Product quality research institute evaluation of cascade impactor profiles of pharmaceutical aerosols, part 3: Final report on a statistical procedure for determining equivalence

Abstract

The purpose of this article is to report final results of the evaluation of a chi-square ratio test proposed by the US Food and Drug Administration (FDA) for demonstrating equivalence of aerodynamic particle size distribution (APSD) profiles of nasal and orally inhaled drug products. A working group of the Product Quality Research Institute previously published results demonstrating some limitations of the proposed test. In an effort to overcome the test's limited discrimination, the group proposed a supplemental test, a population bioequivalence (PBE) test for impactor-sized mass (ISM). In this final report the group compares the chi-square ratio test to the ISM-PBE test and to the combination of both tests. The basis for comparison is a set of 55 realistic scenarios of cascade impactor data, which were evaluated for equivalence by the statistical tests and independently by the group members. In many instances, the combined application of these 2 tests appeared to increase the discriminating ability of the statistical procedure compared with the chi-square ratio test alone. In certain situations the chi-square ratio test alone was sufficient to determine equivalence of APSD profiles, while in other situations neither of the tests alone nor their combination was adequate. This report describes all of these scenarios and results. In the end, the group did not recommend a statistical test for APSD profile equivalence. The group did not investigate other in vitro tests, in vivo issues, or other statistical tests for APSD profile comparisons. The studied tests are not intended for routine quality control of APSD.

In vitro and in vivo aspects of cascade impactor tests and inhaler performance: A review

“…This initiative resulted in the development of a combined procedure based on calculations of chi-square ratio 14 plus impactorsized mass-population bioequivalence (ISM-PBE). 16 The Moderate: specialized entry (induction) port required, some droplets may be too large to be size-fractionated Aqueous nasal spray pump Low: droplets are almost all too large to be size-fractionated, but adapted cascade impactor method may be useful at quantifying proportion of mass G 10 μm aerodynamic diameter that could penetrate beyond the nasopharynx Figure 1. Mass collected on each component of an Andersen 8-stage cascade impactor (A) presented in the natural order of the components in the cascade impactor system; and (B) presented in the rank order of components from highest to lowest associated mass.…”

“…As a result, no specific statistical procedure could be recommended. 16 It is important to note that while these forms of data presentation permit such comparisons to be made on a component-by-component basis, 14 no information is provided linking API mass with aerodynamic diameter.…”

Application of the Modified Chi-Square Ratio Statistic in a Stepwise Procedure for Cascade Impactor Equivalence Testing

“…For scenarios 52-55, the CI equivalence test was also applied when defining deposition sites 4-10 as ISM, which appear to correspond to the ISM definition for a Next Generation Impactor setup. These selections were in accordance with the evaluation of the PQRI WG (6,8,9).…”

“…Henceforth, this scaling of the MmCSRS on the variability of the R product is also referred to as reference variance scaling. When the original CSRS was evaluated for its properties by Product Quality Research Institute (PQRI) "Aerodynamic Particle Size Distribution Profile Comparisons Working Group" (WG), reference variance scaling was not considered (5)(6)(7).…”

“…The stepwise CI equivalence test is then applied to 55 characteristic CI profile scenarios that were published by the PQRI WG (6,8,9). The PQRI WG classified each of those 55 scenarios as either equivalent or inequivalent.…”