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”.
