2. iptonline.com
39Innovations in Pharmaceutical Technology Issue 49
hydrophilic surface – lubricity is a property that
describes how slippery the surface is,while durability
is meant to evaluate how long the slippery behaviour
would last before degrading.Loss of durability in a
hydrophilic surface is often felt in terms of higher
co-efficient of friction.At the micro level,this is seen
as the peeling or sloughing off of the coating.
Manufacturing Concerns
Process engineers will find significantly different
manufacturing set-ups for a PVP-ultraviolet (UV) cure
system,versus a heat cure required by HA coatings.
Advantages to the UV procedure include short cure
times.However,batch size is small,as the number of
devices a UV chamber can hold are limited – typically
10-20.Heat cure systems,on the other hand,can
accommodate batch sizes as big as the drying oven
can handle.Processing a 200-unit batch is common
in continuous dip and heat cure systems,while spray
coating is showing some promise.Most systems
today rely on a dip coat for a base coat or primer
layer,and then a repeat with the hydrophilic coating.
With considerable handling involved and material
transfer required in a cleanroom environment,coating
systems can be expensive and take up a considerable
floor footprint.
Once the choice is made on a coating and system,
adjusting to the next generation (or an alternate
vendor) can often be problematic.Current production
cannot be easily shifted,for regulatory reasons,to a new,
higher performance coating.Risk-averse management
may view a new investment in facilities and coating
resources as outside the firm’s core competency.
Device firms may therefore find flexibility and capital
equipment savings in outsourcing coating services –
several vendors now offer this.
Before making a choice either way, diligence is
required and full access to a functional quality
management system is a must.When taking the
outsourcing route, some degree of control is lost.
For vendors offering coating services, a key
consideration is the incoming inspection of parts
– it is frustrating for the coating service provider to
find a shipment of raw tubing infiltrated with lint,
dirt or other particles. Damage to tips and coils –
key functional parts – can trip up the best of plans.
Furthermore, the coating service supplier should be
able to offer full verification and validation services,
so that in the event of your firm seeking to transfer
manufacturing in-house or to a remote factory, the
process is already well-established and tested.
As part of the manufacturing set-up,it is important to
agree with the coatings supplier about the labelling
degradation or drop-out.Some PVP-coated devices
may appear to be whitish or flaky if the coating
is not applied properly.Hyaluronic acid coatings are
not lubricious when dry,but instantaneously hydrate
when exposed to body fluids to form a hydrogel.
Hydrogels have been favourably viewed as a platform
for drug delivery,but commercial attempts have
been disappointing.
Next Steps
Innovation in device coatings is driven by design
inputs received from clinicians,R&D engineers and
project managers.Recently,a new stakeholder
with considerable weight has arrived in the form
of regulatory agencies.
Hydrophilic coatings have been employed on catheters
for some time,to allow ease of insertion through
large to remote vasculature – lubricity is an assumed
property.A team of scientists at the US FDA has begun
to take a closer look at coatings in terms of what they
elute when in the body – in the form of particulates
– and overall biocompatibility.They are keen to
understand the details of device coatings as part
of the overall review process.
Meanwhile,select coatings vendors have placed
considerable research effort into improving the
robust nature of the bonding in coating layers.
Using US Pharmacopeial Convention (USP) reference
standard 788 as a guide,particulate generation is
measured once a load is placed on a device.The count
of particles below the 10 micron level and above the
25 micron level is measured. Good coatings will
generate well below 25% of the USP 788 limits.
Tests have to be conducted on each device as their
topography may influence the results beyond the
core nature of the coating chemistry.
Industry efforts to find the holy grail of a fully proven
anti-microbial coating face considerable obstacles in
demonstrating safety and efficacy. Proving sustained
release of an anti-microbial agent, effective against
a broad range of bacteria for more than three days,
is problematic.When a coating is 1-4 microns thick,
only so much active agent can fit within the thin layer.
As a result, when wet, the coating will act first for
lubricity and secondly for drug release. If the antibiotic
agent is unable to reach the surface of the coating
or be exposed over time, even less activity can
be anticipated.
Chemically,hydrophilic coatings rely on surface
interaction with water to provide an extremely
lubricious surface.Lubricity,durability and low
particulate count are a few terms associated with
3. 40 Innovations in Pharmaceutical Technology Issue 49
iptonline.com
Particle Counts
Every R&D engineer has a solid quality assurance
and regulatory affairs (QA/RA) team behind them
as a resource and stakeholder.The most common
theme in the FDA’s evaluation of a coated device
is particle counts – low counts are achieved with
a robust coating to the device substrate bond.
The coating vendor should have sample particle
counts on standard substrates as a guide for what
to expect.The device will be tested for particles as
part of overall biocompatibility testing, and the
vendor should match the chemistry of the coating
to ensure the strongest bond.
Regulations and Cost
Regulatory requirements from the US, EU and Japan
require substantial documentation.Therefore, it is
important to ensure that available data contains a
complete list of all raw materials used. Biocompatibility
tests on devices cost close to $25,000, so the vendor’s
ability to provide a level of assurance for success
is mandatory.
Medical device firms seek cost clarity per device
coating, and are loath to pay royalties. In the past,
these have kept the reagent costs low and tied the
success of a product to the coating vendor’s revenue.
However, royalties remain frequent, and may run
between 0.5% and 3% of sales. Unit royalties of
$0.25 to $15.00 per device are also common.
Some coating vendors offer programmes of free
reagents, but include a per-device charge, while
licence fees are another way a coating supplier can
recoup the significant costs of getting a facility up
and running with a validated process. One critical
question concerns waste – the amount of coating
per device may be low, but if your manufacturing
group is disposing of litres of coating, there will
be hidden costs.
Final Thoughts
Coating evaluation must start early. It is important
to organise finance, strategic sourcing, QA/RA and
process engineering together with the R&D team to
avoid surprises. Depending on the manufacturing
equipment, there may not be a choice between PVP or
HA; however, outsourcing should still be considered as
part of device innovation. Furthermore, by arranging
for new components to be coated at a tubing
vendor’s facility, it is possible to introduce the latest
technology without major investment. Finally, making
sure you have access to the coating vendor’s senior
management team is essential – mutual success is far
more likely when both teams understand their roles
and share their expectations.
and documentation needed to adequately characterise
reagents.It is vital that a fully documented certificate
of conformance exists with every shipment,and that
the vendor can provide evidence of analysis from an
independent outside laboratory.
R&D teams need to get coatings defined early in
the design process and choose the right chemistry
to achieve a lubricity and/or durability goal.Coating
thickness and performance following sterilisation
are parameters that take time to evaluate – for
example,if an inner lumen coating is involved,it is
necessary to fully validate the fill and drain technique.
To avoid delays,it is also imperative to establish
and test sterilisation parameters early on,as coating
chemistry will be affected if gamma or e-beam
sterilisation is planned.
Performance Tests
Almost every device manufacturer has some form
of performance test.If you ask an R&D engineer
about the method rationale,the answer will likely be:
“That is the way we have always done it.”This is not
necessarily an issue,but it is important to put your test
results into perspective.PVP coatings fare well in water
but test poorly in phosphate buffered saline (PBS),while
HA coatings test better in PBS than water.It is up to the
manufacturer to decide which is relevant to the body
and the application.
Pinch testing,rotational performance and similar
in vitro tests point to probable coating performance,
but do not equal the benefits of cadaver testing.
Cadavers commonly present multiple issues,including
compromised vasculature. By excising a calcified
femoral artery, it is possible to see how coatings
perform when contact is made with the porcelain-like
sharp features of the inner lumen.A hydrogel coating
is flexible and will maintain thickness and performance,
while a PVP coating will show signs of scoring. It is
necessary to view this to understand the frailty or
robustness of the coating; a dye test using Congo red
for PVP and toluidine blue O for HA helps to highlight
the relevant areas.
Keith Edwards is President and
Chief Executive Officer of Biocoat Inc.
In addition to his responsibility for
corporate management, Keith travels
extensively to clients in the medical
device manufacturing community to
provide Biocoat solutions to real design issues. Prior to
this, he was Group Product Manager at Biomet LLC,
where he oversaw the bone growth stimulation market.
Email: kedwards@biocoat.com
