Bioequivalence requirements for orally inhaled and nasal drug products and use of novel physiologically based biopharmaceutics modeling approaches for assessing in vivo performance

Orally inhaled and nasal drug products (OINDPs) are complex due to the interplay between the device, formulation, and patient characteristics. Establishing bioequivalence (BE) of OINDPs with reference is highly complex and require in vitro, in vivo pharmacokinetic and comparative clinical endpoint studies that are challenging to conduct. In order to increase the rate of submission and approval of generics, regulatory agencies are encouraging the use of alternative in vitro and in silico methodologies to replace complex in vivo studies. The present review attempts to summarize current understanding of alternative BE approaches for OINDPs. In vitro characterization studies required for establishing BE for OINDPs considering USFDA and EMA guidance's are detailed. In silico models such as pulmonary compartmental absorption and transit (PCAT) with emphasis on model input parameters are portrayed. Further, two detailed case studies of inhalation nebulizer and nasal spray formulations are described where PCAT models are developed for predicting BE and local concentrations. Lastly, current understanding of such BE approaches from regulatory perspectives are discussed summarizing recent regulatory workshops and through collation of USFDA product specific guidance's for almost 70 drug products. Overall, this manuscript can act as ready-to-use guide to understand alternative approaches for establishing BE for OINDPs. (c) 2024 American Pharmacists Association. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.