(164f) Design Problem of Pharmaceutical Manufacturing Processes

Authors: 
Sugiyama, H., The University of Tokyo
The modern pharmaceutical industry is requested to realize superior manufacturing processes regarding multiple aspects such as quality, economy, supply reliability, and many others. To this end, the setup of design problem is critical because the choice of design variables, constraints and objective functions determines the capability of the process to be realized. The aim of this presentation is to explore the characteristics of design problem of pharmaceutical manufacturing processes based on the two research examples from the presenterâ??s group.

The first example is on the design of pharmaceutical tablet manufacturing processes considering the choice between batch and continuous technologies. While pharmaceutical tablets are usually manufactured in batch processes, continuous manufacturing technology is in intensive development in both industry and academia. In this work, a decision-support method was proposed for the choice between two technologies with four steps of: (i) process modeling, (ii) evaluation, (iii) sensitivity analysis, and (iv) interpretation. The method was applied to the following design situation, i.e., â??a company launches a new product which is supposed to be marketed for 30 years. The tablet product can be manufactured by either technology which needs to be specified based on the economic evaluation.â? After performing the four steps of method, a better process regarding net present cost could be suggested depending on the API price as well as the maximum demand quantity over the production period of 30 years.

The second example is on the design of solvent recovery processes in API manufacturing. Generally in API manufacturing, various types and large amount of organic solvents are used, which raises concerns regarding environment, health and safety (EHS) risks. In this work, an actual API manufacturing was investigated, and a process was designed for recovering tetrahydrofuran (THF) from the azeotropic mixture with methanol and water. The objective functions were set as the net present value as well as EHS risk evaluation scores. As the process, four alternatives were generated regarding the core separation technology, i.e., (a) zeolite membrane (b) pressure-swing distillation (c) azeotropic distillation, and (d) entrainer. The target THF concentration was set as 99.95 wt% in the initial evaluation, which was in the secondary evaluation relaxed to 95 wt%, a sufficient concentration in the actual API manufacturing. The initial multiobjective evaluation identified the alternatives (a), (b) and (d) as Pareto optima, among which, the alternative (b) was the best in all aspects in the secondary evaluation.

The outcomes in these two research examples were sensitive to the setup of the design problem, i.e., design variable, constraint and objective function. In the first example, treating the choice of batch and continuous as a design variable was meaningful because the superior technology found was depending on the API price and the product demand. In the second example, different results were obtained by regarding the target concentration changeable, which would be considered fix in reality due to the required effort of change management in GMP. The design problem of pharmaceutical manufacturing process has large degree of freedom in nature, however in practice, many variables are considered as hard constraints or determined on an empirical basis. In this regard, MSO can be regarded as the supportive technology for investigating wide range of items in a speedy manner in the design phases of pharmaceutical manufacturing processes.