Exploration of the potential impact of batch‐to‐batch variability on the establishment of pharmacokinetic bioequivalence for inhalation powder drug products

Abstract

Batch‐to‐batch variability in inhalation powder has been identified as a potential challenge in the development of generic versions. This study explored the impact of batch‐to‐batch variability on the probability of establishing pharmacokinetic (PK) bioequivalence (BE) in a two‐sequence, two‐period (2 × 2) crossover study. A model‐based parametric simulation approach was employed, incorporating batch‐to‐batch variability through the relative bioavailability (RBA) ratio. In the absence of batch variability, recruiting a total of 48 subjects in a 2 × 2 crossover study with the reference formulation resulted in a 95% probability of concluding BE. However, this probability decreased to 80% with a 5% batch difference in RBA and further declined to 30% with a 10% batch difference. With a 10% batch difference, the required number of subjects to achieve an 80% probability of concluding BE increased to 84. When considering product differences between the reference and the test formulations, an additional 10% batch difference reduced the study power from 97% to 30% for a T/R bioavailability ratio of 100% in a 2 × 2 crossover study with 48 subjects. As a result, the substantial impact of batch‐to‐batch variability on the study power and type I error of the PK BE study may pose significant challenges for the development of generic Advair Diskus due to its degree of PK batch‐to‐batch variability. Therefore, alternative PK BE study designs and guidelines are needed to adequately address the influence of batch‐to‐batch variability in products like Advair Diskus.