Statistical considerations for design and analysis of stability, comparability and formulation tests

Abstract This article considers designed experiments for stability, comparability, and formulation testing that are analyzed with regression models in which the degradation rate is a fixed effect. In this setting, we investigate how the number of lots, the number of time points and their locations affect the precision of the entities of interest, leverages of the time points, detection of non‐linearity and interim analyses. This investigation shows that modifying time point locations suggested by ICH for stability studies can significantly improve these objectives. In addition, we show that estimates of precision can be biased when a regression model that assumes independent measurements is used in the presence of within‐assay session correlation. This bias can lead to longer shelf life estimates in stability studies and loss of power in comparability studies. Mixed‐effect models that take into account within‐assay session correlation are shown to reduce this bias. The findings in this article are obtained from well known statistical theory but provide valuable practical advice to scientists and statisticians designing and interpreting these types of experiments.