Biological risk assessment should be conducted on all
medical devices before marketing to assure its safety.
This assessment should include consideration of all
toxic endpoints. It should be noted that biological
safety cannot be demonstrated adequately using a
“checklist” approach. A systematic analysis of
biological risks is required. Attention is drawn to
the general principles applying to the biological
evaluation of materials and devices set out in Clause
3 of EN/ISO 10993-1. Unfortunately, the matrix in
EN/ISO 10993-1 is often used as a checklist to perform
a standard set of tests.
What is
actually needed is a qualified toxicologist trained
and experienced in risk assessment, developing an
evaluation programme based on the specifics of the
device. It might well be that data is already
available from other sources that allow evaluation of
the hazard without the need for further tests. It
should be kept in mind that individual considerations
of the device might lead to a need to assess toxic end
points over and above the ones listed in the table.
Such “individual considerations” include, but are not
limited to, the site of exposure of the device and the
duration of exposure. For example regarding exposure
duration, long-term exposure can be obtained via a
single device application (e.g. implants), or via
repeated use of new single use devices (e.g. contact
lenses, colostomy bags). In the first case, the
effects of degradation products need to be assessed in
addition to the exposure to the device materials. In
the second case, longterm exposure to the device
materials still needs to be assessed, but individual
device exposure might be short enough that the
exposure to breakdown products could be negligible.
The
guidance on the specific tests in different parts of
EN/ISO 10993 only discusses the test and sample
methods, it does not specify pass/fail criteria. It is
not possible to comply with the Essential Requirements
by listing the tests done according to 10993 and
indicating a “pass” behind each test. The results of
the tests should be interpreted in the context of the
overall risk assessment to know whether a specific
outcome indicates acceptable risk or not. This once
again emphasises the need for an overall,
scientifically valid risk assessment.
The
three basic types of information required for a
toxicological risk assessment are identified in Annex
C of EN/ISO 14971, i.e.
-
The chemical nature of
the materials (including the toxicity of
ingredients);
-
prior use of the
materials; and
-
biological safety test
data.
Toxicological hazard is a
property of the chemical constituents of the materials
from which a medical device is made and should be
considered in relation to the hazard identification
steps of EN/ISO 14971 (Steps 1 and 2). The latter two
types |
of data
listed above are dependent upon exposure to a
particular material or device and thus predominantly
address the risk of an adverse reaction occurring,
rather than hazard.
Hazard Identification
The
toxicity of a compound or material is investigated
using basic toxicology studies which provide
information on the nature of toxic effects elicited by
a test material, the dosages at which the effects
occur and the no-effect levels. There is a widespread
misconception that ‘medical grade’ materials (or
“surgical grade” or “implant grade”) exist. In the EU
there is no regulation or standard that defines what a
medical grade material would be and indeed,
considerations to achieve acceptability for
implantation in an orthopaedic implant would be quite
different for a vascular stent. Compliance of a
material with a Pharmacopoeial requirement does confer
some reassurance insofar as that is a wellrecognised
starting point.
EN/ISO
14971 requires that relevant characteristics that
could affect safety are listed and, from these,
possible hazards are identified. For a biological
safety assessment, the first step comprises
characterisation of materials. Data relating to
formulations, additives, processing aids, degradation
products, effects of processing, residue levels, etc.
allow the chemical nature of the material(s) to be
fully characterised.
Toxicological hazards can be identified from a
knowledge of the toxicity of the chemicals or
materials listed.
Risk
Evaluation
The
probability that an adverse effect will arise from
exposure to a chemical depends not only on its
inherent toxicity, but also on the amount to which a
subject is exposed and the route of exposure. This
means that information on the identity and toxicity of
materials, residues, degradation products, etc. must
be considered in relation to quantitative data on the
amount present in the final product, its leachability
and systemic availability. This analysis is analogous
to the requirements of Clause 4.4 of EN/ISO 14971. In
practice this means that in many cases an exposure
assessment will already provide sufficient
justification for limiting the number of toxic end
points that need to be addressed in more detail.
Where
significant risks arising from hazardous residues are
identified by this procedure, their acceptability
should be assessed in line with established
toxicological principles. Additional information from
biocompatibility tests or prior use of materials may
be used to provide a basis for further assessment of |
•
Dr. S.S. Murugan is a UK and EU Registered
Toxicologist with more than 20 years experience in
industry. Dr. Murugan obtained his Bachelors, Masters
as well as Doctoral degree in Toxicology from
University of Madras and MGR Medical University. He
has worked with major contract research organizations
(CRO) in India - Head of Genetic Toxicology at IIBAT,
Toxicology and Quality Assurance Manager at SGS and
Scientific Director at RCC India. He has extensive
operational and quality assurance experiences. He has
been instrumental in obtained GLP certification and
has turned around the business at 2 Indian CROs. He
has successfully faced several GLP, ISO17025 and FDA
audits. Additionally, he has faced several national
and international client audits. He was also a member
of CPCSEA guidelines committee, which over sees the
animal experimentation in India. He has experience in
Toxicology as well as Quality Assurance. This two
types of experience helps in understanding QA
requirement for the regulatory submission and
organizing the studies in alignment to the required
quality system. Also he has vast experience in
Toxicology and specialized in Genetic Toxicology. |
•
Dr. T.S. Kumaravel is American Board certified and
UK/Eurotox Registered Toxicologist with more than 20
years experience in industry as well as in academia.
He is a pioneer in conducting Biological Safety
Assessments and Biocompatibility studies on Medical
Devices. Dr. Kumaravel obtained his Bachelor’s degree
in Medicine and Surgery from Stanley Medical College,
Doctoral degree in Pharmacology/Toxicology from
University of Madras and finally obtained PhD in
Genetic Toxicology/Cancer Genetics from MGR Medical
University, Chennai. He then carried out toxicology
research at Hiroshima University, Japan; National
Institutes of Health, USA and Princess Margaret
Hospital, Canada. Subsequently, he has worked with
world leading contract research companies such as
Covance Laboratories and Huntingdon Life Sciences,
where he worked with various international medical
devices clients. He has extensive experience running
and supervising Biocompatibility studies, advising
clients on their requirements to comply with national
and international guidelines such as ISO10993.
Additionally, he has experience of managing regulatory
submissions. He has authored several confidential
reports, 40 peer-reviewed publications and has 50+
conference papers to his name. |