Chemical

Characterization of
Medical Devices
Ensuring Chemical Safety of Medical Devices

White paper

Abstract
Today’s medical devices typically incorporate a variety of components comprised of advanced polymers,
nanomaterials, and other types of compounds. These materials can offer many significant benefits, such
as reduced component size and increased durability. But each material also introduces unique chemical
and physical characteristics that can potentially impact the health and safety of patients and healthcare
professionals.

TÜV SÜD America

TÜV SÜD | Weathering the Storm 1
Contents
ABOUT THE TÜV SÜD EXPERT......................................................................................................................................... 2

1 INTRODUCTION............................................................................................................................................................ 3

2 THE CHEMICAL CHARACTERIZATION PROCESS.......................................................................................................... 4

3 THE IMPORTANCE OF CHEMICAL CHARACTERIZATION IN THE ASSESSMENT OF MEDICAL DEVICES................... 4

4 ESTABILISHING CHEMICAL INFORMATION IS A CONDITION OF APPROVAL FOR MOST MEDICAL DEVICES.......... 5

5 KEY INDUSTRY STANDARDS THAT ADDRESS THE CHEMICAL CHARACTERIZATION PROCESS.............................. 7

6 ISO 10993-18 AND THE CHEMICAL CHARACTERIZATION PROCESS......................................................................... 9

7 STEPS MANUFACTURERS CAN TAKE TO HELP ENSURE THE CHEMICAL SAFETY OF MEDICAL DEVICES............... 12

8 HOW TÜV SÜD CAN HELP............................................................................................................................................. 13

About the Expert

Christine Laube
Medical Product Expert and Biological/Analytical Testing Specialist

Christine Laube has over 14 years of experience in microbiology testing

and the medical device industry. In her current role as Medical Product
Expert and Biological/Analytical Testing Specialist at TÜV SÜD,
Christine is responsible for technical documentation review of MDR
submissions and facilitating biological and chemical testing services.

2 Chemical Characterization of Medical Devices | TÜV SÜD America

1. Introduction

Today’s medical devices typically incorporate a variety of components comprised of advanced polymers,
nanomaterials, and other types of compounds. These materials can offer many significant benefits, such as
reduced component size and increased durability. But each material also introduces unique chemical and physical
characteristics that can potentially impact the health and safety of patients and healthcare professionals.

The chemical characterization of materials is an essential aspect of the regulatory review and approval of medical
devices in the U.S., the European Union (EU), and most major markets around the world. But, given the complexity
of the regulatory process, many device manufacturers are unaware of chemical characterization requirements, or
don’t have a complete understanding of how the requirements apply to their devices. This can lead to interruptions
in the approval process, and result in delays in bringing their medical devices to market.

In this white paper, we’ll discuss the specifics of the chemical characterization process, and the importance of
chemical characterization in the overall evaluation of medical device safety. We’ll also discuss some specific
actions that device manufacturers can take to help ensure the chemical safety of their devices.

TÜV SÜD |America

Weathering
| Chemical
the Storm
Characterization of Medical Devices 3 3
2. The Chemical Characterization Process
Chemical characterization is a The chemical characterization They can also provide critical
process that analytically identifies and process uses a variety of evaluation information about the nature and
quantifies the constituent chemicals technologies and methods, such extent of potential health, safety, or
of a specific material or component. as microscopic and spectroscopic environmental risks that may occur
The process is used to assess a wide analysis, x-ray diffraction, and with the use of such materials over
variety of different products, including chromatography. These and their entire lifecycle.
food and food packaging, modules other techniques can provide
and components found in electronic detailed information regarding a
devices, and toys and garments material’s chemical formulation,
intended for use by children and the purity of chemical composition,
infants. or the presence of impurities or
degradants.

3. The Importance of Chemical Characterization

in the Assessment of Medical Devices
By design, most medical devices Routine disinfection and sterilization For these reasons, chemical
perform their functions through direct processes may also expose medical characterization may be used to
contact or through implantation in devices to substances that could come identify and quantify chemical
the body. Some medical devices in contact with the patient. substances found in medical devices
have indirect contact with the body or materials that may contribute to
through gas pathway, like ventilators, An additional consideration is that, the toxicological and biological risk
or blood pathway, like dialysis over time, through storage or intended management for the device.
machines. Therefore, the importance use, the structural integrity of medical
of evaluating the potential health device components and materials Chemical characterization is an
and safety risks associated with the can be compromised, resulting in the important aspect of the overall
chemicals used in medical devices unintended extraction or leaching biocompatibility assessment process,
cannot be overstated. of chemicals from a device into the which helps ensure that the potential
patient. benefits offered by the use of a given
Exposure to chemicals in medical medical device are not outweighed
devices originates from various Adverse reactions in patients from by the potential biological risks
aspects of device development chemical exposure range from mild associated with that device or its
and use. Chemical substances are allergic reactions, pain, or discomfort components or materials.
routinely used in the composition to more serious medical conditions.
of medical device components and In some cases, chemical exposure
materials. Hazardous chemical could contribute to the rejection of an
exposure could occur from the implanted device by the patient’s body.
constituent chemicals of the device,
or residual process aids used during
the device’s manufacture, such as
lubricants or cleaners.

4 Chemical Characterization of Medical Devices | TÜV SÜD America

4. Establishing Chemical Information is a
Condition of Approval for Most Medical Devices
As part of the biocompatibility assessment process, information on the chemical composition of medical device and
materials intended to come into direct or indirect contact with a patient must be provided to order to obtain regulatory
approval in the U.S. and the EU.

The U.S. Food and Drug Administration (FDA) requires the submission of chemical characterization data as part of its
review of Premarket Applications (PMAs), Premarket Notifications (510(k)s), De Novo applications, and other types of
medical device review requests submitted to the agency. Chemical characterization data is then used to determine the
potential for an unacceptable adverse biological response in a patient resulting from contact between medical device
component and the body.

A 2020 FDA Guidance offers additional clarification on its requirements for the chemical assessment of medical
devices:

“(The) FDA evaluates the safety of medical devices based on duration of

exposure and nature of contact. Inherent in the review of medical devices is an
understanding of the body’s entire exposure to the medical device, including all
chemical entities contained within the device. For devices where the patient-
contacting portions may contain potentially toxic chemicals, the evaluation of
safety should include both chemical risk (i.e., the level of toxicological concern)
and the type and duration of exposure.”¹

TÜV SÜD America | Chemical Characterization of Medical Devices 5

4.1 Reviewing Medical Devices
In reviewing some medical devices, Such justification regarding the
including those made from new Article 10.1 indicates that particular presence of CMR and/or endocrine-
materials that have never been attention should be paid to “the disrupting substances must be based
previously used in a medical devices, choice of materials and substances on:
the FDA may also require data from used, particularly as regards toxicity 1) an analysis and estimation of
toxicity testing to better understand and, where relevant, flammability” potential patient or user exposure to
and evaluate the toxicological risk (Clause a); and “the compatibility the substance;
presented by a given device. The FDA between the materials and 2) an analysis of possible alternative
may also seek additional chemical substances used and biological substances, materials, or designs;
testing data for medical devices that tissues, cells, and body fluids, taking and 3) the rationale for why the
incorporate materials that can change account of the intended purpose use of substitute materials would
over time, such as absorbable or of the device and, where relevant, compromise the functionality,
degradable materials. absorption, distribution, metabolism, performance, or benefit-risk ratio of
and excretion.” (Clause b). the device.
In the EU, Annex I of Regulation (EU)
2017/745² (also known as the Medical Further, Article 10.4.1 of the MDR Meeting the EU’s MDR’s requirements
Device Regulation, or MDR) details requires that medical device on the use of materials and
general safety and performance manufacturers must demonstrate substances with potentially harmful
requirements for medical devices, justification for the use substances chemicals means that manufacturers
including requirements regarding the which are carcinogenic, mutagenic must provide sufficient information
chemical, physical, and biological or toxic to reproduction (CMR), and analysis of the chemicals used
properties of a device. Annex I, Chapter or substances having endocrine- in the manufacturing of their devices.
II, section 10.2 expressly requires disrupting properties for which there Chemical characterization testing
that medical devices be “designed, is scientific evidence of probable and techniques to validate the
manufactured, and packaged in such serious effects to human health in presence and quantity of chemical
a way as to minimize the risk posed by concentrations above 0.1% by weight. substances may be utilized to support
contaminants and residues to patients, the justification for using selected
taking account of the intended purpose materials in their medical devices.
of the device.”

Meeting the EU’s MDR’s requirements on the use of materials

and substances with potentially harmful chemicals means that
manufacturesr must provide sufficient information and analysis
of the chemicals used in the manufacturing of their devices.

6 Chemical Characterization of Medical Devices | TÜV SÜD America

 5. Key Industry Standards that Address the
Chemical Characterization Process
The biological evaluation of medical devices, With that information, the manufacturer can
including the possible use of the chemical then take necessary steps to eliminate or
characterization process, is the focus of the mitigate that risk in their device.
ISO 10993 series of standards. Comprised of
more than 20 individual documents, the series ISO 10993-1, “Biological evaluation of medical
provides detailed information on aspects of devices – Part 1: Evaluation and testing within
the biological evaluation process, and serves a risk management system,”³ is the general
as a basis for medical device biocompatibility standard in the ISO 10993 series. Published
requirements in most jurisdictions. in late 2018, the 5th Edition of the standard
establishes the overall framework for planning
The range of biological hazards associated and executing a biological evaluation process
with a medical device depends on a number to assess the safety of a medical device.
of factors, including the intended use of
the device, the composition of device
materials, and even health vulnerabilities of
individual patients. Therefore, the ISO 10993
standards are not prescriptive. Instead, they
require device manufacturers to adopt a Figure 1 in ISO 10993-1, “Summary of
risk management approach, in which every the systematic approach to a biological
potential biological risk is identified, and evaluation of medical devices as part of
then thoroughly analyzed and evaluated to a risk management process,” presents a
determine the likelihood and the potential detailed decision analysis flowchart of that
severity of the risk. process.

FIGURE 1 ISO 10993-1 Flowchart

TÜV SÜD |America

Weathering
| Chemical
the Storm
Characterization of Medical Devices 7
 Section 6 in the standard, “Biological evaluation process,” discusses how the physical and chemical characterization
processes fit within the overall biological evaluation of a medical device as shown in Figure 1. Specifically, the standard
states that:

“Gathering physical and chemical information on the medical device or

component is a crucial first step in the biological evaluation and its associated
process of material characterization…

The extent of physical and/or chemical characterization required depends on

what is known about the material formulation, what nonclinical and clinical
safety and toxicological data exists, and on the nature and duration of body
contact with the medial device. At a minimum, the characterization shall address
the constituent chemicals of the medical device and possible residual process
aids or additives used in its manufacturer…

Material characterization, if performed, shall be conducted in accordance with

ISO 10993-18.”

Annex B of ISO 10993-1, “Guidance on the conduct of biological evaluation within a risk management process,” also
expressly references the role of chemical characterization as a method for accounting for the safety of “intended
additives, process contaminants, residues and leachable substances” in the overall biological evaluation. Specifically,
chemical characterization “can be useful in selecting appropriate biological evaluation tests,” as well as for estimating the
anticipated risk associated with exposure to individual chemicals.

Other individual standards in the ISO 10993 series that apply to the chemical characterization process include:

ISO 10993-12

“Biological evaluation of medical devices – Part 12: Sample preparation and reference materials,” specifies requirements
for the selection of reference materials and the preparation of samples for biological and chemical characterization testing.

ISO 10993-17

“Biological evaluation of medical devices – Part 17: Establishment of allowable limits for leachable substances,” details the
process for determining allowing limits for substances leachable from medical devices in cases where such limits do not
exist.

ISO 10993-18

“Biological evaluation of medical devices – Part 18: Chemical characterization of medical device materials within a risk
management process,” provides a framework for identifying and quantifying material composition of a medical device,
including chemicals and other ingredients.

8 Chemical Characterization of Medical Devices | TÜV SÜD America

Each of the ISO 10993 standards expressly encourages device manufacturers to review and use existing biological safety
data from all available sources, such as prior scientific research and studies, to determine what additional testing might
be required, if any, and to eliminate unnecessary testing.
The standards also emphasize the preference for in vitro test models over in vivo methods to minimize the use of
animal-based testing.

6. ISO 10993-18 and the Chemical

Characterization Process
ISO 10993-18 lays out requirements for conducting a chemical characterization of a medical device to support claims
regarding its overall biological safety. According to the standard, the goal of chemical characterization is to provide
detailed information on the identities and quantities of:

The materials used in constructing a medical device;

 The chemical constituents in each material;

The chemical substances used in the device’s manufacturing process; and

The potential of the device as constructed and manufactured to release chemical substances to which
patients and device uses might be exposed.

TÜV SÜD America | Chemical Characterization of Medical Devices 9

Section 5 of the standard, “Characterization procedure,” details each of the steps in the characterization process, as
follows:

Section 5.2
“Establish medical device configuration and material composition”—Describe the configuration, intended purpose,
and clinical use of a medical device, including the individual materials used in the construction of a device, the
proportion of those materials used (either by surface area or weight), and its physical structure. Address any gaps in
the configuration and composition data.

Section 5.3
“Assess material/chemical equivalence to a clinically established material or medical device”—Use the information
compiled in Section 5.2 to determine whether a device is equivalent to a previously approved medical device. If
equivalence is verified, no further analysis or testing is required.

Section 5.4
“Assess the hypothetical worst-case chemical release based on total exposure to the medical device’s chemical
constituents”—Again, using the information compiled in Section 5.2, establish the hypothetical worst-case chemical
release and determine the potential health impact of such a release on a patient. If total exposure is determined to be
acceptable, no further testing or analysis is required.

Section 5.5
“Establish an analytical evaluation threshold”—Calculate and verify the analytical evaluation threshold (AET) for the
device. The process for AET is detailed in Annex E of the standard.

Section 5.6
“Estimate the chemical release; perform extraction study”—Conduct an extraction study to identify and quantify
chemical extractables for toxicological risk. ISO 10993-17 details the process for conducting an extraction study.

Section 5.7
“Assess the estimated chemical release (extractables profile)”—Summarize and report the results of the extraction
study in order to assess the risk attributable to each identified extractible.

Section 5.8
“Determine the actual chemical release; perform leachables study”—In some cases, potentially unsafe quantities
of an extractable released from a medical device may be attributable the exaggerated extraction conditions in an
extractables study. If applicable, a leachables assessment using actual or accelerated extraction conditions, such
as elevated temperature, etc., may be more clinically relevant.

Section 5.9
“Assess the actual chemical release (leachables profile)”—Summarize and report the results of the leachables
study in order to assess the risk attributable to each identified leachable.

10 Chemical Characterization of Medical Devices | TÜV SÜD America

 Figure 1 in ISO 10993-18, “General chemical characterization process,” provides a high-level visual, step-by-step
representation of this chemical characterization process within the overall biological evaluation assessment
described in the standard.

FIGURE 1: ISO 10993-18 Flowchart

TÜV SÜD America | Chemical Characterization of Medical Devices 11

The chemical characterization ISO 10993-18 makes clear that
process is deemed completed “chemical characterization alone
when its findings support claims can be insufficient to establish the
of equivalence with a previously equivalence or biocompatibility of
approved medical device, or when the materials and medical devices and
toxicological risk assessment verifies cannot unilaterally substitute for
that any extractables or leachables biological testing.” However, the
identified present an acceptable standard goes on to point out that
health risk. Otherwise, further chemical characterization as part
biological testing is required to assess of an effective risk management
and verify device biological safety. assessment may reduce the need
for certain biological testing.

7. Steps Manufacturers Can Take to Help Ensure

the Chemical Safety of Medical Devices
Conducting a chemical characterization It can also reduce the risk of product It also reduces the chances
consistent with the requirements recalls stemming from unanticipated of discovering unanticipated
of ISO 10993-18 is a critical aspect safety concerns that emerge during issues related to chemical safety
of a manufacturer’s overall effort to the device’s actual use. late in the development cycle
the verify the safety of their medical and disrupting time-to-market
devices. A thorough evaluation of the Manufacturers are encouraged to schedules.
chemical safety of device components integrate chemical characterization
and materials can increase the efforts into their device development Often, device manufacturers find it
likelihood of a smooth and efficient process. Chemical characterization necessary to change suppliers of
regulatory review process. in the early stages of new product critical materials and components.
design allows developers to
proactively address potential safety
considerations.

12 Chemical Characterization of Medical Devices | TÜV SÜD America

Even when materials and Finally, systems, equipment, and
components from new suppliers processes used to manufacture
meet a manufacturer’s specifications, medical devices can change over
there may be subtle but important time. Even something as simple as
differences in the chemical modifying the equipment cleaning
composition of those products. process can impact the chemical
In such situations, chemical profile of individual components
characterization can help confirm and materials. Conducting routine
chemical equivalence, or signal the chemical characterization following
need for additional biocompatibility such changes can verify that they
testing. have not impacted the chemical
safety of a device.

8. How TÜV SÜD Can Help

TÜV SÜD offers medical device manufacturers chemical testing services and product evaluation solutions to meet
various regulations and directives around the world. Specifically, we provide chemical testing services consistent with
the requirements of the ISO 10993 series of standards. These include ISO 10993-18 on the chemical characterization of
materials, and ISO 10993-17, that addresses toxicological risk assessment.

We support the efforts of medical device manufacturers by helping them to understand the chemical characterization
process, and by discussing test outcomes in the context of global regulatory requirements. Our global team of medical
device experts bring decades of technical knowledge and practical experience to their work and stays current on the
ever-changing regulatory landscape through their active involvement in relevant standards development efforts. These
qualifications allow TÜV SÜD to bring unmatched technical expertise to chemical characterization processes, and to
provide our clients with the highest quality medical device safety solutions.

13 SÜD | Weathering the Storm

TÜV Chemical Characterization of Medical Devices | TÜV SÜD America
13
 Sourcing:
[1] “Use of International Standard ISO 10993-1, ‘Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management
process,’” Guidance issued by the U.S. Food and Drug Administration, September 4, 2020. Available at https://www.fda.gov/media/85865/download (as of
January 7, 2021).

[2] “Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation
(EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC.” Available at https://eur-lex.europa.eu/
legal-content/EN/TXT/?uri=CELEX%3A32017R0745 (as of January 7, 2021).

[3] ISO 10993-1 “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process,” Fifth edition, 2018. Available
at www.iso.org (as of January 7, 2021)

COPYRIGHT NOTICE
The information contained in this document represents the current view of TÜV SÜD on the issues discussed as of the date of publication. Because TÜV SÜD must respond to changing market
conditions, it should not be interpreted to be a commitment on the part of TÜV SÜD and TÜV SÜD cannot guarantee the accuracy of any information presented after the date of publication.

This White Paper is for informational purposes only. TÜV SÜD makes no warranties, express, implied or statutory, as to the information in this document. Complying with all applicable copyright
laws is the responsibility of the user. Without limiting the rights under copyright, no part of this document may be reproduced, stored in or introduced into a retrieval system, or transmitted in any
form or by any means (electronic, mechanical, photocopying, recording, or otherwise), or for any purpose, without the express written permission of TÜV SÜD. TÜV SÜD may have patents, patent
applications, trademarks, copyrights, or other intellectual property rights covering subject matter in this document. Except as expressly provided in any written license agreement from TÜV SÜD,
the furnishing of this document does not give you any license to these patents, trademarks, copyrights, or other intellectual property. ANY REPRODUCTION, ADAPTATION OR TRANSLATION OF
THIS DOCUMENT WITHOUT PRIOR WRITTEN PERMISSION IS PROHIBITED, EXCEPT AS ALLOWED UNDER THE COPYRIGHT LAWS. © TÜV SÜD – 2019 – All rights reserved.

DISCLAIMER
All reasonable measures have been taken to ensure the quality, reliability, and accuracy of the information in the content. However, TÜV SÜD is not responsible for the third-party content
contained in this publication. TÜV SÜD makes no warranties or representations, expressed or implied, as to the accuracy or completeness of information contained in this publication.
This publication is intended to provide general information on a particular subject or subjects and is not an exhaustive treatment of such subject(s). Accordingly, the information in this
publication is not intended to constitute consulting or professional advice or services. If you are seeking advice on any matters relating to information in this publication, you should –
where appropriate – contact us directly with your specific query or seek advice from qualified professional people. TÜV SÜD ensures that the provision of its services meets independence,
impartiality and objectivity requirements. The information contained in this publication may not be copied, quoted, or referred to in any other publication or materials without the prior
written consent of TÜV SÜD. All rights reserved © 2019 TÜV SÜD.

14 Weathering
Chemical Characterization of Medical Devices the Storm
| TÜV SÜD| TÜV SÜD
America
Learn about the services we provide for the
healthcare and medical device industry.
https://www.tuvsud.com/en-us/industries/healthcare-and-medical-devices
[email protected]

Add value. Inspire trust.

TÜV SÜD is a trusted partner of choice for safety, security and sustainability solutions. It specialises in testing,
certification, auditing and advisory services. Since 1866, the company has remained committed to its purpose of
enabling progress by protecting people, the environment and assets from technology-related risks. Through more than
24,000 employees across over 1,000 locations, it adds value to customers and partners by enabling market access
and managing risks. By anticipating technological developments and facilitating change, TÜV SÜD inspires trust in a
physical and digital world to create a safer and more sustainable future.

2021 © TÜV SÜD AMERICA | MKG/MHS/1.0_en_US

GLOBAL HEADQUARTERS TÜV SÜD AMERICA

TÜV SÜD AG HEADQUARTERS
Westendstr. 199 TÜV SÜD America Inc.
80686 Munich Germany 10 Centennial Drive
+49 89 5791 0 Peabody, MA 01960
www.tuv-sud.com United States of America
+1 978 573 2500

TÜV SÜD | Weathering the Storm 15