Comparison of free software platforms for the calculation of the 90% confidence interval of f2 similarity factor by bootstrap analysis

Abstract

Introduction: The calculation of the 90% confidence interval of f₂ based on the bootstrap methodology has been proposed and accepted by the main regulatory authorities when the dissolution data shows excessive variability. Different free software platforms allow the calculation of the 90% CI of f₂ by means of bootstrapping. Their use in regulatory submissions is growing, but divergent results have been observed between the available software platforms. Therefore, the objective of this work is to analyze the characteristics of these software platforms and evaluate their results.

Methods and materials: Highly variable in vitro dissolution data from two products were selected. Three different similarity factors, f₂, E(f₂) and bc-f₂, and their corresponding 90% confidence intervals were calculated with three free software platforms, Pheq_bootstrap, Bootf2bca and DDSolver, and computed by four different approaches, normal approximation, bootstrap-t-CI, percentile CI, and bias corrected and accelerated CI.

Results: All three platforms report the same f₂ value, 49.66 upon comparison of products 1 and 3 and 54.87 for products 2 and 3 (no truncation rule). Bootf2bca and Pheq_bootstrap provided the same f₂ and E(f₂) also under other truncation rules (EMA or FDA), which are not implemented in DDSolver. Pheq_bootstrap allowed the calculation of bc-f₂. The conclusion of similarity is based on a bootstrap percentile CI of E(f₂) and f₂ in Pheq_bootstrap and DDSolver, respectively. Bootf2bca provides all four 90% CI.

Discussion: Bootf2bca or Pheq_bootstrap should be considered for the estimation of the 90% CI of the f₂ similarity factor when dissolution profiles show high variability.

Keywords: 90% CI; Dissolution comparison; f(2); f(2)-bootstrap.