Dr. Sherry Parker, Senior Director, Regulatory Toxicology, WuXi AppTec Medical Device Testing 12.15.21
A significant increase in understanding the chemical constituents in medical devices and patient safety risks is underway. Sparked by the publication of ISO 10993-1:2018,1 this standard is intended to instill a greater focus on a risk-based approach to biological evaluations. Further changes and additions to the standards continue to support this effort, and the upcoming version of ISO 10993-172 will provide critical guidance for the evaluation of chemical constituents.
Medical device manufacturers that make the necessary efforts to stay ahead of these evolving standards can increase their chances of future regulatory success. Companies should take advantage of this time before the standards are implemented to stay informed of developments and better understand the impact of the new requirements and their associated revisions.
Impact of ISO 10993-18 on Toxicological Risk Assessments
The publication of ISO 10993-18:20203 established a need for medical device manufacturers to investigate their products’ chemical constituents more rigorously. Consequently, these evaluations can produce considerably larger amounts of data than in the past. This requires toxicologists to assess the risk of each chemical identified.
Companies typically use chemical characterization testing to provide a detailed understanding of the chemical constituents in medical device materials and finished products. By gathering chemical information, often through performing extractable and leachable (E/L) testing, chemists can detect chemical constituents to the level of manufacturing process residuals. Laboratories then evaluate these chemical constituents in a toxicological risk assessment (TRA). Still, results can trigger questions when unknown chemicals remain or potentially toxic substances are present. The combination of these activities helps identify any remaining device concerns before moving forward with additional testing.
One notable revision to ISO 10993-18 is the introduction of the analytical evaluation threshold (AET). Using the AET, laboratories must identify and quantify all chemicals at or above the determined threshold to garner more complete chemical characterization at a level to support the TRA. As the duration of a device’s intended patient exposure increases, experts must set a lower identification and quantification threshold for chemical characterization. Furthermore, to account for the analytical uncertainty of semi-quantitative screening, it is expected that uncertainty factors are used in the AET calculation. This expectation results in reporting chemicals well below the threshold of toxicological concern.
Ultimately, these lower reporting thresholds create massive data sets. Not only are toxicologists challenged by working with these massive data, but the regulatory expectation is to evaluate each chemical’s hazard and toxicological risk. Adhering to these expectations is important when trying to achieve regulatory success.
Suppose testing laboratories cannot reach these low reporting thresholds due to large devices, extraction volumes, or limits of analytical sensitivity. In those cases, laboratories must concentrate the extracts to increase the sensitivity of the analysis. Concentrating extracts is not ideal, as it may produce volatile compounds losses and degradation products. What results is a longer list of extractable chemicals with questionable clinical relevance and even more work for the toxicologist.
In these situations, results are likely to overestimate a realistic level of toxicological risk. Overestimating the toxicological risk of a chemical could result in unnecessary regulatory concerns. An experienced toxicologist can strike the right balance between under and overestimating toxicological risks, and provide their perspective on resolving potential regulatory concerns before implementing additional testing.
Evaluating Relevant Toxicological Risks
For biological evaluations of medical devices, identifying relevant biological risks is critical for determining subsequent testing strategies. Chemical information is now a requirement for biological evaluations according to ISO 10993-1:2018. The use of chemical characterization and understanding the contact nature, duration, and device clinical use provides the necessary information for developing biological evaluation strategies.
Though many biological risks can be addressed with biocompatibility testing, there are also biological risks that can be addressed with a TRA, including systemic toxicity (acute, subacute/subchronic, and chronic), carcinogenicity, genotoxicity, and reproductive and developmental toxicity. Other biological endpoints, including local tissue effects (irritation, sensitization, and implantation), pyrogenicity, and hemocompatibility, are typically addressed with biological testing only.
Experts develop a biological evaluation strategy to plan which endpoints a laboratory addresses with a TRA and which endpoints they deliver with biological testing. If toxicological risks are identified in the assessment, companies may still need to conduct biological testing to mitigate these risks. This comprehensive approach allows for a better understanding of risks and an informed test selection to address biological risks. It will also help to avoid unnecessary testing.
Exhaustive extractions for prolonged and permanent devices can result in hundreds, sometimes thousands, of chemical constituents. Gathering these data is a strenuous task for chemists, who identify and quantify each constituent above the AET – and not every chemistry lab has the capabilities to complete the hard work of identification. The process is also laborious for toxicologists who use this information to assess the toxicological risk associated with each chemical constituent and determine whether it could present a hazardous situation for the patient.
Toxicologists identify clinically relevant toxicological risks based on both hazard and exposure. Chemical characterization data provides the necessary worst-case exposure estimates, while toxicology literature and in silico computational toxicology tools provide necessary hazard information. Toxicologists evaluate potential hazards by mining available toxicological data for critical adverse effects of the medical device’s chemical constituents. When toxicology data is insufficient or unavailable, in silico toxicology prediction tools are used.
Experts derive tolerable intake levels from the existing information that considers sensitive patient populations and uncertainties of extrapolation to human exposure. The information reveals the variation between patients and the nature and duration of contact with extractable/leachable chemicals from the device.
When appropriate, a threshold of toxicological concern (TTC) is applied as described in ISO/TS 21726:2019. Comparing the estimated tolerable intake or appropriate threshold of toxicological concern (TTC) with the worst-case exposure (estimated through chemical characterization), a ratio referred to as the margin of safety (MOS) is used as a tool to assess the overall toxicological risk.
Toxicologists must understand the factors contributing to overall toxicological risk, including the intended clinical use, as medical devices may be intended for multiple patient populations, have different contact durations (e.g., single-use, repeated-use, limited, prolonged, or long-term), or use several devices for treatment. Toxicologists use this information to determine the worst-case scenario to assess risk.
Evaluating relevant biological risks is not done solely through a TRA of medical device chemical constituents. This process must also include endpoints requiring evaluation through biological testing. The overall weight of evidence to support biological safety must combine chemical information, TRA, and biocompatibility data to complete the biological evaluation. Biological evaluations require expertise in medical devices, analytical chemistry, and toxicology. Companies may expect longer timelines with more rigorous chemical characterization and comprehensive TRAs than past experiences. But the upcoming revisions to ISO 10993-17 aim to facilitate TRA conduct.
To better inform overall acceptance of toxicological risks, toxicologists must balance worst-case assumptions and conservative toxicological thresholds with realistic patient risk of exposure to medical device chemical constituents. Awareness is critical to avoid the repercussions of over and underestimating risk.
Overestimating risk can result in unnecessary biocompatibility testing and can needlessly prevent a beneficial device from reaching the market. Conversely, underestimating risk is worse as it could result in safety concerns. Regulatory affairs professionals with an eye on ISO 10993 should utilize their knowledge to carefully select their laboratory testing partners to support the biological evaluation of their medical devices.
The result of insufficiently assessing potential patient safety risks during the early product development phases could limit a company’s available opportunities to address them. These limited options could negatively impact medical device development timelines and outcomes or result in necessary risk control measures.
Upcoming Revisions to ISO 10993-17
The latest revision to ISO 10993 will be a significant change from the 2002 version of ISO 10993-17. The working group for ISO 10993-17 is working to develop and push forward the standard’s latest draft and many experts are already considering how it could improve their assessments.
Those closely following the standard’s progression anticipate it will provide new tools for conducting toxicological risk assessments. The goal for the updates to ISO 10993-17 is to provide a more consistent approach to evaluating chemical constituents, benefitting both the user and the regulator. However, companies should realize that expert judgment cannot be replaced and remains pivotal to a successful assessment.
Key concepts introduced in the latest ISO 10993-17 draft document include the toxicological screening limit (TSL), margin of safety (MOS) evaluation, and exposure dose estimation. Regulatory affairs professionals with a foundational understanding of these components within the standard revisions can better identify gaps in their submissions and select qualified testing partners.
Toxicological Screening Limit (TSL)—The toxicologist's job is to evaluate all reported chemicals identified and quantified above the AET. This responsibility includes performing hazard identification and deriving tolerable intake levels. In addition to the very low reporting thresholds, the exaggerated and exhaustive extraction recommendations in ISO 10993-18 have increased the number of extractable chemicals that must be evaluated. This has led to extensive TRAs and time spent evaluating chemicals present at very low levels.
Intended to minimize the burden of the TRA process, the TSL is an option that reduces the number of chemical constituents the toxicologist is required to review. It does so by screening out chemicals without appreciable toxicological risk. There is a short-term (up to 30 days) and a long-term (>30 days) TSL presented in mg/device that toxicologists can apply to the total quantity of a chemical constituent.
The TSL could offer significant relief to toxicologists and help expedite turnaround times when possible. Overall, it has the potential to reduce the burden of performing a full TRA.
Estimation of Exposure Dose—The exposure dose is the worst-case exposure daily, and experts calculate it from chemical characterization data. Release kinetics of chemicals from a final finished medical device are an important factor they should also consider to determine worst-case daily exposure. Most chemicals are likely to be released at higher levels initially and taper off over time. This curve could result in more short-term toxicological risks, even for long-term devices.
The ISO 10993-17 draft provides guidance on calculating exposure doses of chemicals based on either known or assumed release kinetics. This step allows the toxicologist to understand whether toxicological risks are short- or long-term, and help inform the toxicologist when additional release kinetics information may be needed for a chemical.
Evaluating the MOS—The tolerable intake or TTC ratio of the estimated exposure dose is known as the margin of safety (MOS). The MOS is a tool that assists the toxicologist in evaluating whether the toxicological risk will be acceptable or more information is needed to assess the risk. That could include refining maximum exposure estimates, using biological testing, or applying risk control.
Generally, a MOS greater than one supports acceptable toxicological risk, but that is not the end of the evaluation. Other elements are important for the expert to determine if the risk is acceptable. For example, a chemical constituent’s potency and severity could produce a critical adverse health effect and impact patients receiving the device.
If a toxicological risk is equivocal, toxicologists base the next steps on understanding the toxicological risk. The qualifications and support of an experienced toxicologist are pivotal in determining acceptability of a toxicological risk and the overall biological risk of a final finished medical device.
Since the industry expects the ISO 10993-17 revision to be released in 2022, expert toxicological risk assessors can help to prepare for the new requirements in future regulatory submissions.
Putting It to Practice
While the industry patiently awaits final publication of ISO 10993-17, many organizations are still implementing the changes engendered by ISO 10993-18:2020. These efforts can directly benefit toxicologists in anticipation of new guidance by establishing a solid foundational dataset of the chemicals to be assessed.
References
1 International Organization for Standardization. ISO 10993-1:2018. https://www.iso.org/standard/68936.html. Published August 2020.
2 International Organization for Standardization. ISO 10993-17:2002. https://www.iso.org/obp/ui/#iso:std:iso:10993:-17:ed-1:v1:en. Published 2002.
3 International Organization for Standardization. ISO 10993-18:2020. https://www.iso.org/standard/64750.html. Published January 2020
Dr. Sherry Parker has more than 20 years of toxicology and medical device experience, and is an expert in biological evaluation of medical devices and combination products. She received her Ph.D. in Molecular and Cellular Pharmacology from the University of Miami. In her current position as WuXi AppTec’s Senior Director of Regulatory Toxicology, Dr. Parker provides manufacturers with guidance on global regulatory and technical requirements and testing program design. In May 2019, Dr. Parker was appointed to a three-year term as co-chair of the Biological Evaluation (AAMI/BE) Committee, the U.S. mirror committee for ISO 10993. In addition, she is currently an internationally recognized ISO expert and a U.S. Delegate for TC 194, the technical committee for ISO 10993, and is a past president of the Medical Device and Combination Products Specialty Section of the Society of Toxicology.
Medical device manufacturers that make the necessary efforts to stay ahead of these evolving standards can increase their chances of future regulatory success. Companies should take advantage of this time before the standards are implemented to stay informed of developments and better understand the impact of the new requirements and their associated revisions.
Impact of ISO 10993-18 on Toxicological Risk Assessments
The publication of ISO 10993-18:20203 established a need for medical device manufacturers to investigate their products’ chemical constituents more rigorously. Consequently, these evaluations can produce considerably larger amounts of data than in the past. This requires toxicologists to assess the risk of each chemical identified.
Companies typically use chemical characterization testing to provide a detailed understanding of the chemical constituents in medical device materials and finished products. By gathering chemical information, often through performing extractable and leachable (E/L) testing, chemists can detect chemical constituents to the level of manufacturing process residuals. Laboratories then evaluate these chemical constituents in a toxicological risk assessment (TRA). Still, results can trigger questions when unknown chemicals remain or potentially toxic substances are present. The combination of these activities helps identify any remaining device concerns before moving forward with additional testing.
One notable revision to ISO 10993-18 is the introduction of the analytical evaluation threshold (AET). Using the AET, laboratories must identify and quantify all chemicals at or above the determined threshold to garner more complete chemical characterization at a level to support the TRA. As the duration of a device’s intended patient exposure increases, experts must set a lower identification and quantification threshold for chemical characterization. Furthermore, to account for the analytical uncertainty of semi-quantitative screening, it is expected that uncertainty factors are used in the AET calculation. This expectation results in reporting chemicals well below the threshold of toxicological concern.
Ultimately, these lower reporting thresholds create massive data sets. Not only are toxicologists challenged by working with these massive data, but the regulatory expectation is to evaluate each chemical’s hazard and toxicological risk. Adhering to these expectations is important when trying to achieve regulatory success.
Suppose testing laboratories cannot reach these low reporting thresholds due to large devices, extraction volumes, or limits of analytical sensitivity. In those cases, laboratories must concentrate the extracts to increase the sensitivity of the analysis. Concentrating extracts is not ideal, as it may produce volatile compounds losses and degradation products. What results is a longer list of extractable chemicals with questionable clinical relevance and even more work for the toxicologist.
In these situations, results are likely to overestimate a realistic level of toxicological risk. Overestimating the toxicological risk of a chemical could result in unnecessary regulatory concerns. An experienced toxicologist can strike the right balance between under and overestimating toxicological risks, and provide their perspective on resolving potential regulatory concerns before implementing additional testing.
Evaluating Relevant Toxicological Risks
For biological evaluations of medical devices, identifying relevant biological risks is critical for determining subsequent testing strategies. Chemical information is now a requirement for biological evaluations according to ISO 10993-1:2018. The use of chemical characterization and understanding the contact nature, duration, and device clinical use provides the necessary information for developing biological evaluation strategies.
Though many biological risks can be addressed with biocompatibility testing, there are also biological risks that can be addressed with a TRA, including systemic toxicity (acute, subacute/subchronic, and chronic), carcinogenicity, genotoxicity, and reproductive and developmental toxicity. Other biological endpoints, including local tissue effects (irritation, sensitization, and implantation), pyrogenicity, and hemocompatibility, are typically addressed with biological testing only.
Experts develop a biological evaluation strategy to plan which endpoints a laboratory addresses with a TRA and which endpoints they deliver with biological testing. If toxicological risks are identified in the assessment, companies may still need to conduct biological testing to mitigate these risks. This comprehensive approach allows for a better understanding of risks and an informed test selection to address biological risks. It will also help to avoid unnecessary testing.
Exhaustive extractions for prolonged and permanent devices can result in hundreds, sometimes thousands, of chemical constituents. Gathering these data is a strenuous task for chemists, who identify and quantify each constituent above the AET – and not every chemistry lab has the capabilities to complete the hard work of identification. The process is also laborious for toxicologists who use this information to assess the toxicological risk associated with each chemical constituent and determine whether it could present a hazardous situation for the patient.
Toxicologists identify clinically relevant toxicological risks based on both hazard and exposure. Chemical characterization data provides the necessary worst-case exposure estimates, while toxicology literature and in silico computational toxicology tools provide necessary hazard information. Toxicologists evaluate potential hazards by mining available toxicological data for critical adverse effects of the medical device’s chemical constituents. When toxicology data is insufficient or unavailable, in silico toxicology prediction tools are used.
Experts derive tolerable intake levels from the existing information that considers sensitive patient populations and uncertainties of extrapolation to human exposure. The information reveals the variation between patients and the nature and duration of contact with extractable/leachable chemicals from the device.
When appropriate, a threshold of toxicological concern (TTC) is applied as described in ISO/TS 21726:2019. Comparing the estimated tolerable intake or appropriate threshold of toxicological concern (TTC) with the worst-case exposure (estimated through chemical characterization), a ratio referred to as the margin of safety (MOS) is used as a tool to assess the overall toxicological risk.
Toxicologists must understand the factors contributing to overall toxicological risk, including the intended clinical use, as medical devices may be intended for multiple patient populations, have different contact durations (e.g., single-use, repeated-use, limited, prolonged, or long-term), or use several devices for treatment. Toxicologists use this information to determine the worst-case scenario to assess risk.
Evaluating relevant biological risks is not done solely through a TRA of medical device chemical constituents. This process must also include endpoints requiring evaluation through biological testing. The overall weight of evidence to support biological safety must combine chemical information, TRA, and biocompatibility data to complete the biological evaluation. Biological evaluations require expertise in medical devices, analytical chemistry, and toxicology. Companies may expect longer timelines with more rigorous chemical characterization and comprehensive TRAs than past experiences. But the upcoming revisions to ISO 10993-17 aim to facilitate TRA conduct.
To better inform overall acceptance of toxicological risks, toxicologists must balance worst-case assumptions and conservative toxicological thresholds with realistic patient risk of exposure to medical device chemical constituents. Awareness is critical to avoid the repercussions of over and underestimating risk.
Overestimating risk can result in unnecessary biocompatibility testing and can needlessly prevent a beneficial device from reaching the market. Conversely, underestimating risk is worse as it could result in safety concerns. Regulatory affairs professionals with an eye on ISO 10993 should utilize their knowledge to carefully select their laboratory testing partners to support the biological evaluation of their medical devices.
The result of insufficiently assessing potential patient safety risks during the early product development phases could limit a company’s available opportunities to address them. These limited options could negatively impact medical device development timelines and outcomes or result in necessary risk control measures.
Upcoming Revisions to ISO 10993-17
The latest revision to ISO 10993 will be a significant change from the 2002 version of ISO 10993-17. The working group for ISO 10993-17 is working to develop and push forward the standard’s latest draft and many experts are already considering how it could improve their assessments.
Those closely following the standard’s progression anticipate it will provide new tools for conducting toxicological risk assessments. The goal for the updates to ISO 10993-17 is to provide a more consistent approach to evaluating chemical constituents, benefitting both the user and the regulator. However, companies should realize that expert judgment cannot be replaced and remains pivotal to a successful assessment.
Key concepts introduced in the latest ISO 10993-17 draft document include the toxicological screening limit (TSL), margin of safety (MOS) evaluation, and exposure dose estimation. Regulatory affairs professionals with a foundational understanding of these components within the standard revisions can better identify gaps in their submissions and select qualified testing partners.
Toxicological Screening Limit (TSL)—The toxicologist's job is to evaluate all reported chemicals identified and quantified above the AET. This responsibility includes performing hazard identification and deriving tolerable intake levels. In addition to the very low reporting thresholds, the exaggerated and exhaustive extraction recommendations in ISO 10993-18 have increased the number of extractable chemicals that must be evaluated. This has led to extensive TRAs and time spent evaluating chemicals present at very low levels.
Intended to minimize the burden of the TRA process, the TSL is an option that reduces the number of chemical constituents the toxicologist is required to review. It does so by screening out chemicals without appreciable toxicological risk. There is a short-term (up to 30 days) and a long-term (>30 days) TSL presented in mg/device that toxicologists can apply to the total quantity of a chemical constituent.
The TSL could offer significant relief to toxicologists and help expedite turnaround times when possible. Overall, it has the potential to reduce the burden of performing a full TRA.
Estimation of Exposure Dose—The exposure dose is the worst-case exposure daily, and experts calculate it from chemical characterization data. Release kinetics of chemicals from a final finished medical device are an important factor they should also consider to determine worst-case daily exposure. Most chemicals are likely to be released at higher levels initially and taper off over time. This curve could result in more short-term toxicological risks, even for long-term devices.
The ISO 10993-17 draft provides guidance on calculating exposure doses of chemicals based on either known or assumed release kinetics. This step allows the toxicologist to understand whether toxicological risks are short- or long-term, and help inform the toxicologist when additional release kinetics information may be needed for a chemical.
Evaluating the MOS—The tolerable intake or TTC ratio of the estimated exposure dose is known as the margin of safety (MOS). The MOS is a tool that assists the toxicologist in evaluating whether the toxicological risk will be acceptable or more information is needed to assess the risk. That could include refining maximum exposure estimates, using biological testing, or applying risk control.
Generally, a MOS greater than one supports acceptable toxicological risk, but that is not the end of the evaluation. Other elements are important for the expert to determine if the risk is acceptable. For example, a chemical constituent’s potency and severity could produce a critical adverse health effect and impact patients receiving the device.
If a toxicological risk is equivocal, toxicologists base the next steps on understanding the toxicological risk. The qualifications and support of an experienced toxicologist are pivotal in determining acceptability of a toxicological risk and the overall biological risk of a final finished medical device.
Since the industry expects the ISO 10993-17 revision to be released in 2022, expert toxicological risk assessors can help to prepare for the new requirements in future regulatory submissions.
Putting It to Practice
While the industry patiently awaits final publication of ISO 10993-17, many organizations are still implementing the changes engendered by ISO 10993-18:2020. These efforts can directly benefit toxicologists in anticipation of new guidance by establishing a solid foundational dataset of the chemicals to be assessed.
References
1 International Organization for Standardization. ISO 10993-1:2018. https://www.iso.org/standard/68936.html. Published August 2020.
2 International Organization for Standardization. ISO 10993-17:2002. https://www.iso.org/obp/ui/#iso:std:iso:10993:-17:ed-1:v1:en. Published 2002.
3 International Organization for Standardization. ISO 10993-18:2020. https://www.iso.org/standard/64750.html. Published January 2020
Dr. Sherry Parker has more than 20 years of toxicology and medical device experience, and is an expert in biological evaluation of medical devices and combination products. She received her Ph.D. in Molecular and Cellular Pharmacology from the University of Miami. In her current position as WuXi AppTec’s Senior Director of Regulatory Toxicology, Dr. Parker provides manufacturers with guidance on global regulatory and technical requirements and testing program design. In May 2019, Dr. Parker was appointed to a three-year term as co-chair of the Biological Evaluation (AAMI/BE) Committee, the U.S. mirror committee for ISO 10993. In addition, she is currently an internationally recognized ISO expert and a U.S. Delegate for TC 194, the technical committee for ISO 10993, and is a past president of the Medical Device and Combination Products Specialty Section of the Society of Toxicology.
