The advantages of hydrophilic coatings in allowing ease of insertion through vasculature are well known. Here, Keith Edwards, president and CEO of Biocoat, looks at the considerations and choices to be made when selecting them as part of operational procedures.
Hydrophilic coatings have been gainfully employed on guide wires, catheters, and introducer sheaths to lower friction coefficients. Chemically, they rely on surface interaction with water to provide an extremely lubricious surface but, on interventional devices intended for neurovascular, cardiovascular and peripheral vascular markets, a coating is required.
Lubricity, durability, a low friction coefficient and low particulate count are concepts associated with hydrophilic surfaces. Lubricity is a property that describes how slippery the surface is, while durability means how long the slippery behaviour would last before degrading. Degradation of a hydrophilic surface is often seen in terms of a higher friction coefficient reading. Observed peeling or sloughing off of the coating can generate particulates in vivo, which is generally a catastrophic failure beyond a certain limit.
PVP vs hyaluronic acid
The two significant technologies in biomedical device coatings are polyvinylpyrrolidone (PVP)-based, usually ultraviolet (UV) radiation-cured, and their coatings based on hydrogel with hyaluronic acid (HA) or similar biocompatible polysaccharide. PVP is a well-studied stable platform with a performance similar to soap. It is very slippery when wet but, in demanding applications such as multiple passes, there is a risk of coating degradation or dropout. Some PVP-coated devices may appear to be whitish or flaky if the coating is not applied properly. HA coatings are not lubricious when dry but instantaneously hydrate when exposed to body fluids to form a hydrogel.
UV or heat cure?
Process engineers will find significantly different manufacturing setups for a UV cure system than a heat cure. Advantages of UV include short cure times. Batch size, however, is small because the number of devices a UV chamber can hold is limited, typically up to 20. Heat cure systems can accommodate batch sizes as big as your drying oven will handle. Processing a 200-unit batch is common in continuous dip-and-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 clean room environment, coating systems can be expensive and take up a considerable floor footprint.
Once you have chosen a coating and system, adjusting to the next-generation coating is problematic. Your current production cannot be easily shifted, for regulatory reasons, to a new higher performance coating. Management may view a new investment in facilities and coating resources as outside the firm’s core competency. Your firm will find flexibility and capital equipment savings in outsourcing coating services.
Several coating vendors now offer coating services. You must have full access to a functional quality management system before deciding, and diligence is required because, when you outsource, some degree of control is lost. For vendors offering coating services, a key consideration is the incoming inspection of parts. It is very 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 and other key functional parts can trip up the best of plans.
Your coating service supplier should be able to offer you full verification and validation services so that, in the event you seek to transfer manufacturing in-house or to a factory overseas, the process is well established and tested.
As part of the manufacturing setup, you will need to agree with your coatings supplier about the labelling and documentation needed to adequately characterise reagents. Ensure that you have a fully documented certificate of conformance with each shipment and that the vendor can provide evidence of analysis from an outside independent laboratory. Pharmaceutical standards will likely apply to coatings one day ahead.
Do it yourself or outsource?
If you set up coating in-house, a process engineer can design a line for you that may cost between $40,000 for simple manual work and up to $800,000 for high volume automated production. Some modularity exists so the process can be scaled up. Remember that each time a change is made, regulatory concerns surface.
A coating service vendor may serve a second purpose: qualified back up. Let’s say you make an investment in a coatings facility and have a fire. The extra time you spend qualifying a back-up supplier for coating will keep your supply constant and reduce risk. Some vendors offer this qualified backup for a nominal annual fee.
Lubricity, thickness, coating inner lumens and lubricity after sterilisation
A requirement for any article on coating is to implore R&D teams to get coatings defined early in the design process. Your coatings vendor can help 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. If you plan to coat an inner lumen, count out a UV cure as the energy cannot penetrate to an inner space. Some device validation protocols involve a double ethylene oxide (EtO) sterilisation cycle. Establish and test sterilisation parameters early in the design process to avoid delays.
Pinch testing – how to interpret results
Most device manufacturers have some form of pinch 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." Repetition is not bad, but you need to put your test results in perspective. A few common facts you need to know are:
- PVP coatings fare well in water and test poorly in PBS (saline)
- HA coatings test better in PBS than water
- results from an immersion bath at ambient temperature will differ from results at body temperature
- silicone pads produce different results from Delrin pads
- a rounded pad will differ in profile from a flat surface such as a plate and produce differing results
- pads or plates submerged in the bath will produce different results than outside hovering above.
Choose your metric(s) and stay consistent. Options include:
- coefficient of friction (or grams force) averaged over 30 passes, 15 passes or other number
- lubricity at the 30th pass
- overall degradation in lubricity (increase in grams force) over 30 passes (durability).
Cadaver testing – the calcified femoral artery
Pinch testing, rotational performance and similar in vitro tests point to probable coating performance but cannot compare to cadaver testing. Patients commonly arrive in the operating room with multiple issues and present compromised vasculature. Excise a calcified femoral artery, if that is your access point, and see how your coating performs 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. You have to see this to understand the frailty or robustness of the coating. A dye test of Congo Red for PVP and Toluidine Blue O for HA brings the surface landscape to clear light.
Particle counts USP 788
Every R&D Engineer has a solid 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 particle counts are achieved with a robust coating to device substrate bond. Your coating vendor should have sample particle counts on standard substrates as a guide for what to expect. Your device will be tested for particles as part of overall biocompatibility testing and your coatings vendor should match the chemistry of the coating to ensure the strongest bond.
Data you need
Anticipate that, once you select a coatings vendor, you are married. Regulatory requirements from the EU, Japan and US Food and Drug Administration (FDA) will require substantial documentation. Ensure that the vendor you have supports your data requirements with all information other than their proprietary formulations or techniques. Some licence agreements stipulate the support required and availability of information.
Your vendor should be able to offer a master file at the FDA that is detailed in content to include a battery of biocompatibility tests. These tests on your device will cost close to $25,000 so the vendor’s ability to provide a level of assurance for success is mandatory.
Set up licence fees, reagents and royalties
Navigating the coating cost maze is complex but not difficult. Most medical device firms are loath to pay royalties. In the past, this model kept the reagent costs low and tied the success of a product to the coating vendor revenue. Royalties are common, however, and may run between 0.50% of sales up to 3%. Unit royalties are also common of $0.25-15.00 per device. Some coating vendors also offer programmes of free reagents but a per-device charge.
Licence fees are another way a coating supplier recoups the significant costs of getting your facility up and running with a validated process. One critical question to ask a coating vendor is: "What are you doing to help me reduce waste?" Your amount of coating per device may be low but if your manufacturing group is disposing of many litres of coating, you have a bundle of hidden costs.
Registrations with a coating on the market
Select coating manufacturers have offered updated versions of their coatings to meet advanced performance requirements and FDA concerns over particle counts. Make sure you are able to obtain the PMA or 510(k) numbers of other devices on the market with the coating you are using. The FDA and international agencies have a clear path when an approved device is already on the market.
With particle counts much on the mind of the FDA and your regulatory staff, you should ask what your vendor is doing to characterise the bonding between coating and substrate. Related research on coating performance and improvements will help guide you in material selection as coating chemistry should be optimised for silicone, nylons, Pebax and related urethane substrates.
Where to begin?
Start your coating evaluation early. Get finance, strategic sourcing, QA/RA and process engineering together with your R&D team to avoid surprises. You may not have a choice of PVP versus HA if a major investment exists in the manufacturing equipment. However, consider outsourcing and outsourced coating as part of your innovation. Getting that new component coated at the tubing vendor is a solid strategy to bring in the latest technology without a major investment. Make sure you have access to senior management at your coatings vendor. Your mutual success is clear when both teams know their roles and expectations.