(344e) Large-Scale Experimental Comparison of Batch and Continuous Technologies for Pharmaceutical Tablet Manufacturing

Matsunami, K., The University of Tokyo
Nagato, T., Powrex Corporation
Hasegawa, K., Powrex
Hirao, M., The University of Tokyo
Sugiyama, H., The University of Tokyo
This work presents experimental comparison of batch and continuous technologies for pharmaceutical tablet manufacturing at a scale of 100 kg. The investigation covered the units of mixing, granulation, drying, blending, and compression, for which three processes were established based on batch and continuous technologies. For the batch process, conventional facilities were used, with employing fluidized bed granulation and high shear granulation as the granulation unit. For the continuous process, a recently developed facility was used, which interconnects all the units and is capable of producing tablets at the speed of 25 kg/hr. Common to these three processes, a 100 kg of raw materials were provided that contained ethenzamide as an active pharmaceutical ingredient (API), and mannitol and crystalline cellulose as excipients. As a preparation, experiments at a small scale were performed in order to determine process parameters in the experiments at a scale of 100 kg. During or after the production, samples were taken for investigating the following three items. First was the quality of granules as intermediate products, e.g., particle size distribution, mean diameter, and loose bulk density. Second was the quality of the tablets, e.g., tablet hardness, content of API, and dissolution profiles. Third was the yield of the overall process considering various causes of losses, such as stabilization of the continuous process, sticking to the equipment, or condition setting of compression. For the continuous process, stability of product quality during the process operation was also investigated because the total run time can be up to hours.

The experimental result indicated that the product quality of all processes fulfilled the standard values which are often used in the industry. Granules made by fluidized bed granulation were porous, while granules made by high shear granulation and the continuous process were spherical. Although hardness of tablets made by the high shear granulation process was lower than that by the other two processes, there are no significant differences of dissolution profiles among the three processes. In the continuous process, product quality measured by mean particle diameter of granules was stable for the entire run time except for the initial nine minutes. Because of this reason, yield of the continuous process was lower than those of the other two processes, which indicates that stabilization would be one of the important challenges in continuous technology. In conclusion, the three investigated processes using continuous, fluidized bed, and high sheer granulation showed similarity in terms of product quality. However, intermediate products showed different quality characteristics such as size/shape, and especially in continuous technology, yield was found to be an improvement opportunity. The actual decisions should be based on various aspects such as quality, economy or safety, and thus, development of multiobjective design methodology is desired in future.