(481i) Modelling, Design and Operation of a Continuous Cryogenic Reaction

In the past decade, Pharmaceutical companies have focused on continuous manufacture of small molecules due to quality and control advantages over traditional batch processes. In addition, flow chemistry can enable a diversity of reactions, facilitating the synthetic route to a molecule that may in turn produce a simpler and more effective manufacturing process. Finally, telescoping multiple unit operations together in a continuous supply chain could potentially reduce inventories and lower labour and overhead overall cost.

Until recently, the development and the control of processes in the pharmaceutical industry have been dominated by experimentation. The definition of the optimum process and the control strategy has been supported by Design of Experiments (DoE) feeding into statistical models. Such approaches are extremely cost and time ineffective due to high consumption of material, numerous experiments and high labour requirement.

On the other hand, the mechanistic modelling of drug substance unit operations, such as reactions and separations can yield a high degree of understanding of the chemical and physical phenomena occurring in the process. Furthermore, process optimization can lead to maximizing yield and quality, reducing manufacturing cost and supporting the control strategy through understanding and tracking of critical quality attributes (CQAs) across the process.

In this work the development of a cryogenic reaction process will be discussed. A detailed system model of the process has been developed, which was then used for process design, process optimization and support the QbD strategy. Finally, the developed model was used for online monitoring of the process in GSK’s manufacturing facilities during the clinical batches.