For Medical Device Testing, Every Variable is Important

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Successful and On-Time Medical Device Testing Relies on the Analytical Evaluation Threshold (AET)

The required biological compatibility evaluation of medical devices includes ISO 10993-18:2020 (Part 18) chemical characterization and extractables and leachables testing of medical devices.

For every 10993-18 study performed by a medical device testing lab, a report is generated for a toxicologist to assess, resulting in a toxicological risk assessment (TRA). The toxicologist looks at compounds identified, the confidence level of the identification, and concentration present to perform a risk assessment on the medical device from a chemical viewpoint.

The analytical evaluation threshold (AET), an important part of the extractables and leachables testing in these studies, needs to be calculated for each instrumental technique. The AET is the concentration on an instrument below which analytes do not need to be assessed by a toxicologist per 10993-18.

Correct Calculation of the AET is an Art

Proper calculation of the AET is important to successful and timely medical device testing. If the AET is too high, chemical characterization may omit potentially toxic compounds from the chemical characterization report. If the AET is too low, resources are wasted evaluating thousands of compounds at toxicologically irrelevant concentrations.

The goal is to avoid assessing compounds that will be irrelevant in terms of toxicology impact, and make certain that compounds of interest will be evaluated. This is accomplished by ensuring that instrument limits of quantitation (LOQ) are below the AET..

During device submission to regulatory agencies, like the FDA, EU MDR, and other Notified Bodies, reviewers expect the chemical characterization report to demonstrate that the LOQ is below the AET for all techniques.

Every Variable Is Important to Safety, Time, and Cost

If the AET calculation is too high, there can be risk to patients, and if the AET is too low, the manufacturer faces higher costs and extended testing time. It can also impact the number of devices needed for a study.

How Do You Optimize Experimental Design for the AET?

All the variables in the AET equation have equal impact on the final AET number. No variables are far larger or smaller than the others, and none can be ignored or dominate the result.

Some variables can be controlled (number of devices in extraction, extraction volume, dilution factor, uncertainty factor), others cannot (dose-based threshold, patient exposure count). For the best results, the AET must exceed the LOQ for each technique, minimize or eliminate concentration of extracts, and minimize device consumption.

Optimizing experimental device design for the AET:

Systematically consider and control all variables that can be changed.
Reduce uncertainty factors through method development and relative response factor databases.
Sensitive cutting-edge instrumentation to lower LOQ’s.
Validated concentration methods to ensure analytes are not lost.
Minimize extraction volumes through custom extraction setups.
Involving the toxicologist early to aid in experimental design.

And perhaps most importantly, choose the right medical device testing lab.

Look for a protocol with the AET for each instrumental method clearly calculated including;
- Surface area of patient-contacting portion of device
- Fill volume if applicable
- Duration of patient contact
- Number of devices patient is exposed to
Work with a lab that has experience with numerous devices from experimental and prototype devices including biological materials, drug products, resorbables, and in-situ polymers to routine devices made from materials like titanium or surgical stainless steel. Also, look for a lab that works closely with toxicologists on study design.
If you have an internal lab, consider a partner lab for additional instrumentation or times when there is an internal backlog.
Choose a lab that has vast and recent experience with the FDA in terms of successful submissions and requests for information.