Simulated Use Extraction as an Alternative to Leachables Testing

May 31, 2019

If good materials were selected for the container closure system (CCS) for a parenteral drug product, it is not uncommon for the results of the forced extraction study to be that no extractables were detected above the analytical evaluation threshold (AET).    While the PRQI guidances does allow for the conclusion to drawn from these results that the CCS presents no risk to patient safety, many drug development teams are hesitant to make this conclusion due to the legitimate concern that regulatory reviewers may still request leachables results.    However,  the same drug development team may be hesitant to commit the time and money for unneeded leachables testing.    An alternative study proposed by Pine Lake Laboratories is a simulated use extraction to further support the conclusion of no risk from leachables without the expense and time of full leachables testing.

In a simulated use extraction study, the extraction solvent is selected to closely mimic the pH and solvating strength of the drug product.    For simple drug products, the placebo may be a good choice if it does not present significant interferences to the analytical methods used to detect the leachables.   The extraction solvent should be selected to ensure it is compatible with the analytical methods.

The extraction conditions are selected based upon the intended shelf life of the drug product so that the “real time” storage equivalent can be determined.    According to USP <1663>, the relationship between the diffusion rate and temperature can be expressed empirically by the Arrhenius equation and has been established in ASTM F1980-07 (2011) “Standard Guide for Accelerated Aging of Sterile Barrier Systems for Medical Devices”.     Therefore, the following equation can be used to determine the “real time” storage equivalent for a drug product intended to be stored at  5 C from the results of a simulated use extraction where the CCS is extracted for 60 days at 40 C :

AAR (Accelerated Aging Rate) = Q10 ((Te – Ta)/10)

Where Ta = Normal Storage Temperature = 5 C

Te = Elevated Temperature = 40 C

Q10 = Reaction Rate = 2 

= 2 ((40 –5)/10)

= 11.31

AATD (Accelerated Aging Time Duration) x AAR = Desired Real Time 

60 Days x 11.31 = 679 days or 22.6 Months at 5oC

As can be seen, a simulated use study done at 40 C for 60 days for a drug product intended to be stored at 5 C would give the same results 22.6 months at the target storage condition.   The time and temperature of the simulated use extraction can be altered as need based upon the targeted shelf life and storage conditions.

At the end of the simulated use extraction study, the extractables profile generated will be for an extraction solvent that closely mimicked the drug product under extraction conditions that are equivalent to the intended shelf life and storage conditions.    This extractables profile provides valuable additional information that can be used to ensure patient safety without the need for full leachables testing.