Identification standards are putting pressure on manufacturers’ submissions. Make sure your sensitivity is up to regulations.
Medical Device Regulation (MDR) and International Organization for Standardization (ISO) revisions emphasize the importance of chemical characterization studies and toxicological risk assessments. To ensure successful implementation of both, establishing the analytical evaluation threshold (AET) is key.
Let’s take a closer look at common questions related to the AET, as well as issues you’ll want to keep in mind as you plan for an MDR submission.
What is the purpose of the AET?
The purpose of the AET is to make sure toxicologists and chemists are on the same page. It establishes a concentration threshold for chemical identification, setting stricter requirements for the analytical method sensitivities that labs use and the thresholds they set during chemistry studies. Since chemical characterization requires understanding the level of sensitivity (expressed in units such as µg/mL or mg/L) and toxicology focuses on the threshold at which a chemical could present a risk to patients (as expressed in µg/kg/day), collaboration is critical in designing successful studies.
Why is the AET important?
The AET 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, it could result in regulatory setbacks and added costs.
Being aware of the AET is also important because during the submission process, regulators will review your analytical report to determine if the AET was set and whether you met it. If your product hasn’t met it, you’ll need to provide substantial justification for why not; if regulators don’t find your justification acceptable, they might ask you for more information or insist that you put your devices through additional testing.
How is the AET determined?
Ideally, the AET is set through collaboration with a toxicologist, a chemist, and the manufacturer. It’s based on the dose-based threshold (DBT), the lab extraction volume, and the number of the devices used in the extraction. The number of devices used clinically will also be a factor, as will the expected duration of patient use. For example, devices that typically have contact with patients for 30 days or less have a higher threshold (say, 120 µg/day) because the risk associated with exposure for this amount of time is lower. If the device you’re testing will be used for a longer amount of time, the threshold itself will be lower (1.5 µg/day, for example).
Most extractable studies will utilize one of these thresholds to set the AET. If you’re evaluating specific compounds in a targeted study, your toxicologist should select the threshold specific to that chemical, based on contact type and duration of device usage.
What is the manufacturer’s role in the AET?
Ensuring that the AET is correctly applied to the testing process is a collaborative effort, but ultimately, it falls upon the manufacturer to make sure the standard is met. You’ll be the one to submit the report to regulators. You’ll also have to do your due diligence ahead of testing and make sure your lab is aware of the AET requirement. And you can’t wait until it’s time to prepare your submission to check for AET compliance, as that will risk potentially needing to re-test in order to reach the correct sensitivity. The best course of action is to ask your lab before testing begins if they are equipped with the necessary tools to identify all compounds that are at or above the applicable AET.
Also, you should be aware that your role doesn’t end with confirming that this is the case. It’s also your responsibility to communicate with the toxicologist and the chemist involved – both will need as much information as possible to make sure the appropriate AET is applied.
Should you test in-house or through an outside lab?
If you decide to test in-house, you’ll want to make sure your team is thoroughly trained on the AET requirement and that you have the infrastructure needed to perform complete identification.
Meanwhile, if you work with an outside lab, you’ll be able to utilize their expertise, specialized methodologies, equipment, and personnel. Before you partner with them, be sure to ask the right questions and determine their competencies, especially when it comes to their familiarity with ISO 10993-18. For example, if they already use the AET in their testing protocols, you can be confident that you will avoid setbacks and obstacles during the testing process. As you strategize for meeting MDR compliance, don’t forget to keep in mind the individual standards you’ll need to test against. For some, the adjustment can mean revising timelines and expected costs. We recommend creating a game plan now, including the AET you’ll use and whether you will test in-house or with an external partner.
