Department of Chemical Engineering, University of Massachusetts Lowell, Lowell, MA, USA.
Applied Mathematics and Modeling, Scientific Modeling Platforms, Merck & Co., Inc, Kenilworth, NJ, USA.
Pharm Dev Technol. 2020 Dec;25(10):1204-1215. doi: 10.1080/10837450.2020.1805760. Epub 2020 Aug 18.
Continuous manufacturing of oral-dosage drug products is increasing the need for rigorous process understanding both from a process design and control perspective. The purpose of this study is to develop a methodology that analyzes the effects of upstream process parameters on continuous tablet compaction and then correlates associated upstream variables to the final tablet attributes (e.g. relative density and hardness). The impact of three process parameters (system throughput, blender speed, and compaction force) on tablet attributes is investigated using a full factorial experimental design. As expected, the compaction force was found to be the most significant process parameter. However, importantly, throughput was discovered to have a non-negligible impact which was previously unaccounted for. This impact is proposed to be related to differing levels of powder pre-compression. An empirical model for this relationship is regressed and incorporated into a flowsheet model. The flowsheet model is then used to develop an design space which is compared favorably to that built from experiments. Moreover, in the future, the design space based on the validated flowsheet model can provide better manufacturing flexibility and make control strategy development simpler.
连续化生产口服固体制剂需要从工艺设计和控制的角度对其进行严格的工艺理解。本研究旨在开发一种方法，分析上游工艺参数对连续压片的影响，然后将相关上游变量与最终片剂属性（例如相对密度和硬度）相关联。使用完全析因实验设计研究了三个工艺参数（系统吞吐量、混合速度和压缩力）对片剂属性的影响。不出所料，压缩力被发现是最重要的工艺参数。然而，重要的是，发现吞吐量具有先前未考虑到的不可忽视的影响。这种影响据推测与不同程度的粉末预压缩有关。对这种关系进行了回归，并将其纳入流程图模型。然后使用流程图模型来开发设计空间，并将其与实验构建的设计空间进行比较。此外，将来，基于经过验证的流程图模型的设计空间可以提供更好的制造灵活性，并使控制策略的开发更加简单。
