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Understanding ‘Assumed Release’ in ISO 10993-17:2023

Apr 5, 2024 | General, MDR, Medical Device Testing, Regulatory, Technical Expertise

The latest update to ISO 10993-17:2023 introduces significant changes to how medical device manufacturers and toxicologists can estimate and incorporate constituent release into the toxicological risk assessment (TRA) process. We explore the concept of release kinetics and the novel idea of “assumed release.”

Understanding release kinetics can lead to a more accurate estimate of potential risk in the TRA, but practical challenges limit its application to a few compounds (i.e., targeted analytes). Assumed release, on the other hand, may offer an alternative approach through exposure adjustments based on the fewest number of days in each device category.  

We also examine the regulatory implications of these changes. Regulators across the industry are still adapting and clarifying their positions on the new guidance in ISO 10993-17:2023. For medical device manufacturers, understanding and integrating these new concepts into TRAs is vital for addressing various biological endpoints, achieving regulatory success, and keeping patients safe.

How does ISO 10993-17:2023 explain release kinetics?

Release kinetics is a new term in ISO 10993-17:2023. Release kinetics is defined as the quantity of a constituent released from a medical device as a function of time. Experimentally, release kinetics data can be obtained in a simulated-use or leachables study that evaluates the extractables profile at different time points.

ISO 10993-17:2023 indicates that release kinetics are obtained using targeted approaches. However, truly targeted approaches require a reference standard and are only feasible for one or very few compounds of interest. Therefore, the more commonly conducted non-targeted simulated-use or leachables studies would not necessarily be considered release kinetics studies. However, they provide a profile of constituent release over designated time points and serve to refine exposure estimates in the toxicological risk assessment (TRA).

Introducing ‘assumed release’

ISO 10993-17:2023 also introduces a new concept called assumed release. That is, when experimental release kinetics data are not available, exposure can be assumed to occur based on the fewest number of exposure days for each category (e.g., 2 days for prolonged, 31 days for exposure up to 1 year, and 366 days for exposure greater than 1 year). Adjusting a maximum total quantity extracted by 2, 31, or 366 provides a profile of assumed release.

How will assumed release affect the TRA? 

TRAs based on exhaustive extractables studies have become increasingly complex in recent years. The large number and quantity (e.g., µg/device) of chemicals extracted in these studies generally yield unfavorable TRAs, which then leads to device manufacturers needing to conduct additional biocompatibility testing or follow-up chemistry (e.g., simulated-use studies) to mitigate concerns. 

The simulated-use study provides a more realistic extractables profile due to the clinically relevant extraction conditions (solvent and temperature). Data are collected at multiple time points, so toxicologists can refine exposure estimates in the TRA based on what and how much is released and when. Experimental studies provide helpful information for the TRA, but if they’re conducted following the original extractables study, it can take months to complete the chemistry study followed by the TRA.

Using assumed release data could offer an alternative to this path, potentially reducing the need for follow-up biological or chemical testing saving time and resources. For example, if evaluating a long-term implant (> 1 year), the data from the exhaustive study can be adjusted by 2, 31, and 366 days to provide a profile of assumed release.

These values can then be compared to the appropriate tolerable intakes for those exposure durations to evaluate acute/subacute, subchronic, and chronic exposure. Applying these adjustments to the data already available can potentially reduce the need for follow-up biological or chemical testing.

The regulatory perspective on assumed release

Industry toxicologists and regulators are still grappling with the application of assumed release and potential limitations. ISO 10993-17:2023 stipulates that for a toxicological risk to be acceptable, it must be substantiated by evidence indicating that the assumed release is conservative in relation to the intended use of the medical device. This requirement underscores the need for expert judgment in interpreting the results.

Whether global regulators are prepared for a shift toward assumed release data is a matter of time. Since ISO 10993-17:2023 has been published, EU notified bodies may expect immediate compliance, considering it is the current state-of-the-art. Also, regulators just recently released their recognition of the standard, and assumed release is within the scope of recognition.

The industry is progressing towards a better understanding of ISO 10993-17:2023, but there is still a journey ahead regarding widespread application and regulatory harmonization.

A final word 

Keeping up with regulatory revisions is only half the battle for device manufacturers—they must also navigate new challenges in real time. A TRA that includes information around release kinetics, assumed release, or estimated release in the form of a non-targeted simulated-use or leachables study, allows toxicologists to refine the exposure assessment, ultimately creating a better understanding of potential risk. Because the TRA can address several biological endpoints (e.g., systemic toxicity, carcinogenicity, genotoxicity, developmental and reproductive toxicity), generating a TRA that appropriately evaluates potential risk is invaluable. Manufacturers with questions or concerns about their in-house capacity or capability to collect and apply this new data may consider engaging an experienced lab testing partner for help.

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