Importance Of Biocompatibility For
Medical Polymers
And Regulatory Requirements
Biocompatibility
testing is a decision that is taken based on the available
information on a medical device, which is documented in
the BEP. When adequate information is already existing to
support the biocompatibility of the device, further
testing is not recommended. One of the major information
required here is the chemical/material composition of the
device. In case of polymers, data on the characteristics
such as the levels of residual monomers, oligomers,
surface composition, residual catalysts/initiators,
additives. Process residues, traces, impurities and
chemical structure are useful in determining any potential
hazards. ISO 10993-18:2020 (Biological evaluation of
medical devices — Part 18: Chemical characterization of
medical device materials within a risk management process)
suggests that the compositional details of polymers should
be obtained from the supplier of the material and or
published literature. In the absence of any such data,
these data shall be obtained through chemical analysis.
If the chemical analysis reveals absence of any hazardous
extractables or if the levels of extractables are below
the Analytical Evaluation Threshold (AET), no further
toxicological risk assessment may be required. AET is the
threshold below which it is not needed to identify,
quantify or report leachables or extractables, for
potential toxicological assessment. Therefore, a substance
that is present at a concentration below the AET is
established as having an acceptable toxicological risk
without further assessment. When the levels of the
extractables are above the AET, a toxicological risk
assessment is performed to evaluate safe levels, which
when exceeded would trigger biocompatibility testing.
Given the effects that manufacturing, and processing may
have on a polymer as incorporated into the final finished
medical device, use of material standards may not be
sufficient to identify biocompatibility risks for devices
made from polymers. ISO 10993-1 emphasizes that all
biocompatibility tests be conducted on a final finished
device or representative devices that have exactly the
same composition as the final finished device and have
gone through the same manufacturing, packaging and
sterilization process as the final finished device.
In a case where a biocompatibility testing is required,
the test selection is based on the site of contact and
duration of contact of the device as described in ISO
10993-1-2018.
The rigor of testing depends on the invasiveness of the
device. While a thermometer, which is a surface device
contacting intact for less than 24 h will have to be
tested for cytotoxicity, sensitization and skin
irritation, a pacemaker may require, in addition to these
three tests, testing for systemic toxicity, genotoxicity
and local effects after implantation. Polymeric devices
that contact blood directly or indirectly may require
testing for hemocompatibility as outlined in ISO
10993-4:2017
(Biological evaluation of medical devices — Part 4:
Selection of tests for interactions with blood). An
intravenous catheter requires testing for indirect
hemolysis. A
polymeric implant placed in the heart would require
additional endpoints to determine any thrombogenic
property.
The use of vertical standards is another important thing
to be considered when selecting tests for certain
polymeric medical devices. For example, intra ocular
lenses
(IOLs) have to be tested based on the requirements
outlined in ISO 11979-5:2020 (Ophthalmic implants —
Intraocular lenses — Part 5: Biocompatibility).
With respect to selecting solvents for extraction, great
care should be taken for testing polymers. According to
ISO 10993- 12:2021 (Biological evaluation of medical
devices — Part 12: Sample preparation and reference
materials), extraction solvents should be selected to
optimize compatibility with the device materials and
provide
information on the types of chemicals that are likely to
be extracted in clinical use. Solvents that swell the
polymer, cause the polymer to degrade or dissolve, or
interfere with detection of chemicals should be used with
caution.
Devices containing degradable /absorbable polymers, e.g.
absorbable sutures made of polyglycolic acid/poly
caprolactone, may also require testing for degradation as
described in ISO 10993-6 (Biological evaluation of medical
devices — Part 6: Tests for local effects after
implantation). This is because polymeric, metallic, or
ceramic materials that are intended to be absorbed in vivo
will release soluble components or degradation products.
If the release rate of a material is sufficiently rapid,
elevated concentrations of one or more of the released
products could alter the pH and/or osmolality of an in
vitro test system. Since the in vivo condition provides
the combined presence of perfusion and carbonate
equilibria, when evaluating intentionally absorbable
materials it is possible that adjustment of the pH and/or
osmolality of an in vitro test system will be necessary to
maintain physiologically relevant conditions – thereby
allowing evaluation for other causation and provided a
scientific justification for the adjustments and the
effect on the in vitro test system, as performed without
pH or osmolality adjustment, is documented within the
report. Results from both the standard assay and adjusted
assay should be compared, as modifications can mask
important considerations.
Once the physical, chemical and biocompatibility data are
available, the BER is documented by a toxicologist. The
conclusion that the polymeric device is safe comes with
the collection, review, identification of gaps, testing
and critical review of test reports. Clinical data are
very useful to support the biological evaluation of a
device. Documentation of biological safety of the device
is a continuous process and needs to be updated throughout
the life cycle of a device.
When medical polymers produce the desired favourable
tissue response and clinically meaningful performance,
they are considered biocompatible. The goal of employing
biocompatible polymers is to improve healing functions
while avoiding harmful, negative physiological, allergy,
or toxic effects. |