(400a) Selection Support Methodology Between Batch and Continuous Technologies for Pharmaceutical Tablet Manufacturing Processes

Authors: 
Matsunami, K., The University of Tokyo
Sugiyama, H., The University of Tokyo
Hirao, M., The University of Tokyo
Nakagawa, H., Daiichi Sankyo Co., Ltd.
Miyano, T., Daiichi Sankyo Co., Ltd.
Arai, H., Daiichi Sankyo Co., Ltd.
In solid drug product manufacturing, continuous technology is being developed as an alternative to the conventional batch technology. There are many differences between these two technologies, which may affect critical objectives such as cost-effectiveness, quality, process safety or occupational health. However, general tools are still missing, which can support the choice between batch and continuous technologies, and furthermore, process design of solid drug product manufacturing.

This work presents the selection support methodology between batch and continuous technologies for pharmaceutical tablet manufacturing processes. The methodology consists of four steps and includes iteration: (I) process modeling, (II) evaluation, (III) sensitivity analysis, and (IV) interpretation. The initial input of step I is a design situation, such as a launch of a new product to be manufactured in either technology that needs to be decided. In step I, the processes are modeled with covering the main processes such as weighing, granulation, blending, compression, and coating, and supporting processes such as testing, disposal, cleaning, maintenance of process analytical technology, and heat ventilation and air conditioning. Models are created so that the characteristics of two technologies in the actual manufacturing situations are reflected, such as numbers of operators, product yield or required area for manufacturing. Using these models, evaluation is conducted in step II, which produces results of the objective functions such as net present cost (NPC) after the launch. In step III, sensitivity analysis is conducted in order to quantify the effects of varying input parameters in the evaluation results. Finally in step IV, the results of evaluation and sensitivity analysis are interpreted, and the necessity of iterating the previous steps is investigated. The final outcome of the methodology is the appropriate technology to be chosen, i.e., batch or continuous, for manufacturing, for the tablet manufacturing.

A case study was performed for demonstrating the methodology. The design situation was the launch of a new product for which the estimation is available regarding the API price as well as the maximum demand quantity over the production period of 30 years. It was also assumed that the tablet product can be produced by either technology which needs to be specified based on the economic evaluation. After performing the steps I and II, the quantitative relation between demand quantity/API price and NPC over 30 years was clarified. The NPC did not include the investment cost, since the plant was assumed to have both technologies already. The result showed that continuous manufacturing was more lucrative in the areas of high demand quantity with low API price or low demand quantity with high API price. On contrary, batch manufacturing showed lower NPC in the areas where both API price and demand quantities are both high. Step III identified the number of campaign production in batch manufacturing as one of the most sensitive parameters in the model, for which the step II was iterated. In step IV, an economically appropriate technology was suggested based on the interpretation of the evaluation and sensitivity analysis results.