Medical device manufacturers have a big challenge in preparing for their regulatory device submissions for 2020. In addition to the European Union’s new Medical Device Regulation (MDR) taking effect in May, the International Organization for Standardization (ISO) published the latest version of ISO 10993-18 in January 2020. These updates emphasize the criticality of chemical characterization studies and toxicological risk assessments, and a key concept in successful implementation of these activities is the analytical evaluation threshold (AET).
The AET establishes a concentration threshold for chemical identification, setting stricter requirements for the analytical method sensitivities labs use and the thresholds they set during chemistry studies. Why does this matter? The AET requirement informs both chemical characterization and toxicological risk assessment decisions, setting the baseline at which chemicals should be identified and reported. If manufacturers don’t understand the importance of the AET, they could end up under- or overtesting their products — both of which could result in regulatory setbacks and added costs. Setbacks could be especially problematic ahead of MDR, as labs and notified bodies have shrinking capacity.
Working Together to Set an AET
The purpose of the AET is to ensure that toxicologists and chemists are on the same page. The AET requires toxicological information (including toxicological threshold and exposure assumptions), in addition to information on extraction conditions, to inform chemistry test design and execution. Since chemical characterization requires an understanding of the level of sensitivity (expressed in units such as μg/mL or mg/L), and the toxicologist is concerned with the threshold at which a chemical could present a risk to a patient (as expressed in μg/kg/day), collaboration is critical in designing successful studies.
Satisfying Submission Requirements
Regulators will review the analytical report to determine whether an AET was set and whether the lab was able to meet it. While the standard recognizes that it might not always be possible to achieve the required AET, these situations require substantial justification. You will be expected to recognize the target AET and provide specific information to support why you were unable to meet it. Manufacturers might be asked to provide additional information or to put their devices through further testing if regulators find the justification unacceptable.
If you have already completed testing or submitted reports without ensuring that the new AET requirements were applied, you should anticipate questions from regulators and gather information from the lab to support the threshold used in the study. If you simply excluded AET information from your report because it was not previously required, you can amend your submission to reflect the new standards. Alternatively, you can prepare to respond to an additional information (AI) request.
If, after reviewing results from your lab studies, you discover the thresholds did not meet the new AET requirement, you may need to consider retesting at the appropriate level. It is in the manufacturer’s best interest to do so now, rather than waiting for regulators to require retesting, to stay on top of the MDR preparation timeline.
Determining the AET
Determining the AET is ideally the result of collaboration with the toxicologist, the chemist, and the manufacturer and is based on the dose-based threshold (DBT), the laboratory extraction volume, and number of devices used in the extraction, as well as the number of devices used clinically. The duration of patient contact with the device is also an important consideration. Toxicologists may apply a threshold based on the duration of exposure and associated ICH M7 TTC — also described in ISO/TS 21726: 2019. For example, devices in contact with patients for 30 days or less have a higher threshold — 120 μg/day — because the risk associated with exposure for this amount of time is lower. If the device being tested is intended to be long term, the threshold is lower — 1.5 μg/day. Most extractable studies will utilize one of these thresholds to set the AET. If you are evaluating specific compounds in a targeted study, your toxicologist should select the threshold specific to that chemical, based on contact type and duration of the device.
The Manufacturer’s Role in AET
While toxicologists, chemists, and device manufacturers must work as a team to ensure that the AET is correctly applied to the testing process, ultimately the manufacturer is responsible for ensuring that the standard is met. Manufacturers must do your due diligence ahead of testing to make sure their lab is aware of the AET requirement — the MDR submission could be at risk.
It will be obvious to regulators if AET information is missing from your submission, and they will ask questions if this is the case. If you wait until it’s time to prepare the submission to check for AET compliance, you risk potentially needing to retest in order to reach the correct sensitivity. Ask your lab before testing even begins if they are equipped with the tools necessary to identify all compounds at or above the applicable AET.
The role of the manufacturer does not end with confirming that the lab is equipped to hit the AET. It is also incumbent upon the manufacturer to facilitate the AET conversation between the toxicologist and the chemist, as the manufacturer will be the one held responsible for the report submitted to regulators. There is too much at stake to assume both parties have the information they need to apply the appropriate AET. Keep communication lines open with both specialties and confirm everyone is on the same page regarding test sensitivity.
Deciding Between an In-House Lab and an Outside Testing Partner
Regulators may scrutinize a study more heavily if it’s not conducted by a third party. If a manufacturer tests in house, it is important to ensure that the team is thoroughly trained on the AET requirement and the internal process for meeting it, including adequate instrument sensitivity, experience, and tools to perform complete identification. An OEM may find either need to invest in new equipment and expertise or find an outside testing partner.
If partnering with an outside lab, be sure to ask the right questions to gauge their competencies and determine whether they are a good fit. Asking direct and thorough questions up front improves chances that testing is done right the first time. Ask questions about their familiarity with ISO 10993-18 and whether they’re aware of the changes therein. Ask if they are equipped to identify everything at and above the AET.
Working with a lab that reports unknowns will put your submission at risk. Reporting unknowns can indicate that a lab doesn’t have the expertise, instrumentation, and/or commitment to perform complete chemical characterization. This may cause regulators to reject a submission or issue AIs. On average, repeat testing costs more than $75,000 and 27 weeks of time. Ask how the lab handles unidentified chemicals and whether they provide support in the case of an AI request. In addition, ask about the collaboration between the chemistry and toxicology teams to better understand their ability to apply AET effectively and efficiently between functions.
Partnering with an outside lab can be beneficial, particularly if they already routinely use the AET in testing. Labs with state-of-the-art technology and internal compound databases should be able to more efficiently and thoroughly apply AET. Further, their outside perspective and specialized methodologies — developed through experience with other projects — can reduce the risk of setbacks and obstacles in the testing process. Overall, outside labs offer an opportunity for relief as a manufacturer learns to apply AET while facing tight timelines.
In the rush to achieve MDR compliance, it’s important not to overlook the individual standards that must be tested against. In some cases — such as with AET — the adjustment can mean significant investments in equipment, should you choose to forge ahead on your own. Take the time now to discuss the best path forward so you’re not stuck footing a hefty bill or scrambling to find a viable testing partner that has capacity to help you.
This article was written by Sandi Schaible, Senior Director of Analytical Chemistry and Regulatory Toxicology at WuXi Medical Device Testing, St. Paul, MN. She specializes in extractables and leachables studies. Schaible is a U.S. delegate and international delegate for ISO 10993 part 18 in chemical characterization and a U.S. delegate for ISO 10993 part 13 and the particulates committee (TIR 42). A white paper on how to handle chemistry report unknowns can be downloaded here . For more information, visit here .