E&L Analytical Evaluation Threshold

May 28, 2018

At the completion of the extraction studies, a list of extractables is generated.   The challenge at this point is to select which extractables present a toxicological risk and thus should be monitored as leachable.

To evaluate the toxicity of each observed extractable, the safety concern threshold (SCT) is used.  The SCT is the absolute highest acceptable exposure of a patient to a leachable in drug product and is usually expressed in terms of µg of leachable per day.   If an SCT is not known, the recommended SCT by the PQRI should be used.   The PQRI selected this SCT as representing a threshold below which leachables would have negligible safety concerns from carcinogenic and non-carcinogenic toxic effects.   For orally inhaled and nasal drug products (OINDP), the PQRI recommended SCT is 0.15 µg of each individual leachable per day.   For parenteral and ophthalmic drug products (PODP), the PQRI recommended SCT is 1.5 µg of each individual leachable per day.

To apply the SCT to a given drug product, an analytical evaluation threshold (AET) is calculated based on the SCT of an individual leachable, the number of doses of the drug product administered per day, the number of doses contained in the container closure system (CCS), and the weight of the CCS (can also use volume of drug product in the CCS).   The AET is defined as follows:

AET = (SCT/number of doses per day) x (doses per CCS/weight of CCS) x uncertainty factor

The AET will have units of µg/g unless other units were used in the calculation. Surface area of the component of the CCS or volume of drug product in the CCS instead of the weight may be applicable in some situations. The uncertainty factor is an adjustment for the confidence in the identification and quantitation of the extractables needed for OINDP.   For all other types of drug products, the uncertainty factor is not needed.

All extractables above the AET should either be selected to be monitored as a potential leachable or submitted for a toxicological assessment to determine a compound specific SCT