(284e) Designing for Continuous: A Step Change in Performance

Traditionally the majority of active pharmaceutical compounds have been manufactured at large plant scales using batch methodologies. Continuous manufacturing is becoming an increasing attractive alternative however due to apparent benefits such as smaller manufacturing footprints, increased process safety, lower manufacturing costs and increased supply-chain flexibility. Realising all of the above benefits using conventional continuous equipment is however quite challenging and sometimes not achievable. In this project, a new approach to the design of continuous manufacturing platforms is being presented which is not restricted to using such conventional equipment but which is based around the bespoke design and manufacture of all unit operations, optimised to fit the specific process being examined. Processes are quantified in detail using methods such as computational fluid dynamics (CFD) leading to tailored equipment designs which can be manufactured with high precision using metallic 3D printing.

The first case study presented in this paper examines a biphasic reaction between an amine and an acid chloride in the presence of an aqueous sodium hydroxide solution. In this type of biphasic reaction, the main design challenge is centred around achieving a sufficiently large interfacial surface area between the two phases. Conventionally, an agitated vessel operating in either batch or continuous mode would be used in order to maximise this area. However when tested in this case study, adequate dispersion between the immiscible phases required very high energy input levels of at least 1kW/m³, making such an approach difficult to scale up. Plug flow reactors (PFRs) are the most common continuous alternative to agitated vessels. These typically operate under Taylor flow conditions (where alternating aqueous and organic slugs move sequentially through the reactor), giving only limited contact between the phases. In order to overcome the limitations of these conventional approaches, a bespoke unit operation based upon the specific needs of the reaction is designed in this paper which is capable of achieving extremely high dispersion rates between the two phases under the very low Reynolds numbers typically encountered in the pharmaceutical industry (Re < 5). Due to its optimised design, this unit is able to significantly outperform both conventional methods tested, achieving yields of 98% with residence times of less than 0.067 minutes (the batch agitated reactor achieved a 91% yield with a 6 minute residence time while the flow reactor achieved a 49% yield with a residence time of 7 minutes).

In order to demonstrate the suitability of applying this design approach to the entire manufacturing process, a case study is also presented in which two reactions are coupled together, followed by an extraction and wash step and a liquid-liquid separation. All unit operations within this platform are designed using fundamental engineering principles combined with numerical analyses (based upon the requirements of the specific process), prior to being 3D printed and combined to create a bespoke, sealed, hard-piped manufacturing system. The optimised design of the units enables extremely high throughput rates to be achieved corresponding to 580,000 kg/L/day (compared to an approximate batch productivity of 525kg/L/day).