Passing the test
Medical device manufacturers are required to have their product tested for biocompatibility. A product which is biocompatible will not have any adverse effects on a living tissue or system. Biocompatibility testing is a material-based assessment, so not only do device manufacturers do this testing but component and material vendors do so as well. Which evaluations to perform as well as how to perform these tests, are governed by the International Standardization Organization (ISO) 10993 series of standards. There are currently are twenty chapters in the series. Typical nomenclature is to reference the series, then the chapter number and the effective date. For example the chapter that specifies what tests are required is ISO10993-1:2009. With a little creative web searching you can find a version of the table which specifies which testing categories need to b addressed for each category of patient contact. Of particular note is the FDA’s document, “Use of International Standard ISO-10993, “Biological Evaluation of Medical Devices Part 1: Evaluation and Testing”. But that is where the trail will go cold. The 10993 chapters are under copyright and must be purchased individually from ISO. The subsequent chapters spell out how the biocompatibility tests are to be conducted and what is expected to be reported. These specifications become what FDA evaluates the testing to for compliance and each deviation from the appropriate ISO 10993 standard a justification and an evaluation of the impact.
Truth will out
The device manufacturer has the ultimate requirement of biocompatibility testing as well as needing to demonstrate a proactive risk management process in the design of its product. For many this involves using pre-qualified components or materials. The device manufacturer has to do its testing with the final finished device. It is really late in the game to find out the tubing that they used is cytotoxic or a skin irritant. Therefore, it is more than prudent for the device manufacturer to purchase only biocompatible materials or components. Simply stating, “this material has historically demonstrated biocompatibility” is not sufficient. Let’s use polypropylene for example. The sentence, “polypropylene has historically demonstrated biocompatibility”, is true but an incomplete sentence. The sentence and the speaker are making the assumption that there is no need for quality control and that every sales person tells the complete truth. The sad reality is people make mistakes and try to hide the mistake and hope it goes undetected. I have seen “polypropylene” fail routine biocompatibility tests and I have seen ‘stainless steel’ rust. True stainless steel will not rust and true polypropylene is completely biocompatible. Someone in these supply chains was not truthful.
Passing the test
So, what makes something biocompatible? As the device as a whole is required to conform to ISO 10993, the manufacturer will be looking for components which by themselves can pass ISO10993 and/or USP <88> Class VI testing. The tests are conducted the same whether it is a finished device, a component or the raw resins. The device manufacturer may require the vendor to provide testing certificates to substantiate the claims of biocompatibility. Their levels of risk management will dictate whether or not your testing is enough or recent enough.
There are eight categories of testing under ISO 10993-1 and they are cytotoxicity, sensitization, irritation, acute systemic toxicity which includes pyrogenicity, subacute/sub-chronic toxicity, genotoxicity, implantation and hemocompatibility. The majority of biocompatibility testing is performed using extracts. An extract is where the material is submerge in different vehicles and then placed in an oven at elevated temperatures for a given period of time. The vehicles are then decanted off and used to conduct the tests.
Regardless of what a device is, it needs to demonstrate testing to cytotoxicity, sensitization and irritation. Once product has more contact than just skin, acute systemic toxicity is required. The USP <88> Class VI is a battery of tests which include an intracutaneous irritation test, acute systemic toxicity and a one week implantation.
This is a designation of a material and not to be confused with the designation of medical devices using the same nomenclature. It was originally designed for plastics but has now become a standard for many kinds of materials. If all three tests are passed the material gets a designation of being Class VI. Sub-acute, sub-chronic and genotoxicity tests are lengthy and expensive and typically left to the device manufacturer. A typical battery of biocompatibility tests on a plastic would consist of cytotoxicity, irritation, acute systemic toxicity, short-term implantation and hemocompatibility.
About the author
Laurence Lister is director of biocompatibility services at Toxikon Corporation in Bedford, MA. His 22-year industry experience encompasses every aspect of biocompatibility and toxicology testing, from study design to execution. He is the author of “Biocompatibility Testing: Tips for Avoiding Pitfalls, Parts 1 and 2” as well as a number of other articles.
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Testing testing: Larry Lister, Toxikon, discusses ISO10993 and issues of biocompatability