Chemical characterization of medical devices (part V)

Part V  Where are the pass/fail criteria? Hello, AET!

There are none! Don’t be too disappointed, you already found out about the worst news in this section, it will get better.

Indeed, there are no pass/fail criteria for the chemical characterization, just one fail criterion. According to the MDR (GSPR, section 10.4.1/10.4.2) medical devices shall not have more than 0.1% (w/w) of ‘substances which are carcinogenic, mutagenic or toxic to reproduction’ (CMR) or substances having endocrine-disrupting properties’ (ED). This requirement refers to the overall concentration of these – to put it nicely – undesirable substances, not after extraction. Having a theoretical evaluation if CMR/ED substances could be present in your device, will be of great help as there is not one single test for CMR/ED substances.

If some of these CMR/ED substances are found in the chemical characterization of the extract, it might be needed to dissolve the whole product and to analyze again. Of course, this will lead to technical challenges. So, better try to avoid CMR substances completely under all circumstances.

Fine, avoiding CMR and ED substances. Fine, but what else do I need to do (according to ISO 10993-17:2009)? You have to evaluate all found and identified substances from the analytical methods previously described regarding a potential toxic effect. Evaluating the traces of potassium which are released from your product could be a minor challenge, but evaluating a specific amount of an organic substance which you were not aware of before? How is the toxicity of methylene chloride, methyl methacrylate or cyclohexanone? Probably you need a person, internally or externally, which helps you with this evaluation. If you find regularly similar or same substance in your analytics, this could give a synergistic effect and save a lot of time and effort.

But what about the found and not identified substances within the results? For this you need a trick, and currently, one appropriate trick is the threshold of toxicological concern (TTC) concept as proposed in the ISO 10993-18:2020. The TTC concept was developed for food industry, but can be used for medical devices, too. To put it into simple words: beside a few exceptions like aflatoxin-, azoxy- and nitroso-containing substances it is acceptable to have an exposure of one substance, even an unidentified substance to a patient if it’s below 1.5 µg/day.

Taking into account the used amount of solvent, the surface of the medical device, but also the number of medical devices used for the extraction, and the number of medical devices usually used per day, this can be translated into a concentration. And exactly this concentration shall still be detectable by the analytical method used. Otherwise all unidentified substances – and there will be unidentified or poorly identified substances in >50 % of all analytical runs – will bring you into trouble. How do you want to argue that the unidentifiable substance X is harmless, when the detection limit is too high to give you results according to the used TTC values?

Fine, AET and TTC is important. But is there only one TTC value? Of course, not! Life’s never easy! The value of 1.5 µg/day translated into a detection limit is challenging for the lab as well for you. Why for you? Having 40 detected substances in the extract of your medical won’t make you happy. Fortunately, there are other approaches to TTC, which might be suitable, too. The ISO/TS 21726:2019 proposes an approach based on the contact duration and TTC values from 1.5 µg/day (> 10 years duration of body contact) to 120 µg/day (< 1 month duration of body contact). The concept of Cramer classes proposes an approach based on chemical structures – not applicable in case of completely unidentified substances - with TTC values between 90 to 1,800 µg/day. Please be aware that the last-mentioned concept and the ISO/TS 21726 have explicitly some exclusions and constraints, e.g. excluding all substances which belong to the CoC (cohort of concern). Easy to understand, aflatoxins, N-nitroso compounds and others aren’t tasty. Hopefully, this article was more delicious for you than the CoC!