Kreiser Marius J, Wabel Christoph, Wagner Karl G
Product and Process Development, Pfizer Manufacturing Deutschland GmbH, 79108 Freiburg, Germany.
Department of Pharmaceutical Technology and Biopharmaceutics, University of Bonn, 53121 Bonn, Germany.
Pharmaceutics. 2022 Jan 25;14(2):278. doi: 10.3390/pharmaceutics14020278.
The continuous manufacturing of solid oral-dosage forms represents an emerging technology among the pharmaceutical industry, where several process steps are combined in one production line. As all mixture components, including the lubricant (magnesium stearate), are passing simultaneously through one blender, an impact on the subsequent process steps and critical product properties, such as content uniformity and tablet tensile strength, is to be expected. A design of experiment (DoE) was performed to investigate the impact of the blender variables hold-up mass (HUM), impeller speed (IMP) and throughput (THR) on the mixing step and the subsequent continuous manufacturing process steps. Significant impacts on the mixing parameters (exit valve opening width (EV), exit valve opening width standard deviation (EV SD), torque of lower impeller (T), torque of lower impeller SD (T SD), HUM SD and blend potency SD), material attributes of the blend (conditioned bulk density (CBD), flow rate index (FRI) and particle size (d values)), tableting parameters (fill depth (FD), bottom main compression height (BCH) and ejection force (EF)) and tablet properties (tablet thickness (TT), tablet weight (TW) and tensile strength (TS)) could be found. Furthermore, relations between these process parameters were evaluated to define which process states were caused by which input variables. For example, the mixing parameters were mainly impacted by impeller speed, and material attributes, FD and TS were mainly influenced by variations in total blade passes (TBP). The current work presents a rational methodology to minimize process variability based on the main blender variables hold-up mass, impeller speed and throughput. Moreover, the results facilitated a knowledge-based optimization of the process parameters for optimum product properties.
固体口服剂型的连续制造是制药行业中一项新兴技术，其中多个工艺步骤在一条生产线上组合。由于所有混合成分，包括润滑剂（硬脂酸镁），同时通过一个混合器，预计会对后续工艺步骤和关键产品特性产生影响，如含量均匀度和片剂抗张强度。进行了一项实验设计（DoE），以研究混合器变量滞留质量（HUM）、叶轮速度（IMP）和产量（THR）对混合步骤及后续连续制造工艺步骤的影响。发现对混合参数（出口阀开度宽度（EV）、出口阀开度宽度标准偏差（EV SD）、下叶轮扭矩（T）、下叶轮扭矩标准偏差（T SD）、HUM SD和混合效价SD）、混合物料属性（调节堆密度（CBD）、流速指数（FRI）和粒径（d值））、压片参数（填充深度（FD）、底部主压缩高度（BCH）和顶出力（EF））以及片剂特性（片剂厚度（TT）、片剂重量（TW）和抗张强度（TS））有显著影响。此外，还评估了这些工艺参数之间的关系，以确定哪些工艺状态是由哪些输入变量引起的。例如，混合参数主要受叶轮速度影响，而物料属性、FD和TS主要受总叶片行程（TBP）变化的影响。当前的工作提出了一种基于混合器主要变量滞留质量、叶轮速度和产量来最小化工艺变异性的合理方法。此外，研究结果有助于基于知识对工艺参数进行优化，以获得最佳产品特性。
