Apr 21, 2021 | Medical Device Testing
Medical device biological safety evaluations have advanced significantly over the last ten years, and regulatory requirements are quickly evolving as well. Turnkey evaluation of testing requirements has progressed into a more device-specific evaluation of risks. It is essential for manufacturers to consider how the changes put in place by ISO 10993-18 will impact their product’s testing needs and any historical compliance of chemical characterization studies.
Complying with the new standard requires a variety of highly sensitive and selective analytical equipment, robust databases and, above all, the expertise to sift through data and identify all chemical constituents. Manufacturers are reevaluating their products to ensure past testing strategies still hold up to current regulatory expectations. To understand how the industry got to this point and forecast where it is headed, we need to start from the beginning.
E/L Gains Momentum
When E/L testing first gained a foothold with medical devices in the early 2000s, methods were focused on qualitative measures. Testing did not generally attempt to quantify the amount of specific chemical constituents present but rather verify major materials present and evaluate total extractable residue.
As certain products were facing public litigation, such as pelvic mesh and breast implants, renewed scrutiny around the risks presented by implantable devices quickly caused the expectations for chemical characterization to be more rigorous, selective and quantitative.
As the decade progressed, even more analytically selective and sensitive techniques emerged, and chemical characterization requirements tightened. Regulators responded with an increased focus on testing device materials and a growing interest in customizing testing to better suit medical devices. In 2016, the US FDA Draft Guidance on ISO 10993-1 reaffirmed the value of chemical characterization when evaluating medical devices.
Recent E/L Testing Trends
Expectations grew along with advanced test methods and equipment that could accommodate increasing regulatory requirements. The 2016 US FDA guidance on the use of ISO 10993-1 required two to three solvents per instrumentand three replicates, thus increasing the investment that companies made during biological safety evaluations.
Around 2017, regulatory agencies began requiring exhaustive extractions (that is, multiple extractions on the same device) for permanent implants. Then in 2018, regulators published a revised version of ISO 10993-1, putting new guidance in place. Specifically, it made chemical characterization and the subsequent risk assessment fundamental components in assessing device safety.
This expectation meant submissions must examine chemistry information and risk assessment to drive their biocompatibility test strategy, and manufacturers must provide justification to support final submissions. Additionally, reviewers examined the training and qualifications of the expert personnel performing these tests.
Internally, the U.S. FDA showed increasing alignment around chemical characterization and toxicological risk assessments, asking how those play into evaluating a device’s biological safety. By 2019, reviewers began requiring exhaustive extraction on prolonged devices as well as permanent devices, which extended the timeline needed to perform testing and increased associated costs.
E/L Testing Today & Going Forward
The publication of ISO 10993-18:2020 marked a significant milestone for the medical device industry. The 2020 revision continued to push expectations and the subsequent approach forward.
This revision provided increased guidance for tailoring chemical characterization to each device by establishing thresholds based on device size, duration and type of patient contact, and the target patient population. For example, reviewers began expecting confidence intervals for identification and implemented the analytical evaluation threshold (AET) as a common baseline for chemistry studies. The AET is essential to achieving an accurate risk assessment. It also helps avoid regulatory scrutiny by requiring qualified chemists to work alongside toxicologists.
The methodologies that laboratories employ today are evolving rapidly, perhaps even faster than the standards themselves. Thus, the concept of “state-of-the-art” procedures is gaining attention as regulators’ expectations grow in tandem with the industry’s capabilities. This is evident with the September 2020 release of International Standard ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process.” As we near the upcoming publication of ISO 10993-17, toxicological risk assessments are positioned next to advance the practices in place. Still, manufacturers may find these latest regulations challenging to keep up to date with the continuously evolving regulatory landscape.
Keeping Up with Chemistry
If you have not conducted E/L testing in recent years, it may be time to consider retesting to satisfy the evolved science and regulations. For many products, testing conducted prior to the publication of ISO 10993-18:2020 may need reevaluation according to the new guidance.
Given the new role that chemical characterization has taken in testing and the new expectations to identify biological concerns, it is critical to consider E/L testing as an essential ingredient in preparing a successful medical device submission. Looking to dive further into the details? Check out a detailed recap about ISO 10993 in “Planning and Predicting for ISO 10993: Part 18 & Part 17.“
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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. As an innovation-driven and customer-focused company, WuXi AppTec helps our partners improve the productivity of advancing healthcare products through cost-effective and efficient, socially responsible and sustainable solutions – and has received ESG (Environment, Social and Governance) A Ratings from Morgan Stanley Capital International since 2019. 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 4,200 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.”
For more information, please visit: http://medicaldevice.wuxiapptec.com/
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”.
