Comparison of two approaches for treating cascade impaction mass balance measurements.

The multistage cascade impactor (CI) is the most appropriate tool for measuring the aero-dynamic particle size distribution (APSD) of active pharmaceutical ingredient(s) (API) in the aerosol from an orally inhaled drug product. It is possible to determine the total emitted mass per actuation of the inhaler by summing the individual component results obtained when determining APSD. The determination of total mass per actuation recovered from the CI components (or "mass balance" [MB]) has inherently lower precision than that of a delivered dose (DD) determination. An FDA draft guidance for industry has proposed using CI-determined MB as part of the product specification, with acceptance criteria of +/-15% of the label claim (LC) dosage. We propose instead that MB be used to assess whether the CI measurement of APSD is reliable. Two multitiered test schemes for MB are evaluated that allow for retests to accommodate the variability of the MB measurement. We provide statistical evaluations of both test schemes by using operating characteristic (OC) curves. We find that a two-tiered procedure with broader acceptance criteria but limited opportunity for investigating and retesting MB failure results in a greater risk of rejection of good batches ("false positive" error) without the commensurate reduction in the risk of passing unacceptable batches ("false negative" error). In contrast, a three-tiered procedure with narrower acceptance criteria, but more opportunity to check for potential CI system malfunction/method misapplication and to rerun the CI test, provides a compromise that enables the MB measurement to be used without significantly increasing the probability of false positive errors.