TRA Archives • WuXi AppTec Medical Device Testing

Don’t Let Unknowns Threaten Your Toxicological Risk Assessment

Nov 2, 2020 | Medical Device Testing, Toxicological Risk Assessment

As regulatory expectations intensify, medical device testing can require more time and budget to satisfy standards. The testing plan decisions you make early on can affect the entire process, so it is critical to think long-term and prioritize quality to avoid setbacks. Chemical characterization (ISO 10993-18:2020) and toxicological risk assessments (TRA) (ISO 10993-17:2002) are key examples of new, heightened requirements that are changing how manufacturers approach testing for device success.

To produce a useful TRA for the purposes of understanding potential toxicological risk in the patient, it is vital to identify and quantify (or semi-quantify) every compound extracted from the device. Because most of the chemical characterization studies are semi-quantitative and use a range of surrogates for compound identification, the associated level of identification confidence should also be reported (e.g., tentative, confident, confirmed). If the profile of extractable chemicals from your device is incomplete (e.g., chemicals not identified or reported as “unknowns”), evaluation of potential toxicological risk from your device materials is not able to be assessed, and as such, the chemical characterization and TRA will not meet regulatory expectations.

When evaluating testing partners for chemical characterization, ensure they identify all compounds for each of the applied analytical methods. This will tell you if they are investing the time and resources in testing that puts your device in the best possible position for a TRA. Understanding what unknowns are, why they occur and the challenges associated with completing TRAs with unidentified compounds can help minimize the risk of an incomplete assessment and regulatory submission.

Understanding Unknowns

After a chemical characterization screening, a toxicologist receives a detailed analysis of the chemicals found within the device. Any unidentified chemicals are recorded as unknowns in the report. Ultimately, if the compound identification does not provide enough information for the toxicologist to evaluate the structure, it can be considered as an “unknown.” In some instances, these compounds are reported as simply “unknown compound;” however, something reported as “unknown nitrogen-containing compound” is also considered as unidentified as the descriptor does not contain enough information for the toxicologist to derive a structure and evaluate in the risk assessment.

When completed properly, chemical characterization results should identify all chemicals associated with the device above the analytical evaluation threshold (AET), but limitations in a lab’s testing capabilities or resources can produce a report containing unidentified chemicals. Not only does this leave a certain percentage of the device makeup unknown, but chemicals that are unaccounted for can lead to over- or under-categorizing risk to the end-user.

There are times when testing labs will provide indicators or partial assessments of the compound makeup, such as including whether it contains carbon or is an alkane. As mentioned above, this information on its own is not enough detail for a toxicologist to accurately assess the risk of a device.

To ensure your submission package is adequate, it is critical to partner with a lab that takes a comprehensive approach to chemical characterization.

Unknowingly Putting Your Device at Risk

An inflated number of unknowns can cause several issues in your testing program. Having an inaccurate TRA is not only a potential risk to patient safety, but it can also increase costs during the testing and regulatory processes. If TRA results are not comprehensive, you may need to conduct additional biocompatibility testing, including subchronic or chronic toxicity, genotoxicity, or carcinogenicity testing, increasing costs and delaying regulatory submission timelines. Adequately preparing for the TRA can help you meet internal and regulatory deadlines and reduce the risk of repeating studies.

Working with unknowns can force toxicologists to assume worst-case potential risk. Over-estimating risk is one way to support patient safety; however, with the current regulatory requirements for chemical characterization, which often lead to hundreds of extractable chemicals, this approach is unlikely to yield favorable TRAs, and more often than not result in additional chemistry or biological testing.

Conducting effective chemical characterization tests that produce few unknowns is achievable with the right partners.

Ensuring Adequate Identification

The best way to avoid the uncertainty of unknowns is to partner with a testing lab early in the process that will meet your needs. By working with a lab that has a history of accurate chemical characterization screenings and regulatory submissions, manufacturers can bolster their likelihood of success.

There are plenty of hurdles that you may face when preparing a medical device for regulatory review and selecting a testing partner that delivers reliable, timely and accurate data can improve your chances for a successful submission. The expertise of the staff and scientists is ultimately going to make the most significant difference in the quality of your screenings and TRAs. Training, skills and experience directly link to the accuracy of your reports, making this an imperative consideration when planning for your TRA.

Not every testing lab will complete a chemical characterization free from unknowns. Ask your testing partner if they report any unknowns before finalizing your testing plan with them to avoid losing money and time on an incomplete chemical characterization.

The Importance of Collaboration

Working with a lab that offers both chemistry and toxicology when designing studies can further improve the likelihood of a successful regulatory strategy. Using two separate labs can lead to miscommunications in the design plan and expectations, which may lead to inconclusive results. Through collaboration, chemists and toxicologists can align their efforts throughout the progression of your characterization and TRA. Partnering with a lab that promotes partnership and ongoing communication between the chemist and toxicologist streamlines the process.

As with most aspects of a device’s development, the more information you can provide about your device to all participating groups, the better. Having an integrated lab testing partner reduces assumptions and related risks in your TRA.

Chemistry reports that include unknowns are simply not acceptable for the long-term success of a medical device. Precision and accuracy are unwavering requirements in this industry and regulators will expect to see this demonstrated in your submission.

Connect with your testing partner to discuss their protocols for avoiding unknowns and the steps they take when receiving incomplete chemistry reports. To learn more, contact a WuXi AppTec expert.

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Established in December 2000, WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable companies in the pharmaceutical, biotech and medical device industries worldwide to advance discoveries and deliver groundbreaking treatments to patients. With industry-leading capabilities such as R&D and manufacturing for small molecule drugs, cell and gene therapies, and testing for medical devices, WuXi AppTec’s open-access platform is enabling more than 4,100 collaborators from over 30 countries to improve the health of those in need – and to realize our vision that “every drug can be made and every disease can be treated”.

The Evolving Outlook on Toxicological Risk Assessments

Nov 2, 2020 | ISO10993-17, Medical Device Testing, Toxicological Risk Assessment

Around the world, various regulatory factors are driving the evolution of medical device risk evaluation. The industry is beginning to recognize the limitations of biocompatibility testing. While the data it can provide still have a pivotal role in the assessment process, it may not be able to measure other factors that are becoming increasingly important to consider, such as carcinogenicity or reproductive and developmental toxicological concerns. When it comes to patient and practitioner safety, you must address these risks.

Chemistry, toxicological risk assessment (TRA) and biocompatibility are necessary components of a biological evaluation. A biological evaluation provides evidence-based data focused on device nature and duration of patient contact which ultimately supports the safety of a device. With the additional expectations regarding chemistry were provided in 10993-18:2020, it is natural that the expectations of toxicological risk assessments also need to be further harmonized. ISO 10993-17 is under revision to provide guidance on toxicological risk assessments.

Driving Forces

The toxicological risk assessment and biological testing are conducted to address the biological endpoints appropriate for the device duration and nature of body contact, to support the biological safety of the device. Regulations are the main driver behind the growing role of TRAs, including the EU Medical Device Regulation (MDR) and 2020 guidance from the U.S. FDA. These documents not only help to set expectations, such as the analytical evaluation threshold (AET) but also support the methodologies and approaches to performing this analysis.

ISO 10993 Biological Evaluation of Medical Devices

The ISO 10993 series of standards highlight the importance of biological evaluations as a part of the overall medical device risk management program. Part 1 demonstrates a need for detailed physical and chemical information, and if manufacturers do not provide sufficient data, additional testing, such as E/L studies, will be necessary before designing a biocompatibility testing plan.

In addition, Part 18, updated in 2020, faced an overhaul in its latest revision. This update increased the requirements for characterization of medical device chemical constituents in a final finished form of a medical device. This section has made it challenging for some to achieve characterization to the levels required by regulators. However, as the industry adjusts, the role of this data will become more evident as appropriate TRAs will rely on this information.

FDA Guidance on use of ISO 10993-1

For manufacturers seeking approval in the United States, it is important to consider that the U.S. FDA does not recognize all clauses of all parts of ISO 10993. The FDA Guidance on the Use of ISO 10993-1 most recently published in 2020, which is almost identical to the 2016 version, provides FDA recommendations that may differ from the ISO 10993 requirements.

ISO 14971 Application of Risk Management to Medical Devices

This document requires risk management, including biological evaluation, to continue throughout a product’s lifecycle.

ISO/TS 21726 Biological Evaluation of Medical Devices

When conducting chemical characterization and TRAs, applying the threshold of toxicological concern (TTC) will often reference this technical specification.

Medical Device Regulation

The EU MDR currently recognizes the most current versions of ISO 10993 standards as “state of the art,” meaning notified bodies expect applications to meet current ISO 10993 requirements.

Collating this information and staying updated is a complicated task. Fortunately, lab testing partners not only have an extensive background on regulatory standards but often play a part in shaping what the future of these standards will be.

Upcoming: ISO 10993-17

While not expected to publish until at least 2021, ISO 10993-17 is currently in the revision process and will provide additional guidance on conducting a TRA. The majority of the standard is expected to change, from defining terminology to summarizing recommended steps in the process. Performing these assessments will likely become more standardized, but this does not indicate process simplicity.

Because TRAs consider device risk as a combination of hazard and the level of exposure, detailed background on the device and its use are critical. Manufacturers need to provide as much contextual understanding of a device’s materials, production process and potential exposure parameters (e.g. maximum clinical use, and patient populations). These considerations are important in the design of chemical characterization and the conduct of a valid toxicological risk assessment. Without this information, the result may be under or over-predicting patient risk; both may lead to undesirable outcomes for different reasons.

Partnering with an informed, reliable testing partner can help prevent potential issues with changing guidance. Qualified, expert judgment will be necessary for many parts of this process, such as when scientists evaluate the results for the margin of safety for medical device chemical constituents. It can be an added benefit if the lab performing your device’s TRA has an inside look at what standards are coming.

An Evolving Outlook

As medical devices continue to evolve, so will the standards. Our industry continues to drive innovation, which is something to celebrate. While there are still opportunities for improvement, chemical characterization plays a critical role in modernizing the biological evaluation of medical devices.

For a more in-depth review of the TRA process, watch our webinar “Toxicological risk assessment of medical devices and proposed updates to 10993-17, including the application of TTC values.”