Biocompatibility of Medical Coatings

(by J.J.G. Bos)

This SciNote is meant to give an impression of biocompatibility research that is required by norm, pharmacopoeia and functional demands. The main focus is on coated polymeric medical devices, but the general trend can be applied to other devices as well.

Biocompatibility is to be proved for the complete medical device (packaged and sterilized), not just the coating.

The major part of biocompatibility evaluation methods and criteria can be found in the ISO 10993 series that is listed below. The titles tell the story. I will also give some examples of other ISO norms. Do note that the Essential Requirements List - part of the medical devices directives (MDD, AIMD and IVDD) as set by the European Union - strongly leans on these (commercial!) ISO norms. The norms are recognized world-wide, which thus greatly helps registration of medical devices in countries outside the European Union as well.

• ISO 10993 - Part 1: Evaluation and testing within a risk management process
• ISO 10993 - Part 2: Animal welfare requirements
• ISO 10993 - Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
• ISO 10993 - Part 4: Selection of tests for interaction with blood
• ISO 10993 - Part 5: Tests for in-vitro cytotoxicity
• ISO 10993 - Part 6: Tests for local effects after implantation
• ISO 10993 - Part 7: Ethylene oxide sterilization residuals
• ISO 10993 - Part 9: Framework for identification and quantification of potential degradation products
• ISO 10993 - Part 10: Tests for irritation and skin sensitization
• ISO 10993 - Part 11: Tests for systemic toxicity
• ISO 10993 - Part 12: Sample preparation and reference materials
• ISO 10993 - Part 13: Identification and quantification of degradation products from polymeric medical devices
• ISO 10993 - Part 14: Identification and quantification of degradation products from ceramics
• ISO 10993 - Part 15: Identification and quantification of degradation products from metals and alloys
• ISO 10993 - Part 16: Toxicokinetic study design for degradation products and leachables
• ISO 10993 - Part 17: Establishment of allowable limits for leachable substances
• ISO 10993 - Part 18: Chemical characterization of materials
• ISO 10993 - Part 19: Physico-chemical morphological and topgraphical characterization of materials
• ISO 10993 - Part 20: Principles and methods for immunotoxicology testing of medical devices

Examples of related other ISO norms are:

• ISO 20993: Biological evaluation of medical devices - Guidance on risk management process [4 pages - don't expect too much!]
• ISO 11979-5: Ophtalmic implants - Intra ocular lenses - Part 5: Biocompatibility
• ISO 8638: Cardiovascular implants and extracorpereal systems - Extracorpereal blood circuit for haemodialysers, haemodiafilters and haemofilters
• ...etc. Do not forget the series on product sterility and sterilization validation!

The ISO 10993 nowadays represents a quite extensive range of approaches regarding the investigation of biocompatibility of medical devices. This was not always the case. Biocompatibility issues were and still are (partly) addressed by the pharmacopoeia. Almost any country in the world has its own version, and local legislation requires compliance with their pharmacopoeia. And although ISO 10993 is now accepted almost everywhere, it is still useful to consult (local) pharmacopoeias. Fortunately, many of the pharmacopoeias have been harmonized on essential topics, and the European Union has effectively replaced all national pharmacopoeias for one European Pharmacopoeia (EP). The United States Pharmacopeia (USP) has always been well-regarded all over the world, and is certainly worth checking out. Pharmacopoeias generally provide well-defined test methods and criteria (the how), whereas ISO 10993 still has the tendency to only tell what issues of biocompatibility should be addressed (the what). This makes the two complement each other, rather than compete.

There are a few paragraphs that I want to bring to your attention, regarding coatings and polymeric medical devices:

EP section 3: "Materials for Containers and Containers"
• USP section 661: "Containers - Plastics"
• EP section 2.9.19: "Particulate Contamination: Sub-Visible Particles"
• EP section 2.9.20: "Particulate Contamination: Visible Particles
• USP section 788: "Particulate Matter in Injections"

USP section 788 and EP section 2.9.19 have been harmonized, together with the Japanese Pharmacopoeia. The texts are thus now identical. The idea of the test method is to subject the medical device to a representative in-vitro simulation of its application and assess the typical average number of particles generated in the process. The particle counts are related to size categories. The pharmacopoeias provide clear pass/fail criteria. Visibility of the particles forms an issue of importance. There is a tendency to simply state that what you do not see is not there. This poses a problem for hydrogel particles; they are almost invisible in a watery environment, but hydrogels are notorious sources of particulate matter. The right thing to do is to try and make the particles visible, for instance by pre- or post-staining of the gel. It may also help to experiment with lighting methods, such as angle and color. Hydrogel particles are hardly detected by automatic particle counters. Manual counting of particles caught on filter-sheets - after filtration of the saline solution that was used for the in-vitro simulation - still proves to be the most reliable and honest method when it comes to evaluation of coating particle generation.

The USP and EP sections on containers are about water-based extractions of plastics, and can thus be applied to any polymeric medical device. The assessment of biological impact by leachables from the polymeric devices consists of a number of relatively simple but (combined) very effective tests on the extracts, such as:

• Acidity and alkalinity determination
• Absorbance - UV/VIS spectrometry
• Appearance - visual inspection of color and clarity
• Reducing substances
• Extraneous particles
• Residue on evaporation
• Heavy metals

The pharmacopoeias carefully describe how the extractions and the evaluations should be conducted, and what controls should be used. Clear criteria are provided for pass/fail. It is up to the developer to find out what tests are applicable to the (new) product, so it is worth browsing through the pharmacopoeia - and the ISO 10993 series - in order to set up a well-balanced test plan.

It must be pointed out here that the pharmacopoeias contain lots and lots of useful tests, including those for sterility, (micro-)biological activity, and dosage determinations. They also contain very comprehensive monographs on materials and common drugs. These monographs are extremely useful for setting up proper in-house material specifications and controls. Think of tests and criteria for Incoming Control (IC).

Functional safety tests relate to:

• Product claims - e.g. as advertised in brochures, instructions for use, and on labels
• Clinical application practice
• Product-specific ISO norms and pharmacopoeial requirements
• Residual risk, as result of the product risk analysis

For example: Heparin coatings must be tested on heparin leaching and activity. Lubricious coatings may have to be tested on coefficient of friction as to be expected upon application, e.g. when in contact with blood or other body fluids. Some materials may require additional testing in relation to the sterilization method. Think of increase of ethylene-oxide redidue in excipients or loss of activity of the drugs involved. Product-specific ISO norms are available for catheters, intraocular lenses, ceramic implants, etc, as could be seen in the first section of this SciNote. Product risk analysis proves to be one of the most powerful tools in determining what additional safety tests should be conducted in order to assess and/or reduce residual risk. Product claims are easily overlooked, but they can cause quite some risk when wrongly interpreted by the user. Pharmaceutical companies started to cover product claims with all kinds of disclaimers in order to counterbalance improper expectations (an lawsuits) by the user. Manufacturers of medical devices nowadays do the same. It does not always suffice to hide behind ISO 10993 or pharmacological compliance. Proof of product-specific functional safety thus completes the biocompatibility assessment/evaluation.