Simulation Informed Design and Performance of In Vitro Bioequivalence Trials for Particle Size Distributions
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Research Article Simulation Informed Design and Performance of In Vitro Bioequivalence Trials for Particle Size Distributions William J. Ganley,1,2
Jagdeep Shur,1 and Robert Price1
Received 30 June 2020; accepted 6 October 2020 Abstract. This study used statistical simulations to investigate the performance of the population bioequivalence test applied to image-based particle size measurements (such as morphologically directed Raman spectroscopy) and methods for designing in vitro bioequivalence trials using prior information. Simulations of in vitro population bioequivalence trials were conducted across a range of representative D50 (number-weighted median particle 10 diameter from a log-normal particle size distribution) and span (which is defined as D90D−D 50 where D90 and D10 are the number-weighted 90th and 10th percentiles in particle diameters sampled from a log-normal particle size distribution) values respectively. The performance of the population bioequivalence test in the simulations was driven by an interplay between overall test variability and the widening or narrowing of the bioequivalence region due to variance terms in the test statistic definition. These findings were dependent upon differences in the variability of D50 and span and may generalise to a wider range of in vitro metrics. Trial design optimisation using power and assurance approaches followed patterns consistent with these findings. As more novel scientific methods are applied to the development of complex generic drug products, the procedures outlined in this study may be used at the inception stage of future in vitro bioequivalence trials to reduce the risk of conducting costly trials with low probabilities of success. KEY WORDS: orally inhaled and nasal drug products; particle size distribution; population bioequivalence; simulation.
INTRODUCTION The determination of bioequivalence between complex locally acting drug products is challenging and continues to hinder generic entry to the market for many orally inhaled and nasal drug products (OINDPs). Bioequivalence is defined as equivalence in the rate and extent at which the active pharmaceutical ingredient (API) becomes available at the site of action (1). For locally acting drug products, such as OINDPs, bioequivalence is currently demonstrated through a combination of in vitro, pharmacokinetic, and comparative clinical endpoint tests (2,3). In 2017, FDA pledged to reduce the “hurdles” for generic product development (4) which has involved the publication of several revised product-specific guidance (PSG) documents for OINDPs, some of which include alternatives to comparative clinical endpoint tests Electronic supplementary material The online version of this article (https://doi.org/10.1208/s12248-020-00520-6) contains supplementary material, which is available to authorized users. 1
Nanopharm Ltd, an Aptar Pharma Company, Cavendish House, Hazell Drive, Newport, NP10 8FY, UK. 2 To whom correspondence should be addressed. (e–mail: [email protected])
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