Evaluation of Small-Scale Powder Flow Characterization Tests in the Prediction of Large-Scale Process Failures
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- 作者：Aaron Zettler ; Jon Hilden ; Michael Koenig…
- 关键词：Manufacturing platform ; Formulation ; NDP ; Tablets
- 刊名：Journal of Pharmaceutical Innovation
- 出版年：2016
- 出版时间：September 2016
- 年：2016
- 卷：11
- 期：3
- 页码：189-199
- 全文大小：1,406 KB
- 刊物主题：Pharmacology/Toxicology; Industrial and Production Engineering; Biotechnology; Biochemical Engineering;
- 出版者：Springer US
- ISSN：1939-8042
- 卷排序：11
文摘
In pharmaceutical development, powder flow characteristics are notoriously difficult to predict. Although tests exist that aim to determine the flowability of powders, many have not been definitively correlated with a powder’s performance in downstream processes. Part of the challenge is that powder flow must occur over a broad range of consolidating stresses, including low-stress flow regimes such as the filling of a die cavity in a tablet press and high-stress flow regimes such as the deformation associated with tablet compression. The objective of this work was to characterize several placebo formulations utilizing a variety of standardized and non-standardized experiments and contrasting those results with downstream tablet compression performance. Angle of repose, bulk and tap density, Hausner ratio, Carr’s compressibility index, a visual powder flow assessment, a mass flow rate test, Flodex, and powder shear testing were evaluated on several different blends of placebo powders to determine a predictive test for downstream process performance. The placebo powders consisted of a standard base unit formula, mixed with various levels of four different “pseudo-active pharmaceutical ingredients (APIs)” (i.e., excipients that mimic poorly flowing active pharmaceutical ingredients). All formulations were evaluated by the individual flow tests and then compressed on a rotary tablet press. Formulations were deemed failures if the relative standard deviation of tablet weight was >2 %, material stuck to punches (low lubrication), or exhibited ejection forces high enough to trigger automatic shutdown of tablet press. The 2 % RSD limit is based on internally developed best practices for transferring tablet compression processes from development into manufacturing. The results of the tablet compression process were then compared to the results of the flowability tests to detect any correlations. The Hausner ratio and powder shear test results discriminated marginally between successful and failed batches and were highly correlated with each other.