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Abstract：
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 in silico design space which is compared favorably to that built from experiments. Moreover, in the future, the in silico design space based on the validated flowsheet model can provide better manufacturing flexibility and make control strategy development simpler.
摘要：
从过程设计和控制的角度来看，口服剂量药物产品的持续生产越来越需要严格的过程理解。这项研究的目的是开发一种方法，分析上游工艺参数对连续片剂压实的影响，然后将相关的上游变量与最终片剂属性（例如相对密度和硬度）相关联。三个工艺参数的影响(系统吞吐量、搅拌机速度,和压紧力）使用全因子实验设计研究了片剂属性。不出所料,压实力是最重要的工艺参数。然而,重要的是,吞吐量被发现具有不可忽视的影响，这是以前无法解释的。这种影响被认为与不同水平的粉末预压缩有关。对这种关系的经验模型进行回归并合并到流程图模型中。然后将流程模型用于开发计算机设计空间，该空间与实验构建的空间相比具有优势。此外，在未来,基于经过验证的流程模型的仿真设计空间可以提供更好的制造灵活性，并使控制策略开发更简单。
