The new version of ISO 10993-17 is expected to be published very soon. This is a major revision of the standard for biological safety evaluation of devices and includes guidance for conducting toxicological risk assessments (TRA). Revisions of ISO 10993-1 in 2018 and ISO 10993-18 in 2020 heavily focused on the chemical characterization of materials and further propelled the structural identification of compounds that are above the analytical evaluation threshold from analytical investigation of exhaustive and exaggerated extractions for prolonged and long-term medical devices. The proposed revisions in 10993-17 will expand the toxicological risk estimation including prioritizing chemicals based on the screening limit, estimating an exposure dose for each constituent, and using risk acceptance criteria to evaluate the margin of safety. Regulatory agencies expect manufacturing companies to fully satisfy the requirements of the standard, which might delay the device testing and submission processes. A well-organized TRA is the key to a successful biocompatibility assessment and regulatory compliance. To conduct an accurate and compelling TRA, a thorough understanding of chemical constituents, and collaboration across various areas of expertise (analytical chemists, manufacturers) is a must.
The Toxicological Screening Limit (TSL) of chemical constituents is the amount below which no toxic effects are expected including systemic, genotoxic, or reproductive/developmental toxicity. The highly conservative extraction conditions coupled with extremely low analytical detection limits have greatly increased the numbers of reported compounds and as a result the time and effort spent on the risk evaluation of extractable substances that may have a negligible toxicological concern. The TSL is a provision that screens out extractable compounds that are below a level of concern, thus placing greater emphasis on chemical constituents that truly warrant toxicological evaluation. The concept of TSL is not applicable to compounds that can cause irritation, members of the cohort of concern, chemicals that lack analytical identification, and sensitive populations (neonates). Depending on the intended use of the medical device, TSL may accelerate the toxicological risk assessment and the overall biocompatibility evaluation process. If the chemical excipient is below TSL, it is of negligible toxicological risk and no further risk evaluation is required. However, when the chemical quantity is above TSL, a worst-case exposure dose should be estimated, and further risk evaluation is necessary. This process requires expert judgment whether the chemical constituents of interest can pose a toxicological risk with the intended use.
The exposure dose is a quantity of the chemical that comes into contact with the individual over a specified time. It should reflect the maximum amount of exposure that an individual could experience (worst-case scenario) to the chemical constituent based on the planned use of the medical device. Information from the extractable testing and release kinetics of the extractable could help to estimate a clinically relevant exposure dose. Devices that are applicable to unique susceptible individuals may require an additional exposure dose estimation based on body weights that differ from the average for adults. The medical device contact and duration of use predominantly determine the worst-case exposure dose estimation calculation. If two or more chemical constituents have the same target organ toxicity, the individual estimated exposure doses should be added together. Proper design of extraction or leaching studies is crucial to estimate the clinically relevant exposure dose and to conduct a comprehensive toxicity assessment.
The margin of safety (MOS) provides information on the level of safety or risk involved with a chemical constituent. It is the ratio of the constituent’s tolerable contact level or tolerable intake or threshold of toxicological concern to its estimated exposure dose. If the MOS of a chemical constituent exceeds one, i.e., the estimated exposure dose is within its tolerable toxicological risk, the chemical constituent does not pose any meaningful risk of harm to individual health. If the MOS of a chemical constituent is below one, it does not mean the chemical constituent is any direct health risk to individuals but does warrant further investigation and assessment. An expert toxicologist partnership would help to navigate whether the chemical constituent is a perceived risk or a true potential risk. To ensure regulatory compliance and timely submission, it is even more important today to keep communications transparent and open among all stakeholders (toxicologists, analytical chemists, regulators, and others) of the medical device. The biggest challenge that manufacturers face now is choosing the right laboratory testing partners and other contract research organizations to support their medical devices and products.
To learn more about ISO 10993-17 revision and how it may impact your medical device and biocompatibility testing submission, please contact us today 855.463.1633 | email@example.com | medinstitute.com.
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