Medical device developers are constantly looking for regulatory changes that may impact how they work. Sometimes minor changes in regulation can make their lives a lot easier, while alterations add extra steps to a process elsewhere. Changes to ISO 10993-17 have been anticipated for years, and one aspect of the new version will significantly impact device manufacturers—the toxicological screening limit (TSL).
What is the Toxicological Screening Limit (and why is it important)?
Chemical characterization (i.e., extractables and/or leachables) are often conducted as a first step in a biocompatibility testing program. However, these studies may yield hundreds or even thousands of compounds that subsequently require evaluation in a toxicological risk assessment (TRA). Evaluation of these large datasets in a TRA are both time-consuming and costly, and often the outcome is a recommendation to conduct additional testing. Ultimately, more tools are needed to streamline large risk assessments and help toxicologists better characterize potential risk.
This is where the toxicological screening limit (TSL) comes in. TSL is the cumulative exposure dose to an identified constituent over a specified time that will be without appreciable harm to health. The TSL can be used to establish whether the total quantity of an identified chemical constituent that is present, or that can be extracted, is at a quantity too low to elicit genotoxicity, cancer, systemic toxicity or reproductive/developmental toxicity.
There are two TSLs included in ISO 10993-17:2023—120 µg (micrograms) for short-term risk (≤ 30 days) and 600 µg (micrograms) for long-term risk (> 30 days). In short, if the total quantity of an extracted chemical (accounting for number of devices used at one time), falls below the threshold of 120 µg, no further evaluation of that chemical is required, and if greater than 120 µg, but less than 600 µg, the risk assessment could focus on short-term risk only. Therefore, the TSL screen has the potential to streamline very large datasets of extractable compounds by reducing the number of chemicals that need to be evaluated in the TRA.
The implications of the TSL for manufacturers are considerable. For example, if 1,000 chemicals are extracted in a chemical characterization study, but 70% of those chemicals fall below the short-term TSL (120 µg), this would result in a much smaller TRA, with only 30% of the chemicals requiring evaluation. By reducing the number of chemicals, and the time necessary to complete the TRA, manufacturers can get the results of their assessments earlier and make more informed decisions regarding how to move forward.
Finally, it is worth noting that application of the TSL is optional; however, the potential time- and cost- savings are significant and certainly provide the manufacturer with an option for streamlining TRAs.
How the TSL Relates to ISO 10993-17:2023
The TSL was introduced in ISO 10993-17:2023 to prioritize chemicals for toxicological risk assessment. Borrowing from the threshold of toxicological concern concept from ISO/TS 21726:2019, the updated standard establishes both a short-term and long-term limit based on exposure duration.
Exposure duration is crucial in determining potential toxicological risk. As mentioned above, ISO 10993-17:2023 includes two TSLs, short-term (≤ 30 days, TSL = 120 µg) and long-term (> 30 days, TSL = 600 µg). In both instances, the maximum total quantity of a chemical must be less than the TSL to meet the criteria for exclusion from further evaluation in the risk assessment. When maximum total quantities are below 120 µg, they can be excluded from evaluation of both short- and long-term risk; however, there may be circumstances where a chemical can be excluded from evaluation of long-term risk, but short-term risk will still need to be considered (e.g., maximum total quantity is > 120 but < 600 µg).
Applying the TSL to data generated in a chemical characterization study allows the toxicologist to conduct a comprehensive TRA more efficiently. By screening out compounds below the proposed thresholds, toxicologists can focus their evaluation on those compounds extracted at higher concentrations and have an increased likelihood of presenting a toxicological concern.
Provided that the specified criteria are met—such as the chemical constituents are identified and not Cohort of Concern substances. If the maximum total quantity of a chemical falls below the TSL, no further risk evaluation is deemed necessary. However, the comparison between each chemical’s maximum total quantity and the TSL values must still be documented in the TRA.
For medical device manufacturers, this adds a degree of precision to the risk assessment process and aids in efficiently allocating resources, focusing on the chemicals that require the most attention. As such, understanding and applying the TSL is not just an academic exercise but an essential part of ISO 10993-17:2023.
What Device Manufacturers Should Consider
The introduction of TSL holds immense significance for device manufacturers, potentially saving them significant time and resources. However, several considerations are crucial to effectively leveraging this new tool.
Foremost is understanding the maximum total quantity of each chemical. The maximum total quantity is either the amount that is present, or that can be extracted from a device, and also considers the number of devices to which a patient can be exposed at one time.
For example, if 50 µg/device is extracted from a device in an exhaustive extraction, and a patient is exposed to one device, the maximum total quantity is 50 µg, which would be below the short- and long-term TSL, and as such, would not require further evaluation in the TRA. However, if the patient could be exposed to 10 devices simultaneously, then the maximum total quantity would be 500 µg. In this case, it would fall below the long-term TSL, but not the short-term TSL, and would still need to be evaluated for short-term risk in the TRA.
However, knowing when TSL can be applied and when it cannot is vital. Below are some examples of specific scenarios where the TSL cannot be used:
- Cohort of Concern chemicals: Cohort of Concern chemicals are highly potent toxicants and are excluded from use of the TSL.
- Unidentified compounds: Constituents with unknown or incomplete chemical identity cannot be screened using the TSL approach as it cannot be ruled out that they are not Cohort of Concern chemicals.
- VOCs from gas-pathway devices: Volatile organic compounds (VOCs) from gas pathway devices are evaluated using approaches and thresholds described in the ISO 18562 series.
- Infants and neonates: Devices intended for this vulnerable population cannot rely on the TSL for safety assessments due to their unique susceptibilities.
Even if certain compounds are screened using TSL, documentation comparing the chemical’s maximum total quantity to the TSL remains essential.
In 2022, WuXi AppTec evaluated the protectiveness of the proposed TSLs (short- and long-term) using our internal database of more than 18,000 real-world medical device extractables. This evaluation determined that 1% and < 0.5% of the chemicals evaluated for short- and long-term potential risk, respectively, may result in a derived tolerable intake (TI) less than the TSL.
These observations are consistent with, and lower than, the historical frequency distribution of no observed adverse effect level (NOAEL) values used to establish the well-accepted non-cancer threshold of toxicological concern (TTC) values (i.e., lowest 5th percentile, protective for > 95% of chemicals). Overall, based on an evaluation of medical device extractables from 2015 to 2021, the results support the protectiveness of the TSL approach for medical device chemicals. These data were also presented at the 2022 Society of Toxicology conference.
However, with ongoing advancements in research and technology, our understanding of chemical toxicities continues to evolve. Hence, staying informed about the latest research and regulatory developments is crucial. For complex devices or uncertain situations, consulting with regulatory experts can provide much-needed guidance and ensure the most appropriate application of the TSL approach.
Incorporating the TSL into risk assessment could herald significant efficiency gains for medical device manufacturers without compromising safety. However, it’s important to remember that ISO 10993-17:2023 does not make the application of TSL obligatory—instead, it provides an optimized route to manufacturers who wish to streamline their testing processes. Therefore, manufacturers can perform comprehensive evaluation of all chemicals in their devices if they choose. One key to correctly applying the TSL is partnering with a well-equipped, experienced lab that understands its intricacies and can aptly incorporate it into the TRA. Moreover, evolving standards like ISO 10993-17 underscore the importance of collaborating with a laboratory that keeps pace with regulatory changes, ensuring manufacturers navigate the dynamic landscape of medical device regulation with confidence and compliance.