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The mysteries of the 2018/2019 edition of biocompatibility standard ISO 10993

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Mark Turner, managing director of Medical Engineering Technologies (MET), a UK-based testing facility, explores the mysteries of the 2018/19 edition of ISO 10993 and chemical characterization.

There have been a series of earthquakes in medical device regulation recently. Not only has the world been turned upside down by the new Medical Device Regulation (MDR)1 - the key European regulation system, but the over-arching biocompatibility standard ISO 10993-12 has had revolutionary changes.

When it comes to assessing the biocompatibility of a device, the new edition of the toxicity standard radically increases the emphasis on chemical knowledge (chemical characterization) of the device or drug delivery product. This has been added to the biocompatibility matrix3 as the first requirement for every category of device.

The standard calls for a risk based process in this assessment using chemical characterization as the key input. This characterization includes all the chemical data that can be found relating to the device. It should encompass components, molding materials, any additives, processing materials, packaging materials, labels, inks and every other material involved in making the device. This information would ideally include toxicity information for each material (this can often be found in the literature if the material supplier does not have the data). Also, it is important to consider the chemical formula and quantities of all component materials, health and safety data as well as any other data and test results. Other information (which is not necessarily chemical) also needs to be considered e.g. particle release and materials of biological origin.

Chemical characterization is a combination of information obtained by reviewing information sources including:

The same information is required on any possible contamination. Examples of contamination are:

Once the chemical data has been gathered, a view can be taken on whether it is adequate to demonstrate safety. If all the input materials have good data and it can be rationalized that no new hazards would be introduced during processing, sterilization and storage, further work might be limited to the risk analysis. Possible scenarios for this are that the materials are used in another product which already has full testing in place, or that the input materials individually have data that addresses all the toxicity endpoints and the production, the sterilization and all other processing parameters are exactly the same as other products in a range.

A trained person can conduct this gap analysis, identifying areas of missing information and areas of concern. If the gap analysis identifies information is missing, chemical analysis of extractable materials will be required. Biological testing should only be applied when chemical information gathering (and any chemical testing) delivers inconclusive results. A toxicologist is required to assess the implications of any toxicity information, or its absence. This toxicological risk analysis can conclude whether or not the device is safe to use or if biological testing is required to confirm some aspect of safety. Hence, biological testing is the ‘gold standard’ but also the ‘last resort’.

Case study

We explore an example of chemical characterization for a wound dressing which offers up to 3 days of contact.

Component materials

These all have evidence of safety for up to 24 hours of use and include spun bond polyester contact layer, hydrogel absorber, a polyurethane cover, adhesives and a polythene release liner.

Hazards

The hazards identified in production included:

Results

The toxicologist concluded that the chemical characterization is incomplete because we do not know the quantities or nature of contaminants from production. The biocompatibility test matrix adds implant and sub-chronic risks to those indicated for 24 hours contact.

At this point, a chemical analysis was required to identify and quantify the full range of materials that could be made available to the patient. An ‘extractables and leachables’ analysis or in the case of a medical device a ‘simulated use leachables analysis’ should be conducted.

The analytical chemistry tools available are very powerful and can easily find chemicals in the dressing that would never be released to the patient. Extraction and analytical techniques should be selected to find everything that could migrate in use, but not include chemicals that will not be released when the product is used.

This additional data now completes the chemical characterization of the dressing and allows the toxicological risk analysis to progress.

Conclusion

In conclusion the chemical characterization of a device is now required in ISO 10993 and this is listed in the testing matrix for every category of device. Leachables analysis is not the only route to obtaining this information, but it is the most likely method to find unexpected materials. The vigour of application of chemical analysis should be tailored to the body contact and risk analysis for the device. The chemical characterization, through a toxicological risk analysis, is used to address the toxicity end points required for the body contact involved.

References

  1. European Medical Device Regulation. https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32017R0745
  2. ISO 10993-1:2018 Biological evaluation of medical devices -- Part 1: Evaluation and testing within a risk management process
  3. Biocompatibility matrix extracted from ISO 10993-1. https://met.uk.com/medical-device-testing-services/biocompatibility
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