Sharlee L. More, Ph.D., DABT, Associate Director, Toxicology, Regulatory Affairs, MCRA LLC11.13.23
Toxicological risk assessment (TRA) of medical device constituents is a key aspect of evaluating device biocompatibility. The TRA can be used to address several endpoints including systemic toxicity, genotoxicity, carcinogenicity, and reproductive/developmental toxicity. As such, the last revision to ISO 10993-17 was in 2002. Since the standard is heavily relied on for performing toxicological risk assessments, the release of updated ISO 10993-17 guideline has been long awaited and highly anticipated.
The updated guidelines are expected to create a paradigm shift in the performance of medical device toxicological risk assessments. The first notable change is the title. ISO 10993-17:2002 was called “Establishment of allowable limits for leachable substances” but ISO 10993-17:2023 is labeled “Toxicological risk assessment of medical device constituents.” This title is more descriptive of the standard’s contents and provides more guidance on the requirements for conducting a TRA of extractable or leachable constituents from medical devices. ISO 10993-17:2023 also removed some terms and introduced new ones. The new standard removed “allowable limit,” “benefit factor,” “proportional exposure factor,” “utilization factor,” and “tolerable exposure” and added “toxicological risk,” “Toxicological Screening Limit,” “Total Quantity,” “Exposure Dose,” “Release Kinetics,” “Point of Departure,” and “Margin of Safety.” A description of these new terms and their use in the toxicological risk assessment paradigm of medical device constituents is outlined in this article.
There are some exceptions to TSL use. The TSL cannot be applied to chemical constituents that are cohorts of concerns or compounds with inadequate chemical identity. Additionally, it cannot be used for long-term contacting medical devices in neonates, including preterm, or very young infants. VOCs from gas pathways devices are not eligible to be assessed with the TSL, and the TSL cannot be used to address irritation, or other select endpoints.
There are many advantages of utilizing the TSL during a TRA. The TSL allows a first step in analyzing the risk of known compounds by using a conservative threshold to screen out compounds that need no further evaluation. This allows the toxicologist to focus on compounds at concentrations that may induce toxicity, along with focusing on cohorts of concern substances.
The first option (assuming daily exposure to TQ) has been a conservative approach used historically by toxicologists. However, for long-term or prolonged devices, this can lead to total exposure doses several orders of magnitudes above the TQ determined in exhaustive extraction.
ISO 10993-17:2023 outlines two approaches to estimate patient exposure dose based on kinetic data use. If release kinetic information is obtained during chemical characterization, the experimental data can be used to estimate the patient exposure. If no release kinetic data is available, then assumed kinetic data can be implemented. Assumed kinetic estimates patient exposure by estimating release kinetics based on the TQ extracted and the medical device contact duration. It does not require additional testing to be performed during exhaustive chemical characterization. Specifically, the exposure dose (EEDmax) can be calculated by dividing the total quantity (in mg) present or extracted from the medical device (e.g., from an exhaustive extraction study) by the bodyweight and the assumed worst-case release duration (Rd; in day). The assumed worst-case release duration represents the lowest number of medical device exposure days, considering the ISO 10993-1 exposure category applicable to the medical device. The second table (page 18) outlines the Rd values for each time period for prolonged and long-term medical device contact duration categories.
Utilizing kinetic data to estimate patient exposure to a chemical constituent is a key development. Without guidance for using assumed kinetic data, very conservative approaches often were taken, including assuming the patient is exposed to the TQ every day. This often led to risk characterizations that indicated a potential risk of systemic toxicity, and thus led to more biocompatibility (and sometimes unnecessary) testing. The introduction of kinetic data use allows a risk assessor to conduct a TRA for a scenario that is more representative of clinical exposure. Utilizing kinetic data can produce toxicological risk assessments that identify potential patient risk to hazards while limiting unnecessary testing.
By using kinetic data to estimate patient dose, a TI can be derived that reflects the period duration being considered. For example, if evaluating the scenario in which the total quantity is released over the first 30 days, toxicological data (and the associated uncertainty factors) for sub-acute studies can be relied on rather than a chronic study. This data is more representative of adverse effects from the exposure scenario considered and will often develop a higher TI than for a chronic scenario. As such, an acute TI can be derived for acute exposure periods, while a chronic TI can be derived for chronic exposures. However, it is not necessary to derive a TI for every period duration. Specifically, a chronic TI is sufficient to cover all time points since it is the most conservate TI.
Clarifying when a chemical constituent exposure dose will not harm human health is a necessary update as it clearly states what should be considered a toxicological risk, or requires further justification. There often are inconsistencies between agencies and risk assessors about what MOS is associated with no increased patient risk. This guidance provides better clarification on when toxicological risk must be further addressed.
ISO 10993-17:2023 introduces new tools, including the use of a TSL and kinetic data for estimating patient exposure. While use of all the new tools is not required, these techniques allow toxicologists to focus on chemicals that are present at concentrations that pose a toxicological risk. Further, the TRA more closely reflects patient clinical exposure compared to past conservative assessments. Although the update provides a more consistent approach to evaluating toxicological risk, companies should still rely on expert judgment to ensure a successful TRA since there are nuances to using these new tools.
Dr. Sharlee More is a board-certified toxicologist and an associate director, toxicology, regulatory affairs, at MCRA. Dr. More provides state-of-the-art device toxicology services that remain in line with current and future regulatory expectations. Dr. More is proficient in conducting toxicological risk assessments, designing and evaluating both in-vitro and in vivo biological testing, compiling benefit-risk assessments, writing state of the science reviews, building and applying physiologically based pharmacokinetic models, and helping address deficiencies from the U.S. FDA and EU notified bodies in accordance with international guidelines.
The updated guidelines are expected to create a paradigm shift in the performance of medical device toxicological risk assessments. The first notable change is the title. ISO 10993-17:2002 was called “Establishment of allowable limits for leachable substances” but ISO 10993-17:2023 is labeled “Toxicological risk assessment of medical device constituents.” This title is more descriptive of the standard’s contents and provides more guidance on the requirements for conducting a TRA of extractable or leachable constituents from medical devices. ISO 10993-17:2023 also removed some terms and introduced new ones. The new standard removed “allowable limit,” “benefit factor,” “proportional exposure factor,” “utilization factor,” and “tolerable exposure” and added “toxicological risk,” “Toxicological Screening Limit,” “Total Quantity,” “Exposure Dose,” “Release Kinetics,” “Point of Departure,” and “Margin of Safety.” A description of these new terms and their use in the toxicological risk assessment paradigm of medical device constituents is outlined in this article.
Toxicological Screening Limit
The Toxicological Screening Limit (TSL) is defined as the “cumulative exposure dose to an identified constituent over a specified time period that will be without appreciable harm to health.” The TSL can be used to determine whether the total quantity (TQ) of an identified constituent is too low to elicit genotoxicity, cancer, systemic toxicity, or reproductive or developmental toxicological risk. Therefore, the identified constituent can be judged to be of negligible toxicological risk and does not require further risk evaluation. Default TSLs have been established based on the threshold of toxicological concern values outlined in ICH M7 and ISO/TS 21726:2019. The TTC values, and therefore the TSL values, are protective for carcinogenic and non-cancer effects. They are generally applicable for oral or parenteral exposure routes for adults, pediatrics, and pregnant woman.There are some exceptions to TSL use. The TSL cannot be applied to chemical constituents that are cohorts of concerns or compounds with inadequate chemical identity. Additionally, it cannot be used for long-term contacting medical devices in neonates, including preterm, or very young infants. VOCs from gas pathways devices are not eligible to be assessed with the TSL, and the TSL cannot be used to address irritation, or other select endpoints.
There are many advantages of utilizing the TSL during a TRA. The TSL allows a first step in analyzing the risk of known compounds by using a conservative threshold to screen out compounds that need no further evaluation. This allows the toxicologist to focus on compounds at concentrations that may induce toxicity, along with focusing on cohorts of concern substances.
Estimating Potential Patient Exposure
ISO 10993-17:2023 provides guidance on estimating potential patient exposure to a chemical constituent. There are three specific techniques for estimating the patient exposure dose: Assuming the patient is exposed to the TQ on a daily basis; utilizing experimental kinetic data; and utilizing assumed kinetic data.The first option (assuming daily exposure to TQ) has been a conservative approach used historically by toxicologists. However, for long-term or prolonged devices, this can lead to total exposure doses several orders of magnitudes above the TQ determined in exhaustive extraction.
ISO 10993-17:2023 outlines two approaches to estimate patient exposure dose based on kinetic data use. If release kinetic information is obtained during chemical characterization, the experimental data can be used to estimate the patient exposure. If no release kinetic data is available, then assumed kinetic data can be implemented. Assumed kinetic estimates patient exposure by estimating release kinetics based on the TQ extracted and the medical device contact duration. It does not require additional testing to be performed during exhaustive chemical characterization. Specifically, the exposure dose (EEDmax) can be calculated by dividing the total quantity (in mg) present or extracted from the medical device (e.g., from an exhaustive extraction study) by the bodyweight and the assumed worst-case release duration (Rd; in day). The assumed worst-case release duration represents the lowest number of medical device exposure days, considering the ISO 10993-1 exposure category applicable to the medical device. The second table (page 18) outlines the Rd values for each time period for prolonged and long-term medical device contact duration categories.
Utilizing kinetic data to estimate patient exposure to a chemical constituent is a key development. Without guidance for using assumed kinetic data, very conservative approaches often were taken, including assuming the patient is exposed to the TQ every day. This often led to risk characterizations that indicated a potential risk of systemic toxicity, and thus led to more biocompatibility (and sometimes unnecessary) testing. The introduction of kinetic data use allows a risk assessor to conduct a TRA for a scenario that is more representative of clinical exposure. Utilizing kinetic data can produce toxicological risk assessments that identify potential patient risk to hazards while limiting unnecessary testing.
Deriving the Tolerable Intake
ISO 10933-17:2023 provides more guidance on deriving the Tolerable Intake (TI) for each chemical constituent. The TI is derived by dividing the point of departure (PoD) by the Modifying Factor, which is the product of the uncertainty factors (UFs). The PoD represents the most critical (the lowest) clinically relevant dose. The PoD is typically expressed in mg/kg/day or µg/kg/day. ISO 10933-17:2023 outlines default UFs to implement when deriving a TI. These factors include adjustments for uncertainty in route-to-route extrapolation, exposure duration, PoD, data applicability, and data quality. These UFs, however, are not always the same UFs adopted by other agencies.By using kinetic data to estimate patient dose, a TI can be derived that reflects the period duration being considered. For example, if evaluating the scenario in which the total quantity is released over the first 30 days, toxicological data (and the associated uncertainty factors) for sub-acute studies can be relied on rather than a chronic study. This data is more representative of adverse effects from the exposure scenario considered and will often develop a higher TI than for a chronic scenario. As such, an acute TI can be derived for acute exposure periods, while a chronic TI can be derived for chronic exposures. However, it is not necessary to derive a TI for every period duration. Specifically, a chronic TI is sufficient to cover all time points since it is the most conservate TI.
Assessing Probability of Increased Patient Risk
ISO 10993-17:2023 prescribes a way to assess whether an increased patient risk exists from exposure to chemical constituents in medical devices. A margin of safety (MOS) is calculated as the ratio of the constituent’s tolerable intake (numerator) and its exposure dose (denominator). The guidance states that a chemical constituent exposure dose is considered to be without appreciable health hazards if the MOS exceeds 1 and its contributing values are conservative in nature. Conservative in nature is shown by reducing the TRA’s uncertainty via deriving the TI (application of uncertainty factors) and estimating the worst-case exposure dose (constituent identity and quantity are confident and accurate, respectively, and EEDmax is relevant to medical device use). Toxicological risk, or the “probability of a specified degree of an adverse reaction occurring in response to a specified level of exposure” needs to be further addressed by other means when any of the following apply:- MOS < 1 based on release kinetics is used
- Cancer risk of a human carcinogen, or suspected human carcinogen, exceeds 1 in 100,000 or
- The MOS is judged to represent possible toxicological risk
Clarifying when a chemical constituent exposure dose will not harm human health is a necessary update as it clearly states what should be considered a toxicological risk, or requires further justification. There often are inconsistencies between agencies and risk assessors about what MOS is associated with no increased patient risk. This guidance provides better clarification on when toxicological risk must be further addressed.
Adoption by Regulatory Agencies
ISO 10993-17:2023 is considered state of the art. European Union notified bodies expect ISO 10993-17:2023 guidelines to be utilized in the TRA. If the FDA does not recognize ISO 10993-17:2023 in full, the agency will provide an extent of recognition that specifies what will not be recognized in the updated guidance. Until this is issued, the use of the ISO 10993-17:2023 is “at risk.” There has been no official notification in Japan for adopting ISO 10993-17:2023 but the PMDA typically complies with the latest versions of ISO 10993 standards.Final Take-Aways
The long-awaited updates to ISO 10993-17 did not disappoint, as they provide a systematic approach for conducting a TRA of medical device constituents. It outlines best practices for hazard identification, patient exposure dose approximation, risk estimation, and risk acceptability. Overall, the updated ISO 10993-17 should help with limiting unnecessary biocompatibility testing by providing guidelines that avoid performing overly conservative TRAs.ISO 10993-17:2023 introduces new tools, including the use of a TSL and kinetic data for estimating patient exposure. While use of all the new tools is not required, these techniques allow toxicologists to focus on chemicals that are present at concentrations that pose a toxicological risk. Further, the TRA more closely reflects patient clinical exposure compared to past conservative assessments. Although the update provides a more consistent approach to evaluating toxicological risk, companies should still rely on expert judgment to ensure a successful TRA since there are nuances to using these new tools.
Dr. Sharlee More is a board-certified toxicologist and an associate director, toxicology, regulatory affairs, at MCRA. Dr. More provides state-of-the-art device toxicology services that remain in line with current and future regulatory expectations. Dr. More is proficient in conducting toxicological risk assessments, designing and evaluating both in-vitro and in vivo biological testing, compiling benefit-risk assessments, writing state of the science reviews, building and applying physiologically based pharmacokinetic models, and helping address deficiencies from the U.S. FDA and EU notified bodies in accordance with international guidelines.