Product Quality Research Institute evaluation of cascade impactor profiles of pharmaceutical aerosols: Part 2—Evaluation of a method for determining equivalence

The purpose of this article is to present the thought process, methods, and interim results of a PQRI Working Group, which was charged with evaluating the chi-square ratio test as a potential method for determining in vitro equivalence of aerodynamic particle size distribution (APSD) profiles obtained from cascade impactor measurements. Because this test was designed with the intention of being used as a tool in regulatory review of drug applications, the capability of the test to detect differences in APSD profiles correctly and consistently was evaluated in a systematic way across a designed space of possible profiles. To establish a “base line,” properties of the test in the simplest case of pairs of identical profiles were studied. Next, the test's performance was studied with pairs of profiles, where some difference was simulated in a systematic way on a single deposition site using realistic product profiles. The results obtained in these studies, which are presented in detail here, suggest that the chi-square ratio test in itself is not sufficient to determine equivalence of particle size distributions. This article, therefore, introduces the proposal to combine the chi-square ratio test with a test for impactor-sized mass based on Population Bioequivalence and describes methods for evaluating discrimination capabilities of the combined test. The approaches and results described in this article elucidate some of the capabilities and limitations of the original chi-square ratio test and provide rationale for development of additional tests capable of comparing APSD profiles of pharmaceutical aerosols

Scientific Rationale for Determining the Bioequivalence of Inhaled Drugs.

In recent years, pathways for the development and approval of bioequivalent inhaled products have been established for regulated markets, including the European Union (EU), and a number of orally inhaled products (OIPs) have been approved in the EU solely on the basis of in vitro and pharmacokinetic data. This review describes how these development pathways are structured and their implications for the treatment of airway diseases such as asthma. The EU guidance follows a stepwise approach that includes in vitro criteria as the first step. If all in vitro criteria are not met, the second step is based on pharmacokinetic evaluations, which include assessments of lung and systemic bioavailability. If all pharmacokinetic criteria are not met, the third step is based on clinical endpoint studies. In this review, the scientific rationale of the European Medicines Agency guidance for the development of bioequivalent OIPs is reviewed with the focus on the development of bioequivalent OIPs in the EU. Indeed, we discuss the advantages and disadvantages of the weight-of-evidence and stepwise approaches. The evidence indicates that the EU guidance is robust and, unlike clinical endpoint studies, the pharmacokinetic studies are far more sensitive to measure the minor differences, i.e. deposition and absorption rates, in drug delivery from the test and reference products and, thus, should be best suited for assessing bioequivalence. The acceptance range of the 90% confidence intervals for pharmacokinetic bioequivalence (i.e. 80-125% for both the area under the plasma concentration-time curve and maximum plasma concentration) represent appropriately conservative margins for ensuring equivalent safety and efficacy of the test and reference products