7

The survey participants were asked how frequently their organization held early-stage
meetings with regulators before transitioning to new approaches with biocompatibility strategies
(Figure 27). More commonly, they reported that early-stage meetings were held infrequently
with FDA (46%, 27/59) or notified bodies (41%, 24/59). Fewer reported that those meetings
occurred very often with FDA (29%, 17/59) or notified bodies (19%, 11/59). The remaining
respondents almost never had meetings with FDA (14%, 8/59) or notified bodies (24%, 14/59).
Few also reported that no meetings were held with FDA (12%, 7/59) or notified bodies (15%,
9/59).

110
Figure 27: Frequency of early-stage meetings with regulators before implementing new
biocompatibility strategies

Survey participants were asked at what stage those early-stage meetings were held with
the regulators before transitioning to new approaches to biocompatibility strategies (Figure 28).
Most often, respondents reported that meetings with FDA were held “from time to time” [very
often (16%, 9/57); from time to time (46%, 26/57); infrequently (12%, 7/57); almost never (9%,
5/57); and not at all (18%, 10/57)]. Early-stage meetings with FDA were held after finding
difficulties with pilot implementations somewhat more frequently [very often (28%, 16/57); from
time to time (32%, 18/57); infrequently (18%, 10/57); almost never (7%, 4/57); and not at all
(16%, 9/57)].
Typically, fewer meetings seemed to be held with respect to early-stage meetings with
the Notified Body before changing internal biocompatibility strategies or after finding
difficulties with pilot implementations [before changing strategies: very often (9%, 5/57); from
time to time (33%, 19/57); infrequently (23%, 13/57); almost never (14%, 8/57); not at all (19%,
11/57); after difficulties: very often (11%, 6/57); from time to time (37%, 21/57); infrequently
(21%, 12/57); almost never (16%, 9/57); not at all (16%, 9/57)].
number of respondents

111
Figure 28: Stage where organization held early-stage meetings with regulators

The survey respondents were asked to identify the level of participation of listed
stakeholders in planning for the implementation of revisions to biocompatibility standards in
their company based upon use of a weighted average analysis, from strong to slight participation
(Figure 29). Pre-clinical/biocompatibility stakeholders were identified as having the highest level
of participation ranking, followed by RA, R&D, QA, FDA, and notified bodies (Table 11).
Pre-clinical/biocompatibility staff had the highest weighted average (1
st
), with
participation listed as strong (77%, 48/62); moderate (11%, 7/62); slight (3%, 2/62); and no
participation (5%, 3/62). Participation of Regulatory Affairs was ranked 2
nd
and most commonly
reported as strong (44%, 27/62); moderate (26%, 16/62); slight (19%, 12/62); and none (6%,
4/62). Research and Development and Quality had similar distributions and were ranked 3
rd
and
4
th
[R&D: strong participation (34%, 21/62), moderate (29%, 18/62), slight (24%, 15/62), and no
participation (10%, 6/62); Quality Assurance: strong participation (32%, 20/62), moderate (23%,
14/62), slight (32%, 20/62), and no participation (6%, 4/62)].

112
The feedback on participation from regulators including the FDA and notified bodies was
ranked as lowest [FDA: strong participation (15%, 9/62), moderate (18%, 11/62), slight (26%,
16/62), no participation (34%, 21/62); notified bodies: strong participation (10%, 6/62),
moderate ,16%, 10/62); slight (34%, 21/62), no participation] (34%, 21/62).
An “other” response was “not aware of any planning conducted for the new
biocompatibility standards and therefore which functions were involved.”
Figure 29: Level of participation of listed stakeholders when planning for the
implementation of revisions to biocompatibility standards

Table 11: Level of Participation when Planning for the Implementation of
Revisions to Biocompatibility Standards
Stakeholder: Strong
Participation
Moderate
Participation
Slight
Participation
No
Participation
Weighted
Average Rank Value: 3 2 1 0
Pre-clinical/
Biocompatibility
77%,
48/62, 144
11%,
7/62, 14
3%,
2/62, 2
5%,
3/62, 0
160/4 = 40 1
RA
44%,
27/62, 81
26%,
16/62, 32
19%,
12/62, 12
6%,
4/62, 0
125/4 = 31 2
R&D
34%,
21/62, 63
29%,
18/62, 36
24%,
15/62, 15
10%,
6/62, 0
114/4 = 28 3
number of respondents

113
Table 11: Level of Participation when Planning for the Implementation of
Revisions to Biocompatibility Standards
Stakeholder: Strong
Participation
Moderate
Participation
Slight
Participation
No
Participation
Weighted
Average Rank Value: 3 2 1 0
QA
32%,
20/62, 60
23%,
14/62, 28
32%,
20/62, 20
6%,
4/62, 0
108/4 = 27 4
FDA
15%,
9/62, 27
18%,
11/62, 22
26%,
16/62, 16
34%,
21/62, 0
65/4 = 16 5
Notified Body
10%,
6/62, 18
16%,
10/62, 20
34%,
21/62, 21
34%,
21/62, 0
59/4 = 15 6

Finally, survey participants were asked, “In retrospect, would you have done something
differently to prepare your organization for implementation?” Responses to this question are
listed in Table 12.
Table 12: Responses to Question, “In retrospect, would you have done
something differently to prepare your organization for
implementation?”
General comments:
No, we reviewed everything and went over with the applicable stakeholders. We reviewed the draft
documents ahead of the implementation and were ready when implementation was required.
Not really. I feel it was well prepared and executed.
Comments related to improved awareness of upcoming changes:
Sure, be more aware about what is coming up.
Begin preparing for MDR implementation earlier.
Broad Cross-Functional Awareness of the coming changes, PRIOR to standard release and required
implementation.
Comments related to engagement with FDA and Notified Bodies:
Engaged FDA/notified bodies much more frequently and with more specific, concrete protocols that
include low-level technical details.
Hard to predict FDAs shift in expectations over time and demonstrating that there are few labs that
can actually carry out what is being asked.
Find a way for greater understanding of NB expectations.
Push harder to engage the agencies to get buy in for plans/strategies rather than relying on external
CRO partners.
Engaged with the NB/FDA earlier.
Brought in consultants or earlier meetings with NB.
More discussions with FDA and NBs would have been nice to really understand their perspective on
what they want to see or how they approach certain situations.

114
Table 12: Responses to Question, “In retrospect, would you have done
something differently to prepare your organization for
implementation?”
Comments related to building in-house capacity and expertise:
More open general staff training.
Insufficient in-house expertise in manufacturing, analytical chemistry and toxicological risk
assessment to meet the workload at time of implementation.
I would have sent other functions outside of Biocompatibility (i.e., Regulatory) to trainings or
conferences that educated them on the updates to the standards.
I was not at the organization at the time, but they should have acted sooner on hiring consultants/full-
time staff who truly understood biocompatibility.
An important aspect of not just being prepared for any change to a standard but actually influencing
new standards or updates to existing standards and regulations (not just biocompatibility) is to have
SMEs from specific functions on the ISO, AAMI, ASTM, etc. working groups so that they can at an
early stage feedback anticipated changes to standards back to the organization for assessment and
impact on that organization's products and business, influence the outcome of standards and
regulations where possible, understand the perspective of other industries, companies and regulators
involved in the development of that standard and have early warning of final versions that will be
implemented. This also serves as a development and network opportunity for employees and
benefits the organization.
I would like to see more functions involved in standards committees.
Assessed staff availability against expectations for implementation.
Ask for more resource to meet the new requirement if possible.
Dedicated more time and resources.
Would be better to make entire org aware of the changes because it leads to changes in timeline and
schedule. The expectations for new product development in light of standard revisions needs to be
clear.
Comments related to communication:
Assess change impact for quickly. Share / Disseminate changes / impact to project teams and cross
functions earlier so they can plan accordingly.
More communication with RA and R&D.

4.5 Initial Implementation of New Biocompatibility Requirements
Six questions were asked about the initial implementation of the new biocompatibility
requirements.
First, participants were asked about the level of difficulty when implementing pilot
approaches to the new biocompatibility requirements (Figure 30). A weighted average is
presented in Table 13. Responses varied but overall, most difficulty was seen with the MDR

115
biocompatibility requirements. The feedback was: extremely easy (3%, 2/62); moderately easy
(16%, 10/62); neither easy nor difficult (11%, 7/62); moderately difficult (35%, 22/62);
extremely difficult (16%, 10/62); and do not know (16%, 10/62). The next most difficult was
ISO 10993-18:20, and responses were: extremely easy (2%, 1/62); moderately easy (15%, 9/62);
neither easy nor difficult (13%, 8/62); moderately difficult (45%, 28/62); extremely difficult
(16%, 10/62); and do not know (10%, 6/62).
ISO 10993-1:18 was rated as the second easiest to implement: extremely easy (11%,
7/62); moderately easy (18%, 11/62); neither easy nor difficult (23%, 14/62); moderately
difficult (26%, 16/62); extremely difficult (8%, 5/62); and do not know (13%, 8/62). The easiest
to implement was the FDA 2020 Guidance on 10993-1, with feedback as: extremely easy (16%,
10/62); moderately easy (16%, 10/62); neither easy nor difficult (27%, 17/62); moderately
difficult (19%, 12/62); extremely difficult (3%, 2/62); and do not know (18%, 11/62).
Figure 30: Difficulty implementing pilot approaches to new biocompatibility
requirements

116
Table 13: Summary of Responses: Difficulty of Implementing Pilot Approaches to the
New Biocompatibility Requirements for Participants’ Organizations
Biocompatibility
Requirements
Document
Extremely
Easy
Moderately
Easy
Neither
Easy Nor
Difficult
Moderately
Difficult
Extremely
Difficult
Do Not
Know
Weighted
Average Rank Value: 5 4 3 2 1 0
ISO 10993-1:18
11%,
7/62, 35
18%,
11/62, 44
23%
14/62, 42
26%,
16/62, 32
8%,
5/62, 5
13%,
8/62
158/5 = 32 2
ISO 10993-18:20
2%,
1/62, 5
15%,
9/62, 36
13%,
8/62, 24
45%,
28/62, 56
16%,
10/62, 10
10%,
6/62
131/5 = 26 3
FDA 2020 Guidance
re 10993-1
16%,
10/62, 50
16%,
10/62, 40
27%,
17/62, 51
19%,
12/62, 24
3%,
2/62, 2
18%,
11/62
167/5 = 33 1
MDR
Biocompatibility
requirements
3%,
2/62, 10
16%,
10/62, 40
11%,
7/62, 21
35%,
22/62, 44
16%,
10/62, 10
16%,
10/62
125/5 = 25 4

Survey participants were then asked to specify the principal challenges that their
organizations faced during the pilot phase (Table 14).
Table 14: “What were the principal challenges that respondent organizations
faced during the pilot phase?”
Comments on requirements specific to FDA:
FDA has their own chemical characterization methodology expectations that constantly are being
refined with insufficient guidance given to industry. This is by far the most frustrating.
Challenge is still how regulatory agencies interpret standards and for ISO 10993-18 the constant
shifting of technical expectations related to the studies by FDA.
Lack of lab availability, lack of guidance on FDA's current thinking, FDA's lack of knowledge as it
relates to our specific devices and materials making submissions more challenging,
Balancing requirements in the written standard to FDA requirements all in one system and approach.
General comments:
Politics on who owns it.
Comments related to chemical characterization and E&L testing:
No adequate resource to address the chemical testing needs.
Massive cultural shift for the 'new' [enforcement] of part 18 testing. The company was not even
complaint to ISO 10993-1:2009 so it was a pretty big shift. E&L testing is expensive, extremely long
and labs are not ready for the dramatic increase in demand and scrutiny. Incremental costs and
timelines were not anticipated by project teams.
Comments related to internal challenges:
Educating stakeholders on recently changed requirements and impact on their processes. Also
challenging was ensuring that procedures would be capable of meeting standard requirements and
regulatory expectations. E.g., instrumentation/procedures sufficiently sensitive to achieve required
AETs for chemical characterization.

117
Table 14: “What were the principal challenges that respondent organizations
faced during the pilot phase?”
Training and understanding changes
Staff awareness of changes.
Resourcing
Taking time to educate everyone else on the updates being made and the impact it might have on our
current testing strategy
New plans are not simple to develop and implement.
Testing capacity; project teams' being unaware of new requirements / need for new testing
Previous testing was not performed by a biocompatibility expert so a number the logistics for testing
had to be completely re-examined (e.g., extraction ratios, which parts of the device are truly patient
contacting and how to prepare those for testing, surface are calculations, etc.)
Underestimating the resources required to develop new approaches
Lack of clear requirements from different internal stakeholders’ type of samples needed.
cost/duration of testing
Challenges were to have management understand the reasons for implementing the changes.
Changing mindsets from historical practice to new requirements.
Certainty with selection of tests and retests.
Lack of resources who knows the requirements
MDR related comments:
Understanding the regulatory bodies and their expectations. there are still open questions on the
MDR (e.g., how to address section 10.4.1 if certificate of conformance cannot be obtained from
material suppliers, aged device assessments, reprocessed device assessments, etc.)
Higher scrutiny under MDR

The survey participants were asked to rank difficulties that their organization may have
had with initial implementation of the recently revised ISO 10993-1 biocompatibility standard
and the FDA guidance document on use of ISO 10993-1 from a selection of 5 choices (Figure
31; Table 15). Understanding the revised standard was ranked as the least difficult [extremely
easy (13%, 8/61); moderately easy (31%, 19/61); neither easy nor difficult (30%, 18/61);
moderately difficult (16%, 10/61); extremely difficult (5%, 3/61); do not know (5%, 3/61)].
Obtaining support from areas of the organization and having sufficient resources to implement
fully were ranked 2
nd
and 3
rd
respectively [obtaining support: extremely easy (8%, 5/61),
moderately easy (16%, 10/61), neither easy nor difficult (20%, 12/61), moderately difficult

118
(36%, 22/61), extremely difficult (11%, 7/61), do not know (7%, 4/61); having sufficient
resources: extremely easy (5%, 3/61), moderately easy (18%, 11/61), neither easy nor difficult
(21%, 13/61), moderately difficult (36%, 22/61), extremely difficult (15%, 9/61), do not know
(5%, 3/61)]. More difficult (ranked 4
th
) was aligning with expectations of the FDA or notified
bodies [ extremely easy (5%, 3/61); moderately easy (11%, 7/61); neither easy nor difficult
(30%, 18/61); moderately difficult (28%, 17/61); extremely difficult (18%, 11/61); and do not
know (8%, 5/61)]. The most difficult challenge overall (5
th
) was having sufficient CRO or
internal capacity [extremely easy (2%, 1/61); moderately easy (13%, 8/61); neither easy nor
difficult (20%, 12/61); moderately difficult (30%, 18/61); extremely difficult (23%, 14/61); and
do not know (13%, 8/61)].
Figure 31: Ranking for difficulty with initial implementation of revised ISO 10993-1
biocompatibility standard and FDA guidance document
on ISO 10993-1

number of respondents

119
Table 15: Ranking for Difficulty with Initial Implementation of ISO 10993 and the
FDA Guidance Document
Description of
Difficulty:
Extremely
Easy
Moderately
Easy
Neither
Easy Nor
Difficult
Moderately
Difficult
Extremely
Difficult
Weighted
Average Rank Value: 5 4 3 2 1
Understanding the
revised standard
13%,
8/61, 40
31%,
19/61, 76
30%,
18/61, 54
16%,
10/61, 20
5%,
3/61, 3
193/5 = 39 1
Obtaining support
from areas of my
organization
8%,
5/61, 25
16%,
10/61, 40
20%,
12/61, 36
36%,
22/61, 44
11%,
7/61, 7
152/5 = 30 2
Having sufficient
resources to
implement fully
5%,
3/61, 15
18%,
11/61, 44
21%,
13/61, 39
36%,
22/61, 44
15%,
9/61, 9
151/5 = 30 3
Aligning with
expectations of the
FDA or Notified
Bodies
5%,
3/61, 15
11%,
7/61, 28
30%,
18/61, 54
28%,
17/61, 34
18%,
11/61, 11
142/5 = 28 4
Having sufficient
CRO or internal
capacity
2%,
1/61, 5
13%,
8/61, 32
20%,
12/61, 36
30%,
18/61, 36
23%,
14/61, 14
123/5 = 25 5

The survey participants were also asked if their organizations had other issues with initial
implementation that were not identified in the prior question (Table 16).
Table 16: Additional Issues Related To Initial Implementation of New ISO 10993-1 and
FDA Guidance Document
Yes, general disaster and containment issues. A full disaster plan with fully detailed and current active plans is
crucial. Including IT infrastructure all related backups.
Internal discrepancies in interpretation
Performing a toxicological risk assessment BEFORE embarking on the required biological testing is not feasible
for most of our products due to the complexity of unknowns and compounds with low margins of safety in the
extractable profile
Having sufficient awareness across cross-functions / project teams
Training staff to engage in implementation delayed timely roll-out.

The participants were asked about the level of difficulty that they encountered when
beginning to implement the new ISO 10993-18 chemical characterization standard from six
choices (Figure 32; Table 17). Having sufficient resources to fully implement the standard was
reported to be most difficult overall [extremely difficult (26%, 16/62); somewhat difficult (47%,

120
29/62); neither easy nor difficult (15%, 9/62); somewhat easy (5%, 3/62); extremely easy (2%,
1/62); and do not know (6%, 4/62)]. The area ranked 2
nd
was aligning with expectations of the
FDA [extremely difficult (34%, 21/62); somewhat difficult (32%, 20/62); neither easy nor
difficult (18%, 11/62); somewhat easy (5%, 3/62); extremely easy (5%, 3/62); and do not know
(6%, 4/62)]. Ranked as 3
rd
was having sufficient CRO or internal capacity [extremely difficult
(31%, 19/62); somewhat difficult (42%, 26/62); neither easy nor difficult (8%, 5/62); somewhat
easy (5%, 3/62); extremely easy (0%, 0/62); do not know (15%, 9/62)].
Obtaining support from different areas of the organization was rated lower in difficulty
(ranked 4
th
), with respondents reporting this as extremely difficult (23%, 14/62); somewhat
difficult (29%, 18/62); neither easy nor difficult (27%, 17/62); somewhat easy (8%, 5/62);
extremely easy (5%, 3/62); do not know (8%, 5/62). Least difficult appeared to be aligning with
expectations of notified bodies (ranking 5
th
) and understanding the revised standard (ranking 6
th
)
[aligning with NB: extremely difficult (10%, 6/62), somewhat difficult (32%, 20/62), neither
easy nor difficult (32%, 20/62), somewhat easy (10%, 6/62), extremely easy (3%, 2/62), do not
know (13%, 8/62); understanding the revised standard: extremely difficult (5%, 3/62), somewhat
difficult (40%, 25/62), neither easy nor difficult (21%, 13/62), somewhat easy (18%, 11/62),
extremely easy (10%, 6/62), do not know (6%, 4/62)].

121
Figure 32: Difficulty of implementing the revised ISO 10993-18 standard

Table 17: Difficulty Level of First Attempts at ISO 10993-18 Implementation
Difficulty Level:
Extremely
Difficult
Somewhat
Difficult
Neither
Easy Nor
Difficult
Somewhat
Easy
Extremely
Easy
Weighted
Average Rank Value: 5 4 3 2 1
Understanding the
revised standard
5%,
3/62, 15
40%,
25/62, 100
21%,
13/62, 39
18%,
11/62, 22
10%,
6/62, 6
182/5 = 36 6
Having sufficient
resources to fully
implement
26%,
16/62, 80
47%,
29/62, 116
15%,
9/62, 27
5%, 3/62, 6
2%,
1/62, 1
230/5 = 46 1
Obtaining support
from areas of my
organization
23%,
14/62, 70
29%,
18/62, 72
27%,
17/62, 51
8%,
5/62, 10
5%,
3/62, 3
206/5 = 41 4
Aligning with
expectations of the
FDA
34%,
21/62, 105
32%,
20/62, 80
18%,
11/62, 33
5%,
3/62, 6
5%, 3/62, 3 227/5 = 45 2
Aligning with
expectations of
Notified Bodies
10%,
6/62, 30
32%,
20/62, 80
32%,
20/62, 60
10%,
6/62, 12
3%, 2/62, 2 184/5 = 37 5
Having sufficient
CRO or internal
capacity
31%,
19/62, 95
42%,
26/62, 104
8%,
5/62, 15
5%,
3/62, 6
0 220/5 = 44 3

number of respondents

122
The survey participants were asked if their organizations had additional issues when
beginning to implement the new ISO 10993-18 standard. Responses are listed in Table 18.
Table 18: Additional Issues when First Implementing ISO 10993-18
Comments related to the FDA:
Changing and poor industry communication of FDA expectations, nothing else comes close to the difficulty
we have had.
Dealing with FDA deficiencies without a grace period of adoption. Apparently, no grace period for standards
without defined success criteria. A lot of repeated E&L studies and delayed timelines created internal strife.
The goal post keeps shifting, even when FDA agreement is in place through the Qsub process. Global
recognition is not complete & APAC region remains a significant hurdle to developing a harmonized
approach for global submissions
Comments related to ISO 10993-18:2020:
Having compliant methods and libraries at CRO's with understanding and expertise for -18.
Achieving sufficient analytical technique sensitivity and justifying workup conditions, 2) procedurally
defining when simulated vs exaggerated vs exhaustive extraction would be performed, 3) justifying reference
standard selection, 4) establishing workflows for identification of extractable chemicals, 5) defining
procedures for circumstances triggering subsequent leachable testing, 6) defining procedures for establishing
exhaustive extraction conditions by NVR, especially in cases where the total amount of gravimetric residue
is low, 7) establishing procedures for initial information gathering activities, 8) weighing pros vs cons of
performing information gathering, L&E testing, and other biocompatibility testing in series vs parallel.
Meeting low Analytical Evaluation Thresholds
Technically challenging to implement some requirements (e.g. achieving AET for some device types)
Exaggerated and exhaustive extraction conditions almost always yield unknowns that cannot be fully
identified
Comments related to the medical device industry:
Industry was not ready for the changes. CROs were not ready with respect to their test methods, their
competence and capabilities and resourcing. Most CROs do not have equipment with high enough resolution
to detect/identify compounds down to the limits the ISO requests, and Most CROs do not have competent
personnel or adequate databases to identify compounds.
Top management understanding the need to accept the internal changes and the unexpected need from
Quality and Regulatory to modify the budget for meeting the requirements.
Lack of resources
Having sufficient awareness across cross-functions / project teams
Unique challenges with degradable and partially degradable devices, especially when the amount of clinical
usage is high.

The survey participants were asked to rate the usefulness of four activities associated
with the initial implementation of biocompatibility changes (Figure 33). Internal communication
and awareness meetings were rated the highest by respondents [extremely useful (50%, 30/60);
moderately useful (37%, 22/60); slightly useful (12%, 7/60); and not at all useful (0%, 0/60)].
Communication with FDA and notified bodies was only a little less valuable [extremely useful

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(40%, 24/60); moderately useful (37%, 22/60); slightly useful (17%, 10/60); and not at all useful
(3%, 2/60)]. Ranked somewhat lower were the options related to managing change using project
management techniques and/or obtaining outside education or training [managing change with
project management: extremely useful (23%, 14/60), moderately useful (33%, 20/60), slightly
useful (23%, 14/60), not at all useful (12%, 7/60); obtaining outside training: extremely useful
(22%, 13/60), moderately useful (43%, 26/60), slightly useful (27%, 16/60), not at all useful
(5%, 3/60)].
The survey participants also provided the following activities in the “other” category:
“utilization of consultants to build/revise internal systems,” “on the ground discussions among
project teams and trial-by-fire,” “internal training on a regular timeline,” and “weekly classes
work better than full day conference style training.”
Figure 33: Usefulness of activities during initial implementation of changes

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The survey participants were asked if the FDA was consistent, transparent, and accessible
in communicating changes and expectations (Figure 34). Responses varied substantially. More
disagreed than agreed that FDA had consistent expectations [strongly agree: (11%, 7/61);
somewhat agree (20%, 12/61); neither agree nor disagree (13%, 8/61); somewhat disagree (26%,
16/61); strongly disagree (21%, 13/61); do not know (7%, 4/61)]. More negative than positive
views were also reported when asked if FDA was transparent in communicating changes and
expectations [strongly agree (10%, 6/61); somewhat agree (20%, 12/61); neither agree nor
disagree (18%, 11/61); somewhat disagree (28%, 17/61); strongly disagree (18%, 11/61); do not
know (5%, 3/61)]. Responses were distributed more evenly when asked if FDA was easily
accessible to communicate ongoing changes and evolving expectations [strongly agree: (8%,
5/61); somewhat agree (21%, 13/61); neither agree nor disagree (28%, 17/61); somewhat
disagree (16%, 10/61); strongly disagree (10%, 6/61); do not know (15%, 9/61)].
Figure 34: Was FDA consistent, transparent and accessible?

number of respondents

125
The survey participants were asked to provide rating of the notified bodies (NB), when
their organizations were implementing changes to biocompatibility standards. The question
asked was, “Did the NB have consistent expectations; was the NB transparent and easily
accessible in communication changes and expectations?” (Figure 35). When asked whether
notified bodies had consistent expectations, responses ranged relatively evenly from agree to
disagree [strongly agree: (7%, 4/61); somewhat agree (25%, 15/61); neither agree nor disagree
(16%, 10/61); somewhat disagree (25%, 15/61); strongly disagree (11%, 7/61); do not know
(15%, 9/61)]. When asked whether they were easily accessible to communicate ongoing changes
and evolving expectations, the responses were also quite symmetric [strongly agree: (3%, 2/61);
somewhat agree (23%, 14/61); neither agree nor disagree (21%, 13/61); somewhat disagree
(16%, 10/61); strongly disagree (13%, 8/61); and do not know (21%, 13/61)]. When asked
whether they were transparent in communicating changes and expectations, negative views were
somewhat more frequent than positive [strongly agree: (2%, 1/61); somewhat agree (26%,
16/61); neither agree nor disagree (16%, 10/61); somewhat disagree (28%, 17/61); strongly
disagree (11%, 7/61); and do not know (15%, 9/61)].

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Figure 35: Were Notified Bodies consistent, transparent and accessible?

4.6 Full Implementation of New Biocompatibility Requirements
Eight questions were asked to gain feedback on the degree of full implementation of the
new biocompatibility requirements. Participants were first asked to rate their organizations’ level
of implementation of ISO 10993-1:2018, ISO 10993-18:2020, and the FDA guidance document
on use of ISO 10993-1 (Figure 36). Two-thirds had implemented ISO 10993-1 in full (67%,
40/60) and another near third in part (27%, 16/60). Only a few had not yet implemented the
standard (3%, 2/60) or did not know (2%, 1/60). About half had implemented ISO 10993-18 in
full (55%, 33/60) and a third in part (35%, 21/60). A few had not implemented the standard (7%,
4/60) or did not know (3%, 2/60). Three-quarters had fully implemented the FDA guidance
document (75%, 45/60) and another fifth in part (20%, 12/60). One respondent indicated it had
not been implemented (2%, 1/60) and two did not know (3%, 2/60).
number of respondents

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Figure 36: Degree of implementation of key biocompatibility standards

The survey participants were asked how they would characterize their organizations’
level of understanding of ISO 10993-1:2018, ISO 10993-18:2020, and the FDA guidance
document on use of ISO 10993-1 (Figure 37). Most identified that they understood the
documents: ISO 10993-1: fully understands (72%, 44/61), somewhat understands (26%, 16/61);
and zero (0) do not understand. For ISO 10993-18: fully understands (66%, 40/61); somewhat
understands (33%, 20/61), do not understand (2%, 1/61). For the FDA guidance document on use
of ISO 10993-1: fully understands (67%, 41/61), somewhat understands (25%, 15/61), do not
understand (3%, 2/61).
number of respondents

128
Figure 37: Organization’s understanding of key biocompatibility standards

The survey participants were asked about the level of challenge associated with six
elements or activities important when implementing the ISO 10993-1 standard (Figure 38).
Based upon a weighted average, the ranking from highest to lowest challenge is summarized in
Table 19.
The activity rated as most challenging was evaluating biocompatibility across the
lifecycle [high challenge (34%, 20/58); moderate challenge (43%, 25/58); low challenge (12%,
7/58); and no challenge (7%, 4/58)]. Leveraging tests from similar devices was 2
nd
[high
challenge (33%, 19/58); moderate challenge (38%, 22/58); low challenge (24%, 14/58); and no
challenge (3%, 2/58)]. Using chemical characterization data in a biological evaluation was
ranked as 3
rd
[high challenge (24%, 14/58); moderate challenge (48%, 28/58); low challenge
(22%, 13/58); and no challenge (5%, 3/58)]. Making persuasive justifications to avoid endpoint-
specific testing was 4
th
[high challenge (28%, 16/58); moderate challenge (45%, 26/58); low
challenge (22%, 13/58); and no challenge (5%, 3/58)]. Incorporating history of clinical
number of respondents

129
use/human exposure data into risk assessment was 5
th
[high challenge (17%, 10/58); moderate
challenge (47%, 27/58); low challenge (28%, 16/58); and no challenge (5%, 3/58)], and
evaluating interactions with packaging materials appeared overall to be the least challenging (6
th
)
[high challenge (3%, 2/58); moderate challenge (41%, 24/58); low challenge (40%, 23/58); and
no challenge (14%, 8/58)]. The respondents also reported “other” elements with high and
moderate challenge to be, “establishing competency of authors,” “assessing changes without
repeating testing,” and “finding consistency in review of toxicological risk assessment.”
Figure 38: How challenging were the following elements when fully implementing ISO
10993-1 standard?

number of respondents

130
Table 19: Ranking of Challenge when Fully Implementing ISO 10993-1 Standard
Description of Activity:
High
Challenge
Moderate
Challenge
Low
Challenge
No
Challenge
Weighted
Average Rank Value: 4 3 2 1
Evaluating biocompatibility across
the lifecycle
34%,
20/58, 80
43%,
25/58, 75
12%,
7/58, 14
7%,
4/58, 4
173/4 = 43 1
Incorporating history of clinical
use/human exposure data into risk
assessment
17%,
10/58, 40
47%,
27/58, 81
28%,
16/58, 32
5%,
3/58, 3
156/4 = 39 5
Evaluating interactions with
packaging materials
3%,
2/58, 8
41%,
24/58, 72
40%,
23/58, 46
14%,
8/58, 8
134/4 = 34 6
Making persuasive justifications to
avoid endpoint-specific testing
28%,
16/58, 64
45%,
26/58, 72
22%,
13/58, 26
5%,
3/58, 3
165/4 = 41 4
Leveraging tests from similar devices
33%,
19/58, 76
38%,
22/58, 66
24%,
14/58, 28
3%,
2/58, 2
172/4 = 43 2
Using chemical characterization data
in a biological evaluation
24%,
14/58, 56
48%,
28/58, 84
22%,
13/58, 26
5%,
3/58, 3
169/4 = 42 3

The survey participants were asked to what degree their current biocompatibility
strategies were aligned with the ISO 10993-18 roadmap of performing physical characterization,
chemical characterization, and a toxicological risk assessment, prior to conducting biological
testing (Figure 39). Most commonly, respondents reported that their strategies sometimes
followed the roadmap and the rest of the time, they performed some of the steps concurrently
(40%, 24/60). Somewhat fewer reported that they seldom followed the roadmap sequentially
(33%, 20/60). Only a small minority reported that they almost always followed the roadmap
sequentially (15%, 9/60). Three respondents did not know (5%, 3/60); and four reported “other”
(7%, 4/60), described in Table 20.

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Figure 39: Alignment of biocompatibility strategies with ISO 10993-18 roadmap of
performing physical characterization, chemical characterization, and a
toxicological risk assessment, prior to conducting biological testing

Table 20: “Other” Responses: Degree of Alignment of Current Biocompatibility
Strategies with the ISO 10993-18 Roadmap of Performing Physical
Characterization, Chemical Characterization, and a Toxicological Risk
Assessment, Prior to Conducting Biological Testing
“We ALWAYS follow the roadmap”
There is not a requirement to conduct physical/chemical characterization TESTING and a formal toxicological
risk assessment prior to conducting biological testing. The requirement is to gather what is known in terms of
physical and chemical information to determine what type of biological endpoints need to be assessed. The type
of testing (biological/chemical) and need for toxicological risk assessment depend on what endpoints are being
assessed and what type of testing is conducted.
Manufacturer’s timeline will always necessitate concurrent testing and will hold back full realization of the
purpose of the updated Pt 1
We parallel path characterization and testing as many regions will not accept TRA only

The survey participants were asked to identify areas where their organization struggled
with the 2020 FDA guidance document on use of 10993-1 (Figure 40). Most commonly,
struggles appeared associated with conducting chemical characterization (59%, 34/58). In order
the response numbers were: justifying how prior data can support biocompatibility (57%, 33/58);
using publicly available information to ID and mitigate risks (52%, 30/58); justifying testing
number of respondents

132
components versus device final finished form (50%, 29/58); leveraging biocompatibility from
other manufacturers (50%, 29/58); modifying test protocols for devices with special needs (34%,
20/58); addressing biocompatibility test failures ( 34%, 20/58); identifying tests for non-standard
medical devices (31%, 18/58); and “other” (3%, 2/58). The comment reported for the “other” is
“struggle with continuing changes made by FDA.”
Figure 40: Areas where organization struggled with FDA guidance document on 10993-1

The survey participants were asked how difficult it was to get sufficient information in
eight key areas related to biocompatibility safety assessments (Figure 41). Figure 41 is arranged
from easiest to most difficult to obtain. The respondents reported that sterilization processes were

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easiest to obtain, followed by literature and other publicly available information, materials of
construction, animal study experience, clinical experience, manufacturing processes, chemical
characterization/composition, and similar devices to leverage for comparative purposes. More
specifically, the reported results are as follows:
Literature and other publicly available information: easy to get (54%, 33/61); difficult to
get (31%, 19/61); nearly impossible to get (5%, 3/61); and do not know (10%, 6/61). Clinical
experience: easy to get (38%, 23/61); difficult to get (38%, 23/61); nearly impossible to get (7%,
4/61); and do not know (18%, 11/61). Animal study experience: easy to get (43%, 26/61);
difficult to get (38%, 23/61); nearly impossible to get (5%, 3/61); and do not know (15%, 9/61).
Materials of construction: easy to get (44%, 27/61); difficult to get (41%, 25/61); nearly
impossible to get (8%, 5/61); and do not know (7%, 4/61). Manufacturing process: easy to get
(34%, 21/61); difficult to get (52%, 32/61); nearly impossible to get (10%, 6/61); and do not
know (3%, 2/61). Sterilization process: easy to get (84%, 51/61); difficult to get (11%, 7/61);
nearly impossible to get (0%, 0/61); and do not know (5%, 3/61). Similar devices to leverage for
comparative purposes: easy to get (23%, 14/61); difficult to get (59%, 36/61); nearly impossible
to get (10%, 6/61); and do not know (8%, 5/61). Chemical characterization/composition: easy to
get (26%, 16/61); difficult to get (57%, 35/61); nearly impossible to get (13%, 8/61); and do not
know (3%, 2/61).

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Figure 41: Difficulty to get sufficient information for biocompatibility safety assessments

The survey participants were asked how frequently their organization struggled with the
use of chemical characterization followed by a toxicological risk assessment to justify limiting
the amount of biological testing performed (Figure 42). More specifically, struggles were
characterized as moderately often (49%, 28/57). A few characterized it as very often (11%,
6/57). Several reported that they almost never struggle because they run the full chemical and
biological testing (23%, 13/57). Two responded that they almost never struggle because they do
not perform chemical characterization (4%, 2/57), and three because they do not know how to
use chemical characterization and risk assessment (5%, 3/57). A few did not know (9%, 5/57).

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Figure 42: How frequently does your organization struggle with the use of chemical
characterization followed by a toxicological risk assessment to justify limiting
the amount of biological testing performed?

The survey participants were asked about unexpected outcomes that their organizations
had experienced when interacting with regulators (Figure 43). In order of frequency, they
identified unexpected outcomes related to inconsistencies in interpreting/applying standards by
FDA (72%, 39/54) and notified bodies (NB) (56%, 30/54); varying opinions from different FDA
reviewers (87%, 47/54) and NBs (63%, 34/54); requests for biocompatibility related actions from
FDA (54%, 29/54) and NBs (44%, 24/54) that were not defined in the standards; “raising the
bar” over time on expectations related to biocompatibility strategies by FDA (78%, 42/54) and
NBs (52%, 28/54).

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Figure 43: What unexpected outcomes has your organization experienced as you have
interacted with regulators following implementation of changing
biocompatibility standards?

The survey participants were asked a final question: “Do you have additional comments
to share on unexpected outcomes that your organization has experienced as it has interacted with
regulators following implementation of changing biocompatibility standards?” A summary of
comments with different themes is presented in Table 21.
number of respondents

137
Table 21: Summary of Responses to Question “Do you have additional
comments to share on unexpected outcomes that your organization
has experienced as it has interacted with regulators following
implementation of changing biocompatibility standards?”
Comments related to the medical device industry:
Industry was not ready for the changes. CROs were not ready with respect to their test methods, their
competence and capabilities and resourcing. Most CROs do not have equipment with high enough
resolution to detect/identify compounds down to the limits the ISO requests, and Most CROs do not
have competent personnel or adequate databases to identify compounds. We receive 'unknown'
compounds on our chemical characterization testing on nearly every single test we do. and the DBT
threshold of 1.5 µg adds extreme undue burden to our TRAs. this threshold is extremely low and
scientifically should not apply to the medical device industry. it came from drugs and cosmetics. This
problem is exacerbated by the CROs. most of them do not have sufficient databases to fully identify
all compounds on the devices, and some will not buy/subscribe to external databases because they try
to minimize costs. Notified Bodies are enforcing chemical characterization even when the ISOs
specifically state the updated versions are not meant to be retroactive. the NBs are 'raising the bar' in
excess of what the ISO says, even when we have proven clinical history of a device. the whole
situation is ridiculous. Technology in analytical chemistry is not yet good enough to sufficiently and
reasonably comply with the standards.
Research and focus on the primary goal across the entire organization with solid training and
communication is an important key to success.
The questions often made sense from the perspective of a device manufacturer. As a regulatory
stakeholder I answered some questions based on conversations with regulated industry. Some
questions might make sense to have a "not applicable" option.
General comments:
Noted in sections above
On the whole, the level of evidence being required to assure adequate biocompatibility greatly
exceeds the value of that evidence to that end
Comments related to the FDA and Notified Bodies:
I wish it would be easier to understand the expectations of the regulatory bodies - I often see that a
risk-based approach is not really the route they want to take, even if the device has a low risk based
on intended use scenario; I also wish there would be more consistency between the reviewers.
Regulators are still mostly appeased with endpoint testing regardless of how much safe clinical use is
available.
Collecting PMSF data in terms of complaints complicates leveraging safe history (NB says absence
of complaints does not equal safety). Quality of clinical data has not updated at the same rate of the
expectations of Biocomp standards.
Inconsistent feedback
The use of chemical characterization, followed by a toxicological risk assessment to justify limiting
the amount of biological testing performed is made difficult by the FDA and Notified bodies
inconsistency in review and feedback based on this data type.
ISO 10993-18 (2020) interpretation by regulators conflicts with ICH M7 R1 for devices intended to
contact the patient for > 1 day or for non-consecutive use-cases when determining the toxicologically
justified level of impurity considered acceptable. This represents a large percentage of all medical
devices and leads to differing opinions on the thoroughness of chemical characterization and what
biocompatibility tests (notably genotox and other long-term studies) are required. Regulatory
agencies generally do not possess the scientific expertise/experience nor toxicological understanding
to be appropriately reviewing, let alone recommending requirements for, chemical characterization.

138
Table 21: Summary of Responses to Question “Do you have additional
comments to share on unexpected outcomes that your organization
has experienced as it has interacted with regulators following
implementation of changing biocompatibility standards?”
Regulatory agencies need to train their reviewers better and consistently.
Interpretation of results

139
Chapter 5. Discussion
5.1 Overview of Research
Assuring biocompatibility is a critical part of managing the safety of medical devices. In
this research, survey methods were used to explore the views and experiences of medical device
companies regarding biocompatibility testing in the face of dissonance between revised
international standards and regionally based regulatory expectations during the prior 3-4 years.
However, survey methods have their strengths and weaknesses. Before considering the
implications of these findings, it is important to consider the extent to which delimitations and
limitations might affect the strength of the conclusions that can be drawn from them.
5.2 Methodological Considerations
5.2.1 Delimitations
The current study solicited the views of experts and regulators supporting companies that
sell medical devices in the US and the EU, so that the implications of the new standards and
regulations could be assessed in those two markets. The US and European markets for medical
devices are the largest in the world (Select USA, 2022). Many of the companies represented by
the survey participants would likely also market their products in the other regions of the world,
because medical devices are often commercialized globally to treat medical problems that are
seldom confined within national boundaries. However, not all countries have the same
requirements for biocompatibility testing. For example, China, another rapidly growing market
for medical devices (Boyer et al., 2015), has different rules for product testing that are well
known to be challenging for multinational companies (Liu et al., 2018a). Other countries may
rely on the results of testing developed for the US or EU only after the products are approved or
cleared by their own “stringent” regulatory authorities (Lamph, 2012). The results of this survey

140
cannot, then, reflect the views and experiences in jurisdictions other than the US and EU.
However, an initial focus on the US and EU can provide baseline data needed to assess whether
these two jurisdictions differ. This could also provide a baseline against which other countries
could be assessed by future studies.
The survey was narrowed to focus on two standards, one guidance document, and one set
of medical device regulations (MDR). These four documents, which describe expected elements
of biocompatibility testing practices in the US and EU, underwent major revisions within the
prior 3– 4 years [ISO 10993-1 (International Organization for Standardization, 2018)]; [ISO
10993-18 (International Organization for Standardization, 2020a)]; [FDA Guidance Document
on Use of ISO 10993-1, 2020; (US FDA, 2020, International Organization for Standardization,
2018)]; (Regulation (EU) 2017/745, 2017). Selection of these four documents enabled the survey
to consider the changes holistically; if only one or two had been examined, the survey results
would most likely not be comprehensive. These four documents cover the chemical, physical,
biological and toxicological aspects of biocompatibility safety upon which regulatory policy in
US and the EU is currently based. As described in Chapter 2, other international harmonized
standards also exist that provide specifics on chemical, physical and biological testing. However,
these documents are typically focused on the details of testing procedures or management and
therefore would not be central to the goal of this study.
The framework used to base the survey also delimits the scope and focus of the study.
Frameworks can be valuable because they can assure a more systematic and academically robust
approach to the development of survey questions (Birken et al., 2017). However, no single
framework appeared to encompass the elements considered to be relevant to the research
question. Because I was interested in the way companies were implementing the new

141
requirements, an implementation framework such as that recommended by Fixsen and his
colleagues (Fixsen et al., 2005) seemed well-suited. However, a key factor that affects how the
implementation is designed in programs to develop medical devices are the interactions that take
place with the regulators, a source of information that has previously been characterized as
opaque (DeMarco, 2011). To assure that this relationship was explored as part of the
implementation, a hybrid framework was constructed that also incorporated transparency.
For the purposes of this study, I viewed transparency to be defined as “policies that are
easily understood, where information about the policy is available, where accountability is clear,
and where citizens know what role they play in the implementation of policy” (Finkelstein,
2000). The framework resulting from this hybrid approach was useful because each component
included important elements that could then be captured by a more comprehensive set of
questions than could be referenced if only one component were used. Through the lens of
transparency, questions explored the clarity, accountability, and accessibility of regulatory
interactions, a set of dimensions previously used by Solberg and Richmond to examine
regulatory transparency (Solberg and Richmond, 2012). At the same time, through the lens of
implementation, they investigated the roadmap, stages, and key activities needed for successful
implementation of a major change.
In this study, recruitment for the survey was delimited to biocompatibility subject matter
experts and regulators who supported medical devices sold in the US and the EU. The subject
matter experts included a range of professionals in different job functions who were most likely
to possess the relatively deep knowledge of biocompatibility safety testing needed for purposes
of this research study. Of concern in a study with such a narrow delimitation would be whether
the delimitation to this pool of experts leaves out stakeholders whose views might be important

142
(Orcher, 2014). Here, however, the pool of surveyed experts included a diverse range of
professionals who would have interest, experience, and expertise in the biocompatibility
standards and regulations for medical devices. While other stakeholders would likely have
interests in aspects of this testing such as cost and speed to market, but these aspects fall outside
of the scope of this study. Thus, the key requirement of a robust survey-based research program
of obtaining adequate recruitment and participation of qualified individuals (Sadler et al., 2010)
appeared to be satisfied.
5.2.2 Limitations
Survey studies are also subject to several potential limitations that can impact the validity
of the survey and its subsequent results. First, it is necessary to sample adequately from an
appropriate respondent pool (Orcher, 2014) to prevent biasing the responses to only one
subpopulation. Responses to the initial demographic questions confirmed that professionals
worked in a wide distribution of company sizes and had experience with diverse classes of
medical devices. These features, added to the lengthy experience and expertise affirmed by the
participants, suggests that the dissemination methods were able to assure adequate participation
of qualified individuals. Satisfying this criterion is important to provide the “information-rich”
results key to assuring a robust survey-based research program (Sadler et al., 2010). Further, the
fact that most had been involved in many regulatory submissions incorporating biocompatibility
testing suggests that the experiences they report are based on first-hand experiences within the
company and between the companies and the regulators. Thus, having an inappropriate sample
of participants did not appear to be a limitation that negatively impacted this research study.
Another limitation that can also be important is response rate. Higher response rates can
give more confidence that the results obtained by a survey are representative of the population at

143
large. For example, a survey response rate of 60% or greater is cited as the goal for most research
by Fincham in his article “Response Rates and Responsiveness for Surveys, Standards, and the
Journal” (Fincham, 2008). However, surveys of senior professionals more typically have
relatively low response rates (Sadler et al., 2010). Those individuals are busy and may view
participation in a survey as distracting from more important activities (Galesic and Bosnjak,
2009). Baruch, who evaluated 175 papers that were published in academic management journals,
found an average response rate of about 56% for all surveys but only 36 % for studies of top
management or organizational personnel (Baruch, 1999). This lower response rate seems
consistent with the response rate of 38% seen in this study. In “Conducting Research, Social and
Behavioral Science Methods,” Orcher notes further that, “well-designed and executed
experiments with as few as 30 participants are often published in top-flight journals, especially
when the results of the experiments have important implications for practicing professionals or
for theory development.” Orcher suggests that such lower response numbers can be sufficient if
the researcher can identify participants who are “information-rich,” and can provide a high level
of understanding of the topic under study (Orcher, 2014). The responses to the initial
demographic questions appear to validate that the dissemination methods were able to assure
adequate participation of qualified individuals, a key requirement of a robust survey-based
research program (Sadler et al., 2010).
One factor known to be important to assuring a sufficient response rate is the length of
time needed to complete the survey. Participants who find the survey too burdensome may fail to
start or complete the survey (Galesic and Bosnjak, 2009). However, shorter surveys have fewer
questions, and this can reduce the breadth and depth of the results. In this study, I attempted to
compromise by designing a survey that could be completed in about 15 minutes. This added

144
pressure to assure that the questions were relevant, well structured, and understandable to the
reader (Ball, 2019). The use of focus groups and expert advice has previously been seen as useful
to evaluate whether those experts find the survey questions to be “clearly worded and specific
enough to produce reliable and valid results.” (Ouimet et al., 2004). In this study, the use of a
focus group to critique the survey resulted in several changes that improved its content and
clarity.
Another factor that can influence the survey results is the structure of its questions. Its
design, presentation and ease of use can affect the completion rate and depth of the research
study. The introduction to the survey and the order in which the questions are presented to the
participant are important to consider. The questions should be relevant to the topic and presented
in a manner that will minimize any unintended bias (Ball, 2019). In this study, many of the
questions had a multiple choice or matrix structures that could make it easier to see the
distributions of answers across the respondent pool using simple descriptive statistics. However,
this can also reduce the richness of the responses (Pew Research Center, 2022). Thus, comment
fields that allowed participants to expand on their answers proved to be an important source of
illustrative material. Together, these strategies may have contributed to the high completion rate
of 92% (87/95). Such a high completion rate may also suggest that the respondents found the
topic of sufficient professional interest and importance that they were willing to spend time not
only to answer the questions but also to provide detailed text responses.
Any survey of senior regulatory professionals must also be sensitive to the fact that
survey respondents will be cautious about participating for fear being asked to share proprietary
information. Thus, respondents were assured that their survey responses would be anonymous
and only reported as grouped results. That survey respondents appeared comfortable was

145
suggested not only by the high completion rate but also the often lengthy and candid text
responses.
5.3 Consideration of Results
The objective of this survey was to understand the views, experiences, and challenges of
companies managing the convergence of international standards with nationally based regulatory
expectations and traditional biocompatibility testing approaches across the US and EU. The
survey was carried out using a modified framework constructed by blending implementation and
transparency frameworks. The following discussion presents the results in the context of this
modified framework and considers the phases of implementation, including exploration,
installation, initial implementation and full implementation, and discusses the results related to
transparency at the stage most relevant to the observations.
5.3.1 Exploration Stage
Prior to the start of the survey, it was clear that new requirements represented a
significant change to the philosophy and requirements for biocompatibility testing. Thus,
challenges might be expected to understand how the new standards and rules would be adopted
in a system in which the “way of doing business” had been in place for many years. Preparations
for implementing change typically begin with exploration, a time when a company will confront
new requirements that may impact their current programs (Fixsen et al., 2015). During this stage,
the company must understand and communicate the need for a new system, create organizational
readiness for change, and make a collective decision to move forward with the implementation
(Fixsen et al., 2013, Bertram et al., 2015).
“Exploration” is an important preparatory stage because predicting the logistics of
implementation for major change is no simple task. International standards such as those studied

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here describe high level expectations in a broad and general manner. They do not, and cannot,
make clear how a given company with a specific product would implement those expectations
logistically. Thus, a first step for the organization would be to understand what the standard
means and how that will affect current practice (Preda, 2013).
Not surprisingly, survey responses suggested that substantial effort was expended at this
early stage to understand the needed changes in advance of the implementation deadline. Early
engagement is reflected by findings that most companies had read the draft as well as final
versions of the three biocompatibility documents and were also involved in working groups that
were drafting the ISO standards. Such involvement allows the company to identify the nature of
upcoming changes and give it more time to prepare. Further, involvement in ISO standard
working groups can give a company some opportunity to affect the content of the standards
(International Organization for Standardization, 2022). As one might expect, many respondents
had also attended biocompatibility conferences and solicited help from external experts to
understand the coming changes and clarify questions of interpretation. However, perhaps
surprisingly, relatively few companies engaged consultants or sought help from outside
laboratories at this stage. Certainly, this was not because such outside experts were unavailable,
because only a few respondents found it difficult to find consultants. Currently more than 150
contract research organizations (CRO) exist that support medical device development and many
conduct biocompatibility testing (Roots Analysis, 2020). Perhaps this suggests that many device
companies have sufficient in-house expertise to feel confident that they can assess the changes
without engaging additional specialists.
Approaches to the exploration of change associated with the EU MDRs were similar to
those reported for the related ISO standards. The most important activities for the majority were

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reading early drafts of the regulation and attending conferences and workshops. Next in
importance, however, was working with the notified bodies. In the EU, decisions about
approvals are typically in the hands of these third-party assessors (BSI, 2022), so consulting
these notified bodies when marketing in the EU would in many respects be akin to consulting
with the US FDA when marketing in the US. This might be particularly important in the current
environment; the MDRs are new, and requirements are changing not only for biocompatibility,
but for several other aspects of testing (Crawford, 2020).
What was different in implementing EU MDR was the use of consultants by at least a
third of the respondents. Because most respondents in this survey were in the US, they may have
been less familiar with the EU system and may therefore have sought outside help to understand
the EU approaches. Further, the changes to MDRs have had a substantial impact on notified
bodies in ways that have limited their ability to meet company needs. The new MDRs require
that notified bodies have a higher level of qualification before they can be certified, so the
numbers of certified notified bodies decreased from 125 to about 20 as of late 2021 (Schaible et
al., 2021). As noted by Parker and Pryzgoda, “With a limited number of NBs stretched to
capacity, there is a limited amount of time to review each submission and provide feedback”
(Parker and Pryzgoda, 2020). Thus, companies may reach out to consultants if the notified
bodies are less available to answer questions or provide needed education.
The approaches used by biocompatibility experts here reflect those identified in the
literature when previously implementing other comprehensive standards. Although those
previous implementations have not been evaluated as systematically across companies in the
past, anecdotal and case study reports point to a broad array of activities much like those
identified here. For example, Motwani et al. (1996) examined the implementation of ISO 9000 in

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a single company. They found that early-stage implementation activities included attending
seminars on the standard, establishing management commitment by setting deadlines and goals,
establishing teams with key tasks to accomplish, communicating within the organization, and
establishing a relationship with a third party (Motwani et al., 1996).
During the exploration stage, potential implementation barriers were identified in areas
such as funding, staffing, and organizational change. For many complex implementation
projects, the exploration stage can be expected to take from 1-2 years. However, the efficiency
with which it is carried out depends on “resources allocated (e.g., time, people), access to
information, and authority to make decisions” (Fixsen et al., 2013). Fixsen and colleagues also
note that “lack of readiness and lack of resources are frequently found on the lists of
impediments to success” (Fixsen et al., 2015). The need to secure sufficient resources appeared
to be well-appreciated by the respondents, as reflected by the fact that respondents selected the
statement, “senior management could not provide sufficient resources” as the most highly ranked
challenge. Nevertheless, buy-in and support from key stakeholders is crucial to assure the ability
to move forward with the expensive and time-consuming changes that the new biocompatibility
standards call out (Fixsen et al., 2013).
Another top impediment identified here was a lack of clarity regarding the specific
requirements that a company might need to satisfy for regulatory acceptance. Clarity contributes
to the transparency of regulations and the regulatory process. It helps assure that companies
developing medical devices can have confidence that they are complying appropriately with the
requirements (Sharfstein et al., 2017). Interestingly, survey results seemed to be divided quite
evenly when a multiple-choice question asked if the new standards and guidance document were
sufficiently detailed, suggesting that many were quite satisfied. Nevertheless, the primary theme

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of subsequent comments appeared to be directed at a lack of clarity that was not helped when
regulators gave inconsistent advice or conveyed different expectations. As stated by one
respondent,
FDA, both CDRH and CBER, are extremely inconsistent with their chemistry
testing and TRA expectations. Even when we submit biocompatibility and
chemistry testing plans via pre-sub, we get hammer [sic] with biocompatibility
and chemistry deficiency questions.

Confusion seemed to be found in multiple areas, ranging from changing expectations
about how chemistry studies are performed to inconsistencies in the way the results are
interpreted by the FDA, as noted elsewhere (Crawford, 2020). As one step forward, regulators
might consider developing more detailed guidance to which companies could refer to answer
their commonly recurring questions and to use as a reference if regulatory advice appeared to be
misaligned with specific guidance documents.
Further comments from respondents also pointed to challenges when regulatory agencies
in different jurisdictions had different interpretations and expectations. Such inconsistencies have
been the subject of previous discussions. For example, when performing biocompatibility safety
for EU MDR purposes, Cabonce and colleagues noted that EU member states can have dissonant
expectations and may further be confused about the interpretation of “state of the art” testing
(Cabonce et al., 2021). Regulatory dissonance may increase further when the products enter
additional markets globally. Although ISO standards are the best attempt of the regulatory
agencies and industry to foster harmonization, as stated by one respondent,
Global expectations regarding actual recognition of guidance is far from
harmonized, greatly impeding a ‘once for the world’ approach to
biocompatibility strategy.

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If the regulatory agencies themselves are not consistent in their messaging, then
respondents may look to other information sources to answer their questions. Where to go for
that information was, however, unclear for some. For example, responses suggested that the
information obtained from conference speakers was not always clear. The survey feedback
seems to suggest that in-house biocompatibility experts are working hard to stay up to date with
current biocompatibility standards and understand how the regulatory agencies are interpreting
and applying these regulatory documents (WuXi AppTec, 2020, Fenske, 2020). This approach
may, however, be complicated by the fact that biocompatibility specialists knowledgeable about
the standards appear to be in short supply (Parker and Pryzgoda, 2020).
5.3.2 Installation Stage
The installation stage follows the decision to comply with new biocompatibility
requirements and puts into place the organizational foundation and infrastructure to support the
necessary changes. These include a focus on people, including staffing, training, and coaching;
on equipment, space and documentation including data systems, policies, and procedures; and
establishing leadership strategies (Fixsen et al., 2013, Bertram et al., 2015).
Leadership is well known to be important during the installation stage. Fixsen and
colleagues have suggested that change must be driven by key leadership with the technical and
adaptive competencies to assure an integrated approach (Fixsen et al., 2013). It is an element that
is commonly highlighted when complex changes are required to comply with new regulations or
standards. For example, in their study of 11 Middle eastern companies implementing ISO 14001,
Waxin and coworkers identified that support at the top was key to facilitating the change process
(Waxin et al., 2019). In this study, management of the installation phase appears typically to be
led by specialists in biocompatibility and pre-clinical job functions, presumably because they are

151
best positioned to provide the detailed logistical planning needed for this highly specialized
activity. However, these individuals may not be positioned best to manage the type of cross-
functional planning that is necessary to ensure that the activities are integrated into regulatory
and development strategies more broadly (Schaible et al., 2021). Thus, it may not be surprising
that Regulatory Affairs, Quality, and/or Research and Development were part of at least half of
the installation teams. The participation of other company functions can be especially important
when regulatory changes go beyond biocompatibility to include other aspects of medical device
development, as is typical when changing from MDD to MDR (Parker and Pryzgoda, 2020).
Many companies can then take advantage of both traditional biocompatibility experts and other
types of experts, such as quality engineers, regulatory specialists, and external consultants to
provide the diverse resources needed to achieve success in this area of change and resource
demand (Parker and Pryzgoda, 2020).
The challenges associated with installation can be anticipated to shift to preparing the
logistics of the changes. A clear understanding of what exactly will need to be done can expedite
the planning process. To this end, additional interactions with the regulatory agency or notified
body can be helpful. The FDA strongly encourages conversations prior to start of
biocompatibility testing to reduce questions from the agency at the later stages of the submission
approval process (Crawford, 2020). Similarly, it can be helpful to consult with the notified
bodies to understand how they will interpret biocompatibility requirements to navigate the new
European requirements (Cabonce et al., 2021). However, most respondents here reported that
such meetings were infrequent, “from time to time”. The frequency of such meetings appeared to
increase slightly as companies transitioned into the initial implementation phase and faced
problems with their pilot implementations. However, it remains unclear to what extent these

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occasional meetings were adequate to assure that the implementation phase would go smoothly.
One of the principal concerns identified at this stage continued to be the lack of regulatory clarity
and inconsistent application of the requirements. It is not clear, however, whether transparency
would increase with more frequent or more structured interactions. Certainly, as discussed
below, later stages of implementation were often slowed by difficulties in meeting the unclear
expectations of the regulatory agencies.
To address these concerns, regulatory agencies should be encouraged to find ways to
increase the consistency and reach of their messaging. For example, additional materials or
FAQs (Frequently Asked Questions) might be helpful to clarify in advance how the FDA or
notified body would review biocompatibility test plans. In early 2021, the FDA created a web-
based resource called the Biocompatibility Assessment Resource Center. This web resource
currently contains only a modest set of generic materials. However, it appears to be an initiative
that FDA plans to build into a repository of tools that industry could use during biocompatibility
assessment. In developing this initiative, the FDA seems to recognize that concerns exist, and
that industry that transparency has been a problem. Such a platform could be useful to better
explain FDA’s expectations and to minimize deficiencies related to biocompatibility in device
applications (Lenz, 2021).
Survey responses here suggest that the activities during installation are multifaceted, as
might be expected from the diverse installation activities previously described for ISO 14001 and
9000 standards. For example, in the case study of Motwani and colleagues for ISO 14001,
installation challenges included establishing teams, performing relevant training, establishing
new or revising existing procedures and communicating those changes across the entire
organization (Motwani et al., 1996). All of these areas appeared to cause problems for the

153
respondents in this study. Activities that seemed most challenging appeared to be “procedure and
document changes,” followed by “developing a budget for implementation.” Further, many
companies found it difficult to assure capable staffing and support, including the need to hire
and/or train personnel to the new standard and to set up contracts or agreements with vendors.
Many comments in this area were consistent with the concerns expressed by one respondent that
the company had “insufficient in-house expertise in manufacturing, analytical chemistry and
toxicological risk assessment to meet the workload at the time of implementation.” Changes
associated with quality and laboratory systems appeared to be less difficult to manage. This may
reflect that fact that the space and equipment needed to satisfy the new requirements are mostly
similar to those used previously to conduct biocompatibility testing.
Implementation frameworks often model the stages of implementation as if they occur
sequentially, but in reality, they often overlap (Fixsen et al., 2015). Fixsen et al. have suggested
that the exploration phase can take one to two years. This timeline can be accelerated if
installation overlaps exploration to some extent, allowing installation to begin as early as
possible (Fixsen et al., 2013, Fenske, 2020). Results here suggest that about half of the
organizations started some of the logistical changes associated with 10993-1:2018 one to three
years in advance, and about a third began at the time the new revision was implemented. This
time allotment was similar to that for ISO 10993-18:2020 and for the EU MDRs, but longer than
that typically spent to implement the FDA 2020 guidance document on use of ISO 10993-1. The
shorter time allotted to the FDA guidance document may in part be related to the lengthier and
more extensive recommendations for change in the international standards. Because FDA largely
endorsed the use of the ISO standards, its requirements for change are narrower and should be
relatively easy to put into place.

154
5.3.3 Initial Implementation Stage
During initial implementation, the organization and its people begin to use new skills and
adapt to new ways of working. In this fragile stage, external support such as technical assistance,
coaching, and supervision are often needed to facilitate the implementation of the changes
(Fixsen et al., 2013). It is at this stage when the organization will also make mistakes that can
drive methodical improvements, with the goal of long-term and sustainable impact on the
eventual full implementation (Bertram et al., 2015). Further, issues associated with changing the
approaches and procedures may frustrate personnel, who will generally be most comfortable
with the “status quo.” Uncertainty about changes in roles, responsibilities, and practices are well-
known to be a normal part of the change process (Hussain et al., 2018).
Many different types of activities are necessary to drive the early stages of
implementation of a major change such as has occurred with biocompatibility. When asked about
the value of some of these activities, survey participants most commonly indicated that internal
communication and awareness meetings were valuable, as was communication with FDA and
notified bodies. These results highlight the importance of communication to align the
biocompatibility strategies of an organization within its various departments and with the
regulators who will review and approve new medical device applications. These types of
activities are consistent with the recommendations of FDA and industry experts, who emphasize
the importance of early communication with FDA and notified bodies to align biocompatibility
strategies (Crawford, 2020).
During installation, companies also must solidify new staff competencies, procedural
capabilities and a sustainable organizational culture (Bertram et al., 2015). The organization and
its people will now begin to test the new skills and adjust to new ways of working. However,
results suggested an interesting inconsistency in the views of the respondents. On one hand,

155
“managing change using project management techniques” and “obtaining outside education or
training” were typically ranked lower than the other activities in assuring initial implementation.
This might not be too surprising considering that much of the training appears to have been
performed during the installation stage. However, the same respondents identified that “having
sufficient CRO or internal capacity,” together with “having sufficient resources to fully
implement,” were two of the top three areas of difficulty. As highlighted by Parker and
Pryzgoda, biocompatibility specialists are in short supply. The demand for these types of
specialists by the medical device industry is high and this will limit capacity both internally and
with external partners such as CROs (Parker and Pryzgoda, 2020). These observations may
suggest that the investment in training during the installation phase, while substantial, still fell
short of what was needed once the implementation began.
Despite much effort at earlier stages to understand the requirements of the new
biocompatibility testing standards, nearly half of the respondents reported some level of
difficulty with implementation. Of the four regulatory documents, the most difficult to
implement were the MDR biocompatibility requirements. This is not surprising given the short
timelines, unclear expectations, and limited number of notified bodies available to support the
MDD to MDR transition (Schaible et al., 2021, Crawford, 2020).
The next most difficult regulatory document to implement was ISO 10993-18:2020,
because of challenges to obtain sufficient resources and aligning with expectations of FDA.
Additional challenges when implementing ISO 10993-18 included securing sufficient CRO or
internal capacity and obtaining support from different areas of the organization. It is not
surprising to see that ISO 10993-18 is particularly difficult to implement. The new standard has
significant differences from its prior version: FDA has only partially recognized the standard,

156
and the EU has not harmonized the meaning of “state of the art testing” when following the
recently changed standard (Schaible et al., 2021). Additional challenges reported when beginning
to implement the new ISO 10993-18 standard were mostly related to the inconsistent application
of the standard and problematic communication with regulators. Technical challenges related to
the application of the testing methodology and internal company challenges (i.e., resources,
readiness for the change, senior management support), were also problematic for many. These
challenges may come in part from lack of full recognition of the 10993-18:2020 standard by the
FDA, as well as the obvious pressures of adopting such a challenging testing program in a short
time frame (Cabonce et al., 2021).
Challenges relating to transparency continue as a theme during initial implementation as
organizations try to align their strategies with regulatory expectations. Better clarity and
consistency can speed innovation because it can give the industry a better understanding of
expectations and milestones (Sharfstein et al., 2017). However, this was a stage in which the
consistency, clarity, and accessibility of FDA and notified bodies still appeared to be
problematic. Most respondents noted in their comments that the FDA and notified bodies had
inconsistent expectations and communication. As stated by one respondent,
The goal post keeps shifting, even when FDA agreement is in place through the
Qsub process. Global recognition is not complete & APAC region remains a
significant hurdle to developing a harmonized approach for global
submissions
Issues with transparency in general have long been of concern to regulators and industry.
In 2010, the FDA established a transparency task force to evaluate the need to modernize its
approach to communications around regulations and policies (Sharfstein et al., 2017). In a 2015
interview with Jeffrey Shuren, MD, FDA Center for Devices and Radiological Health, Dr.
Shuren discusses the significant work performed at CDRH to improve consistency and

157
transparency and acknowledges the continuing need for on-going improvements (Shuren, 2015).
The fact that some in this survey found it easier to work with a Notified Body than with the FDA
is also not surprising, because the notified bodies have a different relationship with industry
(Parker and Pryzgoda, 2020). The MDRs authorize the notified bodies to interpret the standards
and to work with manufacturers to ensure compliance before a submission is reviewed.
However, these are services for which the company pays, so companies often expect that the
notified bodies will be responsive and “on their side.” A similar relationship is not possible with
the FDA given the need for the FDA to also police the industry on behalf of the government
itself.
5.3.4 Full Implementation Stage
During full implementation, success relies on the ability to freeze new processes so that
future activities can be sustained efficiently (Hussain et al., 2018). Internal rather than external
supports are directed at maintaining the changes (Fixsen et al., 2013) and at seeking
opportunities to improve the new system, as needed (Bertram et al., 2015). At this point, one
would expect that needed changes are well understood and fully implemented. I was fortunate to
find that most respondents worked in companies that had reached the stage of full
implementation so that they could report on the success and problems with this stage.
Of the three documents most used in the US, companies continued to be most challenged
by ISO 10993-18. Perhaps this is because it is still not fully harmonized in the US and EU. When
it was partially recognized by FDA in July 2020, FDA changed its expectations for chemical
characterization and toxicological analysis, but many still see this transition as in flux (Crawford,
2020). Additionally, and as previously discussed, EU is still harmonizing this standard across

158
member states. “State of the art” testing is the expectation; however, the definition of “state of
the art” has yet to be fully defined (Cabonce et al., 2021).
Further, industry may interpret the standards differently from the regulators with respect
to when and how much chemical characterization testing must be performed. That they are
“covering their bets” seems clear from their feedback; most respondents observed that the
expected sequential ordering of chemical, toxicological, and animal testing occurred
“sometimes.” This finding may reflect the observations of others that the expected power of the
chemical characterization to offset biological testing has been less effective than it seemed to
promise. Chemical information alone cannot provide much insight into the effects of physical
factors on biocompatibility when a device occupies space in living tissue. The chemical data may
also be insufficient to address endpoints such as irritation, sensitization, pyrogenicity,
implantation, or hemocompatibility because gaps exist in chemical-specific toxicological
information (Sussman et al., 2022). Thus, many organizations appeared here to struggle
“moderately” or “very” often when trying to use chemical characterization and toxicological risk
assessment to justify limiting the amount of subsequent biological testing. For them, it might
make more sense to conduct some amount of animal testing in parallel with chemical
characterization, anticipating that it will be eventually needed. Such a strategy would help to
accelerate the testing program in case additional tests proved necessary from the results of the
toxicological assessment.
As previously discussed, an ideal state of full implementation will have well-run systems
and practitioners who have adjusted to using the new systems arising from the change (Bertram
et al., 2011). Six key elements or activities important when implementing the ISO 10993-1
standard over time were therefore examined to understand their degree of difficulty. One element

159
that stood out was the new requirement of ISO 10993-1:2018 to evaluate biocompatibility across
the complete product lifecycle. This is a relatively new requirement of ISO 10993-1:2018
(Weidmann, 2021) with very general wording: “The biological safety of a medical device shall
be evaluated by the manufacturer over the whole life-cycle of a medical device” (International
Organization for Standardization, 2020a) The updated FDA guidance document on use of ISO
10993-1 reinforces the requirement to characterize the biocompatibility of a medical device over
time by evaluating its biological performance throughout its life cycle (Rutledge, 2021).
Additionally, the relatively new MDR, which is still being implemented by the medical device
industry, includes new requirements to evaluate device safety across the product’s lifecycle
(Khorashahi and Agostino, 2021). However, the details of how to satisfy these new requirements
appear to be opaque to those in the trenches of industry and regulatory agencies. This
requirement may continue to be an area of challenge until a defined set of expectations and
practices has been established and a history of acceptance by the regulatory community is
achieved.
Many respondents also had problems trying to leverage tests from similar devices and
make persuasive justifications to avoid endpoint-specific testing. It can be difficult to leverage
tests from similar devices, because even minor differences between a new device and a
comparator can affect biocompatibility. For example, two different devices may be composed of
identical starting materials, but they may have different biocompatibility profiles because of
different downstream manufacturing steps or different residual cleaning or sterilizing agents. The
acceptability of these potential risks requires expert evaluation and depends on persuasive
justification from comparable results from a previously tested device. A similar situation exists
when trying to produce a persuasive justification to avoid endpoint-specific testing. Both types of

160
activities can be subjective and thus are vulnerable to conflicting interpretations of individual
reviewers (WuXi AppTec, 2020, Song, 2020). Less subjective, and indeed less challenging,
appeared to be two other types of activities: incorporating the history of clinical use/human
exposure data into risk assessment and evaluating interactions with packaging materials.
A similar ranking of challenges was identified when respondents were asked about their
experience with implementing the FDA guidance document; top on the list were struggles
associated with conducting chemical characterization and justifying how prior data could be used
to support biocompatibility. It is likely that additional time, experience, and alignment between
the medical device industry and the regulators will be needed before expectations around these
activities will stabilize (Song, 2021, Crawford, 2020). The results highlight the need for
continued interaction between industry and the regulatory agencies as well further clarification of
expectations to minimize “shifting targets” for meeting biocompatibility requirements
(Crawford, 2020).
Another important set of activities that base the new system of biocompatibility testing is
the need to collect comprehensive information about the medical device under development.
When asked about these activities, it was clear that more defined and objective data, such as that
associated with sterilization processes or materials of construction, were relatively easy to obtain.
Further, it appeared relatively easy for biocompatibility experts to analyze the literature and other
publicly available information. In contrast, respondents had more difficulty obtaining
information about chemical characterization/composition or about similar devices to leverage for
comparative purposes. This is not unexpected, as it reflects the highly competitive and
sometimes secretive nature of the medical device industry. For example, only partial information
on the chemical composition of the components making up a medical device may be available

161
from the vendors (Song, 2020), and complex manufacturing methods, such as in situ
polymerization, may unintentionally introduce chemicals that will not appear in the formulation
information alone (Sussman et al., 2022). When searching for a predicate device to leverage for
testing purposes, differences in cleaning or manufacturing processes can make it difficult to find
an acceptable predicate (Song, 2020). The survey results underline the importance of having
experienced biocompatibility experts who are deeply involved throughout the biocompatibility
safety evaluation process (Fenske, 2020) and who appreciate the need to understand the device in
its entirety, from the starting materials, throughout the manufacturing process, and then through
final sterilization and packaging (Song, 2020).
5.4 Conclusions and Recommendations
The primary regulatory requirements for the biocompatibility evaluation of medical
devices have changed significantly since 2018. These changes represent a significant shift in
biocompatibility testing philosophy and approach. The present study concludes that the medical
device industry has been significantly challenged to understand how to implement these new
standards and rules. Their previous “way of doing business” requires significant modification to
align with the evolving interpretations and expectations from the FDA and notified bodies.
Further, the new requirements impose demands on company resources that are often difficult to
align with budgets allocated by cost-sensitive senior management.
This research has shown that an implementation framework, such as described by Fixsen
and colleagues, provides a useful roadmap to evaluate the pressures and practices that can be
present as implementation proceeds (Bertram et al., 2015). By dissecting the activities in stages,
the results give insights into areas in which better planning or more effective communication
could reduce industries’ struggles with the new biocompatibility requirements. At the top of the

162
list appeared to be challenges of interpretation when standards are lacking in detail, compounded
when regulatory expectations are opaque or inconsistent. Unfortunately, the goal of the chemical
and toxicological analyses will not be achieved if companies feel that this testing does not
predictably allow the company to reduce its eventual animal testing burden. Until the new
requirements for chemical characterization and toxicological assessments prove their worth,
industry may continue to follow a hybridized approach to assure timely completion of animal
testing.
In the meantime, however, the results presented here illuminate areas in which
intervention might streamline implementation and improve alignment with regulatory
expectations. First would be greater consultation and communication between industry and
regulatory agencies. Although the FDA encourages companies to interact prior to the start of
biocompatibility testing, such meetings are slow to schedule and require burdensome
preparation. This may be one reason why industry is reluctant to engage with the regulators
through one-to-one conversations. It may be that a more educational approach through the new
Biocompatibility Resource Center or through more detailed guidance documents or FAQs might
help to clarify expectations in a more efficient way for both the regulators and the companies.
Such a publicly available resource could also help to reduce the inconsistencies that were
identified by many respondents in this study. Another opportunity for industry is to develop a
guideline for “best-in-class” implementation of international harmonized standards. This could
be facilitated by an industry group such as the Advanced Medical Technology Association
(AdvaMed) or Association for the Advancement of Medical Instrumentation (AAMI) and could
include both industry and regulators to collaborate and develop a recommended roadmap for
implementation of harmonized standards. Incorporating an implementation framework into the

163
roadmap and inserting key activities along the timeline would provide valuable guidance for
industry and would be especially useful to small and start-up medical device companies. A
further opportunity exists to have international harmonized standards, such as the
biocompatibility documents studied here, expanded to facilitate complete acceptance by most
regulatory agencies globally. This would allow for a common approach and strategy to
biocompatibility testing for use internationally.
A second area of concern throughout the early and middle stages of implementation is the
need to train and retain qualified personnel. Going forward, the shortage of experienced
biocompatibility experts will be exacerbated by the difficulties of training new experts. Most
reference texts on biocompatibility still focus on animal studies and a checklist approach; those
references will all require revision. Academic programs rarely cover biocompatibility testing to
any great extent, so that training is acquired mostly on the job. Unless efforts are expanded to
increase educational opportunities for a new generation of biocompatibility experts, companies
will find it hard to hire personnel with up-to-date knowledge and experience in this changing and
important area.
What might be interesting for future research is to understand if the experiences of
companies differ even when using the same biocompatibility testing strategy. This research
suggested that inconsistencies exist in regulatory approaches, but the nature of those
inconsistencies is still not completely clear. Another topic for future research is to understand
how far physical and chemical characterization and in vitro testing will be able to go, in the
current drive to replace animal use entirely. What would it take to create safe and effective
medical devices while eliminating the need for most, if not all, in vivo testing?

164
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device - aspects to be considered [Webinar], Society of Toxicology, 6 May. Available at:
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February 2022).
Williams, D. F. (1987) Definitions in biomaterials: Proceedings of a consensus conference of the
European Society for Biomaterials, Chester, England, March 3-5, 1986. Amsterdam,
N.Y.: Elsevier.
Williams, D. F. (2008) On the mechanisms of biocompatibility, Biomaterials, 29(20), 2941-
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Wu, F., Bills, E. L. and Eisner, J. (2019) Advancing regulatory science through comprehensive,
rational risk management, Biomedical Instrumentation & Technology, 53(1), 70-74.
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176
Appendices
Appendix A. Current Trends in Biocompatibility – Yartzoff Survey

177
Current Trends in Biocompatibility -
Yartzoff Survey

Start of Block: Default Question Block

Q1 GENERAL INFORMATION

Thank you for participating in this survey to examine challenges faced by the medical device
industry as it has dealt with changes in biocompatibility standards within the past 5 years. These
changes have redesigned biocompatibility testing into a two-stage process in which chemical
characterization is followed by a toxicological risk assessment prior to selection of biological
testing. Your responses are very important to this research, and will be kept confidential. The
survey results will be compiled and presented as part of the overall analysis. This survey
should take approximately 15 minutes to complete. If you cannot answer a question, please
feel free to skip or come back to it.

Q2 My functional role can best be described as ... (please select all that apply)
Biocompatibility testing (1)
Study Director (2)
Biocompatibility strategy development (3)
Regulatory Affairs (4)
New Product Development (R&D) (5)
Quality Assurance/Risk Management (6)
Toxicologist (7)
Other (please describe) (8) ________________________________________________

Q3 My current responsibilities are aligned most closely with the following function
Specialist (1)
Scientist (2)
Manager (3)
Director (4)
VP (5)
Other (please specify) (6) ________________________________________________

178

Q4 I have worked in some aspect of biocompatibility for ...
Under 2 years (1)
2 to 10 years (2)
More than 10 years (3)
I have no familiarity with biocompatibility (4)

Skip To: Q47 If I have worked in some aspect of biocompatibility for ... = I have no familiarity with
biocompatibility

Q5 I work for a company that is conducting or supporting biocompatibility studies on medical
devices.
Yes (1)
No (2)

Q6 My current organization is best described as a ...
Medical Device Manufacturer (1)
Contract Research Organization or Laboratory (2)
Consultancy to the Medical Device Industry (3)
Regulatory Agency or Notified Body (4)
Other (please specify) (5) ________________________________________________

Q7 Which statement best describes the size of your organization?
Small / Emerging (1 - 500 employees) (1)
Medium (501 - 2000 employees) (2)
Large (Greater than 2001 employees) (3)

Q8 How many marketing submissions for new products that include biocompatibility
assessments do you submit/support each year?
Less than 5 (1)
5 to 25 (2)
26 to 50 (3)
Greater than 50 (4)

179
Q9 Which classes of medical devices does your organization sell/support in the United States?
(choose all that apply)
in vitro diagnostic products (1)
Class 1 (2)
Class 2/3 (3)
We do not sell devices in the US (4)

Q10 Which classes of medical devices does your organization sell/support in Europe? (choose
all that apply)
in vitro diagnostics (1)
Class I (2)
Class IIa (3)
Class IIb/III (4)
We do not sell devices in the EU (5)

Q11 How do you rate your level of expertise of medical device biocompatibility?
Expert (1)
Intermediate (2)
Novice (3)

Q12 Please rate your level of experience implementing the following documents.
Expert (1) Intermediate (2) Novice (3)
Not familiar with
this document
(4)
ISO 10993-
1:2018 (1)

ISO 10993-
18:2020 (2)

FDA guidance
re 10993-1 (3)

180
Q13 What best describes the implementation timeline for the recently revised ISO 10993
standards in your company?

Already
implemented
fully (1)
In the process of
implementation
(2)
Still planning (3)
Have not begun
(4)
ISO 10993-
1:2018 (1)

ISO 10993-
18:2020 (2)

FDA guidance
re 10993-1 (3)

181
Q14 Please check all applicable boxes to describe the activities that your organization uses to
get an early understanding of biocompatibility standards and guidance documents.
ISO 10993-1:18 (1) ISO 10993-18:20 (2)
FDA Guidance
Document on 10993-
1 (3)
Involved with the
working group
making changes to
the document (1)

Read the early drafts
of the document (2)

Attended
conferences and
workshops about
biocompatibility (3)

Sought help from
external consultants
(4)

Read the final
document after
release (5)

Sought help from
outside laboratories
(6)

We did not do
anything (7)

Other (8)

182
Q15 How useful were the following resources when planning to implement the new systematic
approach to biological evaluation, where an initial toxicological risk assessment precedes
biological testing?

Most
preferred
source (1)
Very
useful (2)
Somewhat
useful (3)
Not useful
(4)
Did not
use (5)
Do not
know (6)
FDA guidance
document on
10993-1 (1)

ISO 10993-
1:18 (2)

Conferences/
trainings (3)

White
papers/articles
(4)

Information on
FDA/EMA
website (5)

Consultants
(6)

Colleagues (7)
Internet
search (8)

Other (9)

183
Q16 Please identify your agreement with the following statements suggested by others as
possible impediments to understanding the new biocompatibility regulations and approaches.

Strongly
Agree (1)
Somewhat
Agree (2)
Neither
agree nor
disagree
(3)
Somewhat
Disagree
(4)
Strongly
Disagree
(5)
Do not
know
(6)
We were unclear
where to go with
questions about the
revised
biocompatibility
standards or
guidance
documents. (1)

Speakers at
conferences were
unclear about
regulatory
expectations. (2)

We could not find
consultants who
understood the
requirements. (3)

Senior
management could
not provide
sufficient
resources. (4)

We did not see a
need to implement
the new standards
quickly. (5)

We were not aware
of changes to the
standards/guidance
documents. (6)

Other (7)

184
Q17 Do you agree with the following statements related to ISO expectations as possible
impediments to understanding the new biocompatibility approaches?

Strongly
Agree (1)
Somewhat
Agree (2)
Neither
agree nor
disagree
(3)
Somewhat
Disagree
(4)
Strongly
Disagree
(5)
Do not
know (6)
ISO 10993-
1:18 is not
sufficiently
detailed in its
expectations.
(1)

ISO 10993-
18:20 is not
sufficiently
detailed in its
expectations.
(2)

FDA
guidance
document on
use of ISO
10993-1 is
not
sufficiently
detailed in its
expectations.
(3)

Q18 Please comment on other issues that complicated your early exploration of the changing
biocompatibility standards and guidance documents.
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

185

Q19 Before EU medical device regulations (MDR) became active, what pre-planning did your
organization do to prepare for changes related to the new biocompatibility requirements ?
(select all that apply)
We read the early drafts of the regulations (1)
We attended conferences and workshops on new EU MDR (2)
We made changes to our organization (3)
We sought out help from external consultants (4)
Worked with our Notified Bodies (5)
We did not do anything (6)
Do not know (7)
Not relevant (8)
Other (please fill in) (9) ________________________________________________

Q20 In what ways did your organization plan/prepare to implement the newly revised
biocompatibility standards? (please select all that apply)

Had members on the ISO working groups (1)
Attended conferences and workshops (2)
Employed expert consultants (3)
Researched to understand upcoming changes (4)
Hired new staff with expertise on upcoming changes (5)
Held internal communication meetings to create awareness (6)
Made changes to our organization so we could be ready to implement the coming changes (7)
Built or expanded our internal laboratories (8)
Expanded relationships with outside laboratories (9)
Reached out to regulatory agencies/Notified Bodies (10)
Other (11) ________________________________________________

186
Q21 What parts of your organization were involved in your planning/preparation for upcoming
changes to the biocompatibility standards? (please select all that apply)
Regulatory Affairs (1)
Research & Development (2)
Biocompatibility/Pre-clinical (3)
Quality (4)
Operations (5)
Other (please describe) (6) ________________________________________________

Q22 How early did your organization start planning/preparing for changes to the following
biocompatibility standards and guidance documents?

Between 1 to 3
years in
advance of the
revision (1)
At the time that
the new revision
was
implemented (2)
At least one
year after the
new revision
was
implemented (3)
Implementation
is still incomplete
(4)
ISO 10993-1:18
(1)

ISO 10993-
18:20 (2)

FDA 2020
guidance
document on
use of ISO
10993-1 (3)

MDR
Biocompatibility
requirements (4)

Q23 Were you satisfied with your company's preparation to transition to the new
biocompatibility requirements?
Extremely satisfied (1)
Somewhat satisfied (2)
Neither satisfied nor dissatisfied (3)
Somewhat dissatisfied (4)
Extremely dissatisfied (5)

187

Q24 Please rank the following changes that your organization made to be ready to implement
the recently revised ISO 10993-1:2018 biocompatibility standard and the FDA Guidance
Document on use of ISO 10993-1.

Most important
(1)
Very important
(2)
Slightly
important (3)
Not at all
important (4)
Changed
procedures or
controlled
documentation
(1)

Changed the
quality system
(2)

Added or
changed office
space (3)

Set up contracts
or agreements
with new
vendors (4)

Developed a
budget for
implementation
(5)

Expanded lab
capabilities and
capacity (6)

Hired new staff
(7)

Hired
consultant(s) (8)

Other (fill in) (9)

188
Q25 Please rank the following changes that your organization made to be ready to implement
the recently revised ISO 10993-18:2020 chemical characterization standard.

Most important
(1)
Very important
(2)
Slightly
important (3)
Not at all
important (4)
Revised
procedures or
controlled
documentation
(1)

Changed the
quality system
(2)

Added or
changed office
space (3)

Set up contracts
or agreements
with new
vendors (4)

Developed a
budget for
implementation
(5)

Expanded lab
capabilities and
capacity (6)

Hired new staff
(7)

Hired
consultant(s) (8)

Other (fill in) (9)

189
Q26 How frequently has your organization held early stage meetings with regulators before
transitioning to new approaches with biocompatibility strategies?
Very often (1) Infrequently (2) Almost never (3) Not at all (4)
Notified Body
(NB) (1)

FDA (2)

Q27 At what stage has your organization held early stage meetings with regulators before
transitioning to new approaches to biocompatibility strategies?

Very often
(1)
From time to
time (2)
Infrequently
(3)
Almost
never (4)
Not at all (5)
With FDA
before changing
internal
biocompatibility
strategies (1)

With FDA after
finding
difficulties with
pilot
implementations
(2)

With Notified
Body before
changing
internal
biocompatibility
strategies (3)

With Notified
Body after
finding
difficulties with
pilot
implementations
(4)

Other (please
describe) (5)

190

Q28 Please identify the level of participation of listed stakeholders when planning for the
implementation of revisions to biocompatibility standards in my company.

Strong
participation
(1)
Moderate
participation
(2)
Slight
participation
(3)
No
participation
(4)
Pre-
clinical/Biocompatibility
(1)

RA (2)
R&D (3)
QA (4)
FDA (5)
Notified Body (6)
Other (please
describe) (7)

Q29 In retrospect would you have done something differently to prepare your organization for
implementation?
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

191
Q30 How difficult was it for your organization to implement its pilot approaches to the new
biocompatibility requirements?

Extremely
easy (1)
Moderately
easy (2)
Neither
easy nor
difficult
(3)
Moderately
difficult (4)
Extremely
difficult (5)
Do not
know (6)
ISO 10993-
1:18 (1)

ISO 10993-
18:20 (2)

FDA 2020
Guidance re
10993-1 (3)

MDR
Biocompatibility
requirements
(4)

Q31 What were the principal challenges that your organization faced during the pilot phase?
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

192
Q32 Please rank the difficulties that your organization may have had with initial
implementation of the recently revised ISO 10993-1 biocompatibility standard and FDA
guidance document on the use of ISO 10993-1.

Extremely
easy (1)
Moderately
easy (2)
Neither
easy nor
difficult
(3)
Moderately
difficult (4)
Extremely
difficult (5)
Do not
know (6)
Understanding
the revised
standard (1)

Having
sufficient
resources to
implement
fully (2)

Obtaining
support from
areas of my
organization
(3)

Aligning with
expectations
of the FDA or
Notified
Bodies (4)

Having
sufficient CRO
or internal
capacity (5)

Q33 Did your organization have other issues with initial implementation of the recently revised
ISO 10993-1 biocompatibility standard and FDA guidance document on the use of ISO 10993-
1, that are not identified in the question above?
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

193
________________________________________________________________

Q34 How difficult were your first attempts at implementing the recently revised ISO 10993-18
chemical characterization standard?

Extremely
difficult (1)
Somewhat
difficult (2)
Neither
easy nor
difficult
(3)
Somewhat
easy (4)
Extremely
easy (5)
Do not
know (6)
Understanding
the revised
standard (1)

Having
sufficient
resources to
fully
implement (2)

Obtaining
support from
areas of my
organization
(3)

Aligning with
expectations
of the FDA (4)

Aligning with
expectations
of Notified
Bodies (5)

Having
sufficient CRO
or internal
capacity (6)

Q35 Did you have other issues with your first attempts at implementing the recently revised ISO
10993-18 that are not identified in the question above?
________________________________________________________________
________________________________________________________________

194
________________________________________________________________
________________________________________________________________
________________________________________________________________

Q36 How useful were the following activities during initial implementation of biocompatibility
changes?

Extremely useful
(1)
Moderately
useful (2)
Slightly useful
(3)
Not at all useful
(4)
Internal
communication
and awareness
meetings (1)

Communication
with FDA and
Notified Bodies
(2)

Managing the
change using
project
management
techniques (3)

Outside
education or
training (4)

Other (please
describe) (5)

195
Q37 Please rate the following statements when your organization was implementing changes
to biocompatibility standards.

Strongly
Agree (1)
Somewhat
Agree (2)
Neither
agree nor
disagree
(3)
Somewhat
Disagree
(4)
Strongly
Disagree
(5)
Do not
know (6)
FDA had
consistent
expectations
(1)

Notified Bodies
had consistent
expectations
(2)

FDA was
transparent in
communicating
changes and
expectations
(3)

Notified Bodies
were
transparent in
communicating
changes and
expectations
(4)

FDA was
easily
accessible to
communicate
on-going
changes and
evolving
expectations
(5)

Notified Bodies
were easily
accessible to
communicate
on-going
changes and
evolving
expectations
(6)

196

Q38 Please rate your organization's level of implementation for the following standards:

Fully
implemented (1)
Partially
implemented (2)
Not
implemented (3)
Don't know
about
implementation
(4)
ISO 10993-1:18
(1)

ISO 10993-
18:20 (2)

FDA Guidance
Document on
use of ISO
10993-1 (3)

Other (4)

Q39 How would you characterize your organization's current understanding of the following
standards?
Fully understands (1)
Somewhat
understands (2)
Does not understand
(3)
ISO 10993-1:18 (1)
ISO 10993-18:20 (2)
FDA Guidance
Document on use of
ISO 10993-1 (3)

197
Q40 How challenging were the following elements when fully implementing the ISO 10993-1
standard (select all that apply)?

High
challenge (1)
Moderate
challenge (2)
Low
challenge (3)
No challenge
(4)
Do not know
(5)
Evaluating
biocompatibility
across the
lifecycle (1)

Incorporating
history of
clinical
use/human
exposure data
into risk
assessment (2)

Evaluating
interactions
with packaging
materials (3)

Making
persuasive
justifications to
avoid endpoint-
specific testing
(4)

Leveraging
tests from
similar devices
(5)

Using chemical
characterization
data in a
biological
evaluation (6)

Other (please
describe) (7)

198
Q41 How aligned are your current biocompatibility strategies with the ISO 10993-1:2018
roadmap of performing physical characterization, chemical characterization and a toxicological
risk assessment, prior to conducting biological testing?
We almost always follow the roadmap sequentially (1)
We follow the roadmap sometimes; the rest of the time, we perform some of the steps
concurrently. (i.e. biological and chemical testing at the same time) (2)
We seldom follow the roadmap sequentially (3)
Other (please describe) (4) ________________________________________________
N/A I do not know (5)

Q42 In what areas has your organization struggled with the 2020 FDA guidance document on
use of 10993-1 (select all that apply )?

Using publicly available information to identify and mitigate risks (1)
Conducting chemical characterization (2)
Identifying tests for non-standard medical devices (e.g.; nanotechnology) (3)
Leveraging biocompatibility information from marketing applications of other manufacturers (4)
Where differences exist, justifying how prior data can support biocompatibility (5)
Justifying tests of representative components rather than devices in final finished form (6)
Addressing biocompatibility test failures (7)
Modifying test protocols for devices with special needs (e.g., extractions) (8)
Other (please describe) (9) ________________________________________________

Q43 How difficult was it to get sufficient information in the following areas related to
biocompatibility safety assessments ?

199

Easy to get
(1)
Difficult to get
(2)
Nearly
impossible to
get (3)
Do not know
(4)
Literature and other publicly
available information (1)

Clinical experience (2)
Animal study experience (3)
Materials of construction (4)
Manufacturing processes (5)
Sterilization processes (6)
Similar devices to leverage
for comparative purposes
(7)

Chemical
characterization/composition
(8)

Q44 How frequently does your organization struggle with the use of chemical characterization,
followed by a toxicological risk assessment to justify limiting the amount of biological testing
performed?
We very often struggle (1)
We moderately struggle (2)
We almost never struggle because our devices require very few biological tests or does not
require chemical characterization. (3)
We almost never struggle because we run the full range of chemical characterization and
biological testing at the same time. (4)
We almost never struggle because my organization does not know how to use chemical
characterization and toxicological risk assessment to limit biological testing. (5)
I do not know (6)

200
Q45 What unexpected outcomes has your organization experienced as you have interacted
with regulators following implementation of changing biocompatibility standards? (please
choose all that apply)

Inconsistencies
in interpreting or
applying
biocompatibility
standards. (1)
Varying
opinions from
different
reviewers (2)
Requests for
biocompatibility
related actions
not defined as
requirements in
biocompatibility
standards. (3)
“Raising the bar”
over time on
expectations
related to
biocompatibility
strategies. (4)
Interactions with
the FDA (1)

Interactions with
a Notified Body
(2)

Q46 Do you have additional comments to share on unexpected outcomes that your organization
has experienced as it has interacted with regulators following implementation of changing
biocompatibility standards.
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

Q47 Thank you for participating in this survey. Your time is valuable and we appreciate your
help.

End of Block: Default Question Block

Abstract (if available)

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Asset Metadata

Creator Yartzoff, Michael Andrew (author)

Core Title Current practices in biocompatibility assessment of medical devices

School School of Pharmacy

Degree Doctor of Regulatory Science

Degree Program Regulatory Science

Degree Conferral Date 2022-08

Publication Date 05/06/2022

Defense Date 04/06/2022

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag biocompatibility,chemical characterization,FDA Guidance Document on use of ISO 10993-1,ISO 10993-1,ISO 10993-18,medical devices,OAI-PMH Harvest

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Richmond, Frances (committee chair), Bain, Susan (committee member), Cosenza, Mary Ellen (committee member), Davies, Daryl (committee member)

Creator Email mayspock@aol.com,yartzoff@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-oUC111271664

Unique identifier UC111271664

Document Type Thesis

Format application/pdf (imt)

Rights Yartzoff, Michael Andrew

Type texts

Source 20220506-usctheses-batch-939 (batch), University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

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Repository Name University of Southern California Digital Library

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