The Importance of the AET
The Analytical Evaluation Threshold (AET) came about from the PQRI best practises document (2005) and it was the first time that a level for the identification and quantification of extractables and leachables was defined. It is important to stress that the AET is not a safety threshold but an identification threshold and once an extractable or leachable has been identified and quantified a toxicologist can assess whether that particular species is safe at that particular exposure level.
The AET is critical in developing your analytical approaches to identifying and quantifying extractables. The instrument sensitivity for a given analyte is fixed as each detector can only detect a fixed amount. There are then a large number of variables that can be used by the analytical chemist to design the extraction study, with an outline shown in figure 1.
In order to explore what options are available to an analytical chemist, in terms of study design and method development, it is worth reviewing the calculations used to determine the AET.
The calculations are similar for both medicinal products and medical devices and are taken from the PQRI best practises and ISO10993-18.
- For medical Devices
AET (µg/mL) = DBT (µg/day)* (A/(B*C*D)) / UF* S
Dose-Based Threshold (DBT) = Threshold of Toxicological Concern (TTC) (ICH M7) = Safety Concern Threshold (SCT)
A = number of medical devices extracted
B = extract volume
C = number of medical devices that contact the body/day
D** = dilution factor (D>1), if concentrated (D<1). If not diluted/concentrated (D=1)
UF = uncertainty factor of analytical methods (UF >=1)
S= number of sequential extractions
- For medicinal Products
AET (µg/mL) = SCT (µg/day)* (A*E/(B*C*D)) / UF
E= number of does/device
C= number of doses/day
The areas that an analytical chemist can control to achieve low AETs are around the minimum solvent to sample ratio, the amount that a solution can be concentrated without losing potential analytes and finally the amount that can be loaded onto the analytical equipment. The thresholds, the amount the patient uses/day are outside the control of the analyst.
There can be challenges around the use of identical devices in different applications and this is why the requirement for extractable and leachable testing rests with the end user. Take the following example: A syringe that is used to deliver two doses per day to a patient with a device which contains 1 dose.
Depending on the devices application the AET can give vastly different results. For all calculations the same number of samples are added to the solvent.
Whilst the above number are worst case, and a concentration step could easily be used to improve detection levels the number of components in a volume of solvent is quite conservative.
The AET is a very important concept in extractable and leachable testing and is key in designing and developing these studies. It is also important to remember that the AET must be above the limit of detection of the method.