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.For example, application of an AET to this GCMS chromatogram allows the analyst to focus quantitation and identification time solely on the peaks above the green evaluation threshold line.
EKG has published a more extensive discussion of AETs on our website, including some guidance on safety-based thresholds and explanation of how to perform an AET calculation.
Extractables and Leachables Studies at EKG Labs
Understanding the complex chemical interactions between pharmaceuticals and materials is critical to designing a proper extractables and leachables program. We can perform E&L analytical studies with the ultimate goal of submitting data for FDA review and approval. EKG Labs is familiar with guidance from organizations such as ISO, FDA, ICH, USP, and BPOG. Our capabilities include:
- Full scale GMP analytical extractables and leachables programs
- Method Development
- Method Validation
- Material/Chemical Characterization
- Impurity Identification
About EKG Labs
EKG Labs is an analytical service provider for the pharmaceutical and medical device industries. Our wide variety of analytical services support product development, regulatory filings, and analytical chemistry investigations.