Current Understanding of the Equivalence Evaluations for In Vitro Tests on Generic Dry Powder Inhaler Drug Products in Japan

Applications of Exhaled Breath Condensate Analysis for Drug Monitoring and Bioequivalence Study of Inhaled Drugs

“…Japan's pharmaceutical and medical devices agency (PMDA) has announced fundamental principles for the bioequivalence assessment of inhalers in 2016. This agency indicated the three-stage evaluation for developing inhalation products, including in vitro studies, PK reports, and clinical endpoint studies, the same as FDA steps (71,81). It delineated the significance of the delivered dose in line with fine particle mass and at least four sets of stages at three flow rates (10th, 50th, and 90th percentiles; e.g., 30 l/min, 60 l/min, and 90 l/min) in in vitro tests to confirm bioequivalence (81).…”

“…This agency indicated the three-stage evaluation for developing inhalation products, including in vitro studies, PK reports, and clinical endpoint studies, the same as FDA steps (71,81). It delineated the significance of the delivered dose in line with fine particle mass and at least four sets of stages at three flow rates (10th, 50th, and 90th percentiles; e.g., 30 l/min, 60 l/min, and 90 l/min) in in vitro tests to confirm bioequivalence (81). Furthermore, the PMDA takes into account clinical population variance based on various stages of lung disease that could be resolved using in vitro tests (81).…”

“…It can be understood from the previous sections that the critical parameters in the bioequivalence assessment of corticosteroids in various guidelines are relative glucocorticoid receptor binding affinity, glucocorticoid receptor dissociation constant (Kd, nmol -1 ), relative potency, device efficiency (delivered lung dose) (lung deposited dose/nominal dose), pulmonary residency time (lung retention time (FF)), and bioavailability (F oral = oral bioavailability, F inh = inhalation bioavailability), systemic clearance of the exogenous glucocorticoids (CL = total body clearance), plasma protein binding, Vd = apparent volume of distribution at steady-state, and t 1/2 = plasma elimination half-life (71,81).…”