What is an Analytical Evaluation Threshold (AET)?
An important concept in extractables and leachables analysis, and specifically in medical device chemical characterization, is the analytical evaluation threshold or AET. AET is defined by the International Organization for Standards (ISO) as “a threshold below which the analyst need not identify or quantify leachables or report them for potential toxicological assessment”. The AET is a concentration threshold derived from a previously established safety-based threshold above which detected leachables are identified and quantified as possible.
While nominally an AET is a leachables concept, it can be applied to extractables, since extractables are meant to project the worst-case scenario for leachables. AET is only applied to organic extractables or leachables, since permitted daily exposures (PDEs) have been established for individual metals/elements (to learn more about heavy metals analysis and elemental impurities, click here).
In Annex E of the 2020 update of ISO 10993-18, “Chemical characterization of medical device materials within a risk management process”, ISO presents several dense pages exploring the concept of an AET.
The Purpose of an AET
AET establishes analytical limit (the on-instrument limit of detection and limit of quantitation) needs. An AET ought to be higher than the LOD always and higher than the LOQ if the method is fully quantitative. This means that an AET has practical lab functionality for analysts, in order to ensure that the analytical work performed is sensitive enough to provide all possible identifications above the TTC.
The application of an AET is also extremely useful in reducing identification burden, which is the most time-consuming and costly portion of an E&L study. It ensures that the analyst does not spend excess time attempting to accurately quantify or identify peaks that can already be dismissed as low toxicological risk.
An AET is generally most relevant to screening analyses. During a targeting analysis, the purpose is to accurately and precisely establish the concentration of specific, previously-identified analytes in the sample.
Safety thresholds establish a dose of leachables below which substances present an acceptably low toxicological safety risk, even without identification. This number relates specifically to the product/device of interest and its functionality in a patient.
There are a number of somewhat-interchangeable terms to describe such thresholds based on toxicological safety concerns (for the purposes of this discussion):
- DBT: dose-based threshold
- TTC: threshold of toxicological concern
- SCT: safety concern threshold
It is noted that these thresholds make exceptions for special case compounds of known high toxicity termed “cohorts of concern”, specified elsewhere in ISO (ISO/TS 21726 and ISO 10993-17). EKG intends to discuss this concept in the near future; stay tuned!
Choosing a Threshold
Determining a safety threshold and, by extension, an AET prior to experimentation is optimal. When not feasible, we can retroactively apply an AET at the reporting phase to already collected data. Regardless of whether or not an AET is determined beforehand, EKG Labs calculates observed extractables and leachables into units directly comparable to thresholds such as a TTC (generally µg/device).
EKG Labs can provide some guidance for selection of dose-based thresholds, given our years of E&L and FDA experience, but ultimately the responsibility for justifying the reporting threshold (AET) lies with the client. We have found that it is most helpful for us when clients are able to engage a toxicologist for initial discussion of TTC establishment before performing analysis. It can also save our clients significant time and money to initiate toxicology conversations early. While EKG Labs does not have an in-house toxicologist, we do have long-standing and close partnerships with some outstanding toxicologists and can pair up our clients appropriately.
AETs are generated by converting dose-based thresholds (such as a DBT, SCT, or TTC) to analytical concentration-based thresholds (the AET). This calculation takes into account the use of the medical device/pharmaceutical product and the experimental conditions.
AET=DBT/UF x A/(BC)
- AET is the analytical evaluation threshold
- DBT is the dose-based threshold (TTC or SCT), generally in mass per day
- UF is the analytical uncertainty factor
- A is the number of devices/products used to generate the extract
- B is the volume of the extract
- C is the number of devices/products the user is exposed to
Any dilution or concentration factors, as relevant, are also taken into account. Because the AET is concentration of extractable/leachable in an extract, the AET is specific to a lab and an experimental procedure. The value has practical functionality to analyst, but it does not have real-world or toxicological significance as it relates specifically to individual extraction conditions.