Process Development and Scale-up of Mixing Sensitive Continuous Flow Reactions in Pharmaceutical Drug Substance Manufacturing

The manufacturers of active pharmaceutical ingredients and their intermediates have recently rediscovered flow chemistry and continuous processing. This renewed interest in these technologies has arisen from the anticipated benefit in supply chain flexibility and economics and regulatory pressure in addition to the obvious opportunity for improved control over heat and mass transfer, improved process safety, access to high pressure and high temperature conditions, and convenient use of supported catalysts and biocatalysts.

In some parts of the community, there has been an assumption of ease and straightforward scalability for flow chemistry. However, when a flow step is embedded between two batch operations, the flow step would ideally be completed within the same amount of time as a typical batch operation, which in our experience is usually 8 - 24 hours. To achieve this requirement, productivity obtained in a laboratory scale reactor would need to be increased by several orders of magnitude, precluding the simple scale out or numbering-up approaches. In the case of reactions that require optimal mixing for selectivity and yield, the need to preserve the same mixing characteristics at production scale is essential. Achieving this goal would depend on our ability to characterize mixers and define the minimum mixing requirements to maintain the same process performance.

This presentation will discuss various strategies that have been used to scale up flow chemistry applications from the laboratory bench-top to the manufacturing environment. Techniques such as dimensional analysis and mixing characterization via a modified 4th Bourne reaction will be presented as methods to relate mixing to reaction performance. The integration of process analytical technologies with these techniques leads to streamlined analysis and further process understanding. Results from these studies have also inspired 3D-printed stainless-steel static mixer designs for custom applications. In addition, this presentation will discuss on-going efforts aimed at further understanding and modeling of mixing-sensitive reactions.