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

Abstract

Abstract. Equivalence testing of aerodynamic particle size distribution (APSD) through multi-stage cascade impactors (CIs) is important for establishing bioequivalence of orally inhaled drug products. Recent work demonstrated that the median of the modified chi-square ratio statistic (MmCSRS) is a promising metric for APSD equivalence testing of test (T) and reference (R) products as it can be applied to a reduced number of CI sites that are more relevant for lung deposition. This metric is also less sensitive to the increased variability often observed for low-deposition sites. A method to establish critical values for the MmCSRS is described here. This method considers the variability of the R product by employing a reference variance scaling approach that allows definition of critical values as a function of the observed variability of the R product. A stepwise CI equivalence test is proposed that integrates the MmCSRS as a method for comparing the relative shapes of CI profiles and incorporates statistical tests for assessing equivalence of single actuation content and impactor sized mass. This stepwise CI equivalence test was applied to 55 published CI profile scenarios, which were classified as equivalent or inequivalent by members of the Product Quality Research Institute working group (PQRI WG). The results of the stepwise CI equivalence test using a 25% difference in MmCSRS as an acceptance criterion provided the best matching with those of the PQRI WG as decisions of both methods agreed in 75% of the 55 CI profile scenarios. KEY WORDS: aerodynamic particle size distribution; bioequivalence; cascade impactor; chi-square ratio statistic; orally inhaled drug products.

In Vitro Testing for Orally Inhaled Products: Developments in Science-Based Regulatory Approaches

“…Once methods are developed fully, additional work to understand their performance will be required. One such method being developed is the modified chi-square ratio statistic considered by Weber (15,104). In vitro data analysis has, over time, been viewed in two different ways.…”

Innovation for Generic Drugs: Science and Research Under the Generic Drug User Fee Amendments of 2012

“…The FDA has a series of research projects that explore various in vitro options, which can support generic drug development programs for orally inhaled drug products (OIDPs) by streamlining the current regulatory pathways or even replacing the less sensitive, time‐consuming, and costly comparative clinical end point bioequivalence study currently recommended under a weight‐of‐evidence approach. These projects include research to create and validate a sensitive and predictive dissolution test system, methods for comparative cascade impaction, and efforts to establish more predictive in vitro methods to investigate and compare the total dose and the aerodynamic particle size distribution of different OIDPs exiting different mouth‐throat models under realistic inhalation flow conditions . These new in vitro tests can also aid generic product developers in understanding the impact of both manufacturing processes and excipient sources on batch to batch variability.…”

Current Scientific and Regulatory Approaches for Development of Orally Inhaled and Nasal Drug Products: Overview of the IPAC-RS/University of Florida Orlando Inhalation Conference

“…The following review papers in this issue provide an integrated view of talks and discussions related to a given topic: & Application of the modified chi-square ratio statistic in a stepwise procedure for cascade impactor equivalence testing (by Ben Weber et al) (6) & Effect of device design and formulation on the in vitro comparability for multi-unit dose dry powder inhalers (by Jag Shur et al) (7) & In vitro, pharmacokinetic, pharmacodynamic, and safety comparisons of single and combined administration of tiotropium and salmeterol in COPD patients using different dry powder inhalers (by Stephen Horhota et al) (8) & Safety of β2-agonists in asthma: linking mechanisms, meta-analyses, and regulatory practice (by Sanjeeva Dissanayake) (9).…”