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Frequently Asked Questions

 7. What is the analytical evaluation threshold (AET)? 

 

The AET, which is calculated from the SCT (see Q6), has been defined by the PQRI guidance document 'Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products (OINDPs)', as the threshold at or above which a chemist should begin to identify a particular leachable and/or extractable and report it for potential toxicological assessment.

 

For non OINDPs, the AET can be calculated from the TTC or the LTL exposures defined by ICH M7 (see Q5). Additionally for elemental extractables and leachables, AETs for individual elements can be calculated from the PDEs defined in ICH Q3D 'Guideline for Elemental Impurities'.

 

To be useful, the AET should be expressed in terms of the amount of an individual leachable in a particular product, e.g.,

 

  • µg per vial

  • µg per canister

  • µg per bottle of e-liquid

  • µg per mL

  • µg per dose

  • etc.....

 

The units used to express the AET will vary for different products depending on

 

(i) the particular dosing regimen for a drug, e.g. 

 

  • number of doses per vial

  • number of vials per day

  • number of mLs per dose

  • number of mLs per day

  • etc.....

(ii) the way an ENDS or e-liquid is used, e.g.

  • number of times the ENDS is used per smoking episode

  • number of times the ENDS is used per day

  • volume inhaled 

(iii) the technique(s) used to detect and quantify individual leachables and/or extractables

 

In practise, the calculated AET is adjusted by an "uncertainty factor" to account for the variability in response of individual leachables and/or extractables analysed by any given analytical technique/method, to give the final or working AET.

For E&L studies, methods are developed and validated to monitor for specific leachables and/or extractables, or can be employed as general screening methods. In the latter case, the variation in response of individual compounds to a given analytical technique becomes extremely important. Careful consideration must be given to the uncertainty factor applied to the calculated AET, to ensure the final AET is appropriate for its intended purpose. 

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