Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Valencia, Spain; Interuniversity Research Institute for Molecular Recognition and Technological Development, Polytechnic University of Valencia-University of Valencia, Valencia, Spain.
Department of Essential Medicines and Health Products (EMP), World Health Organization, Geneva, Switzerland.
Eur J Pharm Sci. 2020 Apr 15;146:105259. doi: 10.1016/j.ejps.2020.105259. Epub 2020 Feb 10.
The calculation of the 90% confidence interval of f 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 f 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.
Highly variable in vitro dissolution data from two products were selected. Three different similarity factors, f, E(f) and bc-f, 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.
All three platforms report the same f 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 f and E(f) also under other truncation rules (EMA or FDA), which are not implemented in DDSolver. Pheq_bootstrap allowed the calculation of bc-f. The conclusion of similarity is based on a bootstrap percentile CI of E(f) and f in Pheq_bootstrap and DDSolver, respectively. Bootf2bca provides all four 90% CI.
Bootf2bca or Pheq_bootstrap should be considered for the estimation of the 90% CI of the f similarity factor when dissolution profiles show high variability.
当溶出数据显示出过度的变异性时，主要监管机构已经提出并接受了基于自举法计算 f 的 90%置信区间的方法。不同的免费软件平台允许通过自举法计算 f 的 90%CI。它们在监管提交中的使用正在增加，但在可用的软件平台之间观察到了不同的结果。因此，本工作的目的是分析这些软件平台的特点，并评估它们的结果。
选择了两种产品的高变异性体外溶出数据。使用三个免费软件平台 Pheq_bootstrap、Bootf2bca 和 DDSolver，以及四种不同的方法，即正态逼近、bootstrap-t-CI、百分位数 CI 和偏置校正和加速 CI，计算了三个不同的相似性因子 f、E(f)和 bc-f 及其对应的 90%置信区间。
比较产品 1 和 3 以及产品 2 和 3（无截断规则）时，三个平台都报告了相同的 f 值，分别为 49.66 和 54.87。在其他截断规则（EMA 或 FDA）下，Bootf2bca 和 Pheq_bootstrap 也提供了相同的 f 和 E(f)，而 DDSolver 则没有。Pheq_bootstrap 允许计算 bc-f。相似性的结论是基于 Pheq_bootstrap 和 DDSolver 中 E(f)和 f 的 bootstrap 百分位 CI。Bootf2bca 提供了所有四个 90%CI。
当溶出曲线显示高度变异性时，应该考虑使用 Bootf2bca 或 Pheq_bootstrap 来估计 f 相似性因子的 90%CI。
