With hundreds of medical device companies continuously producing new, innovative technologies to improve and expand on their product ranges as well as an ever-increasing demand for these important devices, the global medical device market value is predicted to rise to $483.8 billion by 2022.

But as the industry has grown, so too has the demand for safer and more effective products. As a result, there has been an increase in new regulations, particularly in the EU and the US.

It is certainly not uncommon for manufacturers to market their products internationally, and as a result, different regulatory requirements may have to be met.

When it comes to demonstrating biological safety, different regions generally follow the same core principles (notably the evaluation strategy described in ISO 10993), although there are some subtle differences that medical device companies should be aware of.

For example, in Europe, under the new MDR medical devices cannot contain substances classified as Carcinogenic, Mutagenic, or toxic for Reproduction (i.e. Category 1A or 1B CMRs), or endocrine-disrupting substances in amounts over 0.1% w/w without justification.

If marketing in the US, particularly within the state of California, the Safe Drinking Water and Toxic Enforcement Act of 1986 (better known as Proposition 65) will need to be considered. The Office of Environmental Health Hazard Assessment (OEHHA) currently maintains a list of substances that are known to cause cancer or reproductive toxicity, as well as ‘Safe Harbor Levels’ for some of these hazardous substances. A warning label is required on any product (or medical device) that contains any of these carcinogens or reproductive toxins unless it can be shown that the anticipated exposures to such chemicals would not pose a significant risk of cancer or reproductive toxicity. This can be achieved by comparing the estimated exposures with the Safe Harbor Levels for each hazardous substance. In the absence of an OEHHA Safe Harbor Level, it may possible to derive a No Significant Risk Level (NSRL) or Maximum Allowable Dose Level (MADL), as appropriate, from the toxicological literature, and compare these values with the anticipated exposures.

Furthermore, if selling a medical device in Canada, then manufacturers are required to inform Health Canada as to whether their devices contain bis(2-ethylhexyl) phthalate (DEHP) or bisphenol A (BPA).

Conforming to such regulatory requirements would not be possible without a robust understanding of the component materials of a medical device. As the newly published ISO 10993-1 guidance illustrates, chemical characterisation is of the utmost importance. This characterisation may include not only a list of raw materials, but also extractables and leachables profiles. Cross-referencing these chemical constituents with those listed as carcinogens, mutagens or substances known to cause reproductive or developmental toxicity according to Regulation EC No 1272/2008 and Proposition 65 may therefore be an important exercise, depending on the intended geographical market, and may be worth encompassing within the biological evaluation process.

Bibra routinely screens raw materials and extractables/leachables profiles for hazardous substances in biological evaluations, and can provide either reassurance that these high-concern chemicals are absent or, if they are present, provide the additional expertise to address these.



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