GRADUATE SCHOOL OF BIOMEDICAL ENGINEERING

BIOM 9410 REGULATORY REQUIREMENTS OF MEDICAL TECHNOLOGY

BIOM 9410

REGULATORY REQUIREMENTS OF MEDICAL

TECHNOLOGY

Module 3

The Regulatory Requirements associated with

Biocompatibility

LEARNING OUTCOMES
At the end of this module, you should be able to

• Provide an overview of the concept of biocompatibility

• Describe the regulatory requirements associated with biocompatibility testing

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INTRODUCTION
Refer back to the Medical Device Product Development and Marketing Map
presented in Module 1 and the description of GLP in Module 2. The information in
this module relates to one of the wide range of tests that are carried out according to
GLP at an early stage of the development of a medical device.

Imagine that basic research at the university or research institution has resulted in a
product concept. In the product development and nonclinical testing stage, these
ideas and concepts are turning into design specifications, prototype devices and a
set of preferred materials for manufacture. In order to determine the safety and
efficacy of these devices, a wide variety of tests are performed on the prototypes and
the materials that have been selected for use in manufacture and one range of tests
performed relates to the “biocompatibility” of the device.

For those of you who haven’t done the Biocompatibility course, let’s discuss what
biocompatibility is first. Unfortunately, there is no single, all-encompassing
description of biocompatibility. In the book, Biological performance of materials:
fundamentals of biocompatibility (1992), Jonathan Black describes biocompatibility
as “biological performance in a specific application that is judged suitable to that
situation”. David Williams in his book, The Williams Dictionary of Biomaterials
(1999), says it is “the ability of a material to perform with an appropriate host
response in a specific application”.

So biocompatibility is “suitable” or “appropriate” biological performance. It is

important to understand that it does not necessarily imply inertness but, rather,
behaviour that is suitable or appropriate to the situation.

Biological performance is how biomaterials and living systems interact and

comprises two major components:

1. Material responses or how the biomaterial responds to the living system and

2. Host or living system responses or how the living system responds to the
material (other than the intended therapeutic response)

In order to more fully understand biocompatibility, we will look at some basic

information about material and host responses in the next section.

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THE COMPONENTS OF BIOCOMPATIBILITY

1. Material Responses

When a biomaterial is exposed to a living system, a number of events that alter that
material occur immediately. Other factors can cause more gradual changes in the
material over time.

On initial contact with living systems, all materials adsorb proteins and other
molecules. This alters the surface characteristics of the material or what the living
system “sees” when it looks at the material. Some other material alterations that can
occur on contact with living systems include:

• Swelling (absorption of fluid into the material)

• Leaching (extracts from material leach out into surrounding fluid)

• Dissolution and degradation

• Corrosion and/or

• Wear

These material alterations can lead to altered physical properties, altered chemistry
and/or the release of leachables and/or degradation products. All of these effects
can affect the “biocompatibility” of the material.

2. Host Responses

Biomaterials that come into contact with living systems usually cause some form of
trauma to the tissue, ranging from minor disruption of the skin to major surgical
trauma. Even non-invasive diagnostic devices such as transcutaneous ultrasound
can cause elevation of temperature in tissues that can damage cells. Host
responses are responses seen in “living systems”. Living systems can be humans,
sheep dogs or any other living system. Host responses can be categorised into two
main types based on location of the response:

• local (in the immediate vicinity of device) and

• systemic (distributed throughout the host)

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Local and systemic host responses can also be categorised as:

• nonspecific responses and

• specific immune responses

Some nonspecific responses include:

• coagulation and haemolysis

• inflammation

• wound healing and

• tissue remodelling

Some specific immune responses include:

• hypersensitivity and

• rejection

Other “abnormal” responses include:

• carcinogenesis and

• genotoxicity

PRINCIPLES OF DESIGN BASED ON BIOCOMPATIBILITY

Given the nature of potential material and host responses described above, the
design and development of medical devices almost always involves the issue of
biocompatibility at some stage. Design issues relating to biocompatibility include not
only the selection of appropriate materials for the technology or device in question
but also the appropriate physical design of the device. For example, implantable
medical devices should not include sharp corners in order to limit tissue damage.

Most biocompatibility issues do, however, relate to materials. The selection of

appropriate materials should be based on:

• engineering data or the mechanical and physical requirements of the

material,

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• comprehensive literature searches to ascertain the history of both the

material and device,

• previous material responses and

• known host responses.

Initial material selection usually begins with a set of mechanical and physical
specifications defined by the physical requirements of the device. For example, the
physical requirements of a subclavian catheter relate to the required size and
flexibility of the device.

The range of materials considered is then restricted by their biocompatibility

characteristics. With the subclavian catheter example, thousands of the
commercially available plastics would have suitable flexibility characteristics at the
sizes required but very few have the biocompatibility characteristics suitable for the
application. So, the material selection process is one of narrowing down the
available range by both definition of the physical and mechanical requirements as
well as the biocompatibility characteristics of potential materials.

Comprehensive literature searches aid in the selection of appropriate materials and

rejection of those not suitable for the application.

For regulatory reasons, it is usually more expedient to use and gain regulatory
approval for a material already used in similar medical applications to the device
being developed. This means the approach to materials selection is usually
conservative and the tendency is almost always to use an existing medical material
with known responses and physical/chemical characteristics rather than attempting
to use a new material with unknown responses.

Once the material is selected, biological evaluation is performed to determine the

potential toxicity resulting from contact of the material with the body. The material
should not, either directly or through the release of their material constituents,
produce adverse local or systemic effects, be carcinogenic or produce adverse
reproductive and developmental effects. Evaluation of any material requires data
from systematic testing to ensure that the benefits provided by the final product will
exceed any potential risks produced by the device materials.

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Tests conducted on biomaterials include acute screening tests such as:

• in vitro tests (tissue culture, blood contact tests) and

• in vivo tests (systemic toxicity, skin irritation, sensitisation)

and chronic animal tests such as:

• in vivo material tests (implantation tests, biodegradation, carcinogenesis)

• in vivo device tests (functional testing in model systems)

The article at http://www.mddionline.com/article/considerations-biocompatibility-

evaluation-medical-devices describes some of the considerations for the
biocompatibility evaluation of medical devices and explains many of the concepts
more fully.

HISTORY OF BIOCOMPATIBILITY TESTING GUIDELINES

Biocompatibility testing guidelines have been developed relatively recently with most
of the development initiated in the USA. The American Society for Testing and
Materials (ASTM) developed ASTM F 748, originally adopted in 1982. ASTM F 748
recommends specific test methods and distinguishes between tissue types and
contact periods. A description of ASTM F 748 can be found via the ASTM website:
www.astm.org.

Following ASTM F 748, the Tripartite Biocompatibility Guidance (TBG) was

developed by a joint working group with participants from USA, Canada and UK and
ratified on April 24, 1987. The recommendations were similar to those in ASTM F
748 but without distinction between contact periods. Although aspects of the tests to
be performed were described, no specific tests were recommended.

The International Standards Organisation (ISO) then formed Technical Committee

194 to draft the ISO 10993 set of standards. ISO 10993 draws from the TBG but
restores the exposure classes outlined in ASTM F 748. ISO 10993 was first ratified
in 1992 (ISO 10993-1:1992(E)).

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THE ISO 10993 SUITE OF STANDARDS

The ISO 10993 Biological Evaluation of Medical Devices suite of standards is
generally accepted around the world as the set of standards with which medical
device manufacturers must comply in order to have their devices approved by
regulatory bodies. It comprises details of how a manufacturer can decide which
tests are appropriate for each device as well as a wide array of tests covering
various aspects of biocompatibility.

ISO 10993 is implemented in various ways around the world. The general concepts
embodied in the standard are described on the website
http://www.mddionline.com/article/considerations-biocompatibility-evaluation-
medical-devices.
The FDA’s description of the implementation of ISO 10993 in the USA can be found
at
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocum
ents/ucm080735.htm.

Use of ISO 10993 and details of biocompatibility testing in UK can be found at in

Guidance Note 5 at

http://www.mhra.gov.uk/home/groups/es-era/documents/publication/con007509.pdf

Useful practical information is also available at

http://www.mddionline.com/article/testing_tips and
http://www.mddionline.com/article/testing_tips2.

In summary, the ISO 10993 suite of standards is based on the following principles:

1. Materials should be characterised to provide an understanding of formulation,

potential impurities, an extractables, and to provide the basis for
specifications.

2. Leachable chemicals and degradation products should be considered in

evaluating the toxicology of a device.

3. The availability of chemical extractables and degradation products to the

patient when exposed to the device should be considered in designing testing
programmes.

4. Testing should be conducted according to good laboratory practices and

evaluated by competent, informed persons.

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5. Full experimental data should be made available to reviewing authorities.

6. Changes in the composition of materials, manufacturing practices or intended

use of the device should be evaluated with respect to possible changes in
toxicological effects to patients.

7. All relevant data, including information from nonclinical sources, clinical

studies and postmarket experiences should be taken into account when
evaluating a device.

The ISO 10993 suite of standards currently comprises 18 different published

standards and two draft standards each covering a particular aspect of
biocompatibility and details are outlined below:

10993-1 Biological evaluation of medical devices - Part 1: Evaluation

and testing within a risk management process. The latest
version of 10993-1 was released in 2009 and contains
information on risk management as well as evaluation and
testing. For information on the earlier versions, see
http://www.mddionline.com/article/practical-guide-iso-10993-part-
1151introduction-standards A draft update is given at
http://www.fda.gov/downloads/medicaldevices/deviceregulationandg
uidance/guidancedocuments/ucm348890.pdf

10993-2 Biological evaluation of medical devices – Part 2: Animal

welfare requirements

10993-3 Biological evaluation of medical devices – Part 3: Tests for

genotoxicity, carcinogenicity and reproductive toxicity. For
more detail, see http://www.mddionline.com/article/practical-guide-
iso-10993-3-genotoxicity

10993-4 Biological evaluation of medical devices – Part 4: Selection of

tests for interactions with blood. For more detail, see
http://www.mddionline.com/article/practical-guide-iso-10993-4-
hemocompatibility

10993-5 Biological evaluation of medical devices – Part 5: Tests for in

vitro cytotoxicity. For more information on 10993-5, see

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http://www.mddionline.com/article/practical-guide-iso-10993-5-
cytotoxicity

10993-6 Biological evaluation of medical devices – Part 6: Tests for

local effects after implantation. For more detail, see
http://www.mddionline.com/article/practical-guide-iso-10993-6-
implant-effects

10993-7 Biological evaluation of medical devices – Part 7: Ethylene

oxide sterilisation residuals. For more information, see
http://www.mddionline.com/article/guide-iso-10993-7-and-aami-tir-19-
eto-sterilized-devices

10993-8 Biological evaluation of medical devices – Part 8: Selection

and qualification of reference materials for biological tests
(withdrawn)

10993-9 Biological evaluation of medical devices – Part 9: Framework

for identification and quantification of potential degradation
products

10993-10 Biological evaluation of medical devices – Part 10: Tests for

irritation and delayed-type hypersensitivity. For more info, see
http://www.mddionline.com/article/practical-guide-iso-10993-10-
sensitization and http://www.mddionline.com/article/practical-guide-
iso-10993-10-irritation

10993-11 Biological evaluation of medical devices – Part 11: Tests for

systemic toxicity. For more information on 10993-11, see
http://www.mddionline.com/article/practical-guide-iso-10993-11-
systemic-effects and http://www.mddionline.com/article/practical-
guide-iso-10993-11-designing-subchronic-and-chronic-systemic-
toxicity-tests

10993-12 Biological evaluation of medical devices – Part 12: Sample

preparation and reference materials. For more information on
10993-12, see http://www.mddionline.com/article/practical-guide-iso-
10993-12-sample-preparation-and-reference-materials

10993-13 Biological evaluation of medical devices – Part 13:

Identification and quantification of degradation products from
polymeric medical devices

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10993-14 Biological evaluation of medical devices – Part 14:

Identification and quantification of degradation products from
ceramics. For more information on 10993-14, see
http://www.mddionline.com/article/practical-guide-iso-10993-14-
materials-characterization

10993-15 Biological evaluation of medical devices – Part 15:

Identification and quantification of degradation products from
metals and alloys

10993-16 Biological evaluation of medical devices – Part 16:

Toxicokinetic study design for degradation products and
leachables

10993-17 Biological evaluation of medical devices – Part 17:

Establishment of allowable limits for leachable substances.
See http://www.mddionline.com/article/assessing-biological-safety-
polymers.

10993-18 Biological evaluation of medical devices - Part 18: Chemical

characterization of materials. For more information on 10993-18,
see http://www.mddionline.com/article/industry-confronts-challenge-
new-testing-standard

10993-19 Biological evaluation of medical devices -- Part 19: Physico-

chemical, morphological and topographical characterization of
materials

10993-20 Biological evaluation of medical devices -- Part 20: Principles

and methods for immunotoxicology testing of medical devices

CATEGORISATION OF MEDICAL DEVICES

The most important step in determining the biocompatibility of a device is to
determine the tests required to be performed. To facilitate the selection of the
appropriate tests for a particular device, ISO 10993 - 1 describes how the
characteristics of the device materials and the nature, degree, frequency and
duration of its exposure to the body must be considered when selecting tests. It then
walks the manufacturer of the device through a series of flowcharts and tables to

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determine the tests required. The flowcharts and tables used for this categorisation
can be found in ISO 10993 - 1 (available at the Australian Standards website through
the UNSW electronic library – Sirius). The FDA has used a slightly modified version
of these tables in the past but we will use the ISO version in this course.

The category of a device or material for biocompatibility purposes is defined by the

nature of contact and the duration of contact. The tables walk you through this
determination and you should look at the tables while reading the next section and
then categorise a few devices in the exercises below.

1. First, define the nature of contact of the device

• Non-contact devices (not included in the scope of the standard)

• Surface-contacting devices

• Skin (eg electrodes, bandages, prostheses)

• Mucosal membranes (eg contact lenses, IUDs, colonoscopes)

• Breached or compromised surfaces (eg dressings for burns)

• External communicating devices

• Blood path, indirect (eg IV administration sets)

• Tissue, bone, dentin (eg arthroscopes, dental cement, skin staples)

• Circulating blood (eg oxygenators, dialysers, intravascular catheters)

• Implant devices

• Tissue/bone (eg orthopaedic pins, pacemakers, breast implants)

• Blood (eg pacemaker electrodes, heart valves, vascular grafts)

2. Then, define the duration of contact of the device

• Limited exposure (up to 24hr)

• Prolonged exposure (24hr to 30 days)

• Permanent contact (exceeds 30 days)

Remember that multiple exposures must be assessed for potential cumulative

effects.

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Once the nature and duration of contact have been determined, the tables in ISO
10993-1, then define the set of tests to be carried out for that particular material and
application.

SUMMARY

1. There is no single, simple concept of biocompatibility.

2. Biocompatibility does not imply inertness but rather “suitable” biological

performance.

3. Biocompatibility encompasses both

• the host response to material/device and

• the material response to physiological interactions.

4. Biocompatibility testing can include in vitro and in vivo laboratory studies and
nonclinical trials.

5. Internationally accepted guidelines have been developed that define the

minimum requirements for testing to demonstrate safety. These are the ISO
10993 suite of standards.

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