Flow chemistry: The CDMO perspective
Dr Franz Amann of Carbogen Amcis examines the practical use of flow chemistry in industrial synthesis, focusing on how CDMOs are adopting this method to meet customer demands
Figure 1- Ideal vs. real scale-up
Flow chemistry is a tool for chemists with distinct advantages over traditional batch processes. Its allows reactions to be performed more intensively, largely because the volumes handled at any given time are smaller, the high surface-to-volume ratio provides excellent heat transfer and mixing can be much faster. While the total quantity of material processed may remain the same, the reaction zone is typically compact, making it easier to manage risks and optimise reaction conditions.
In the early 2000s, the concept of‘ micro-reactors’ introduced many in the pharmaceutical sector to flow chemistry. These small, structured devices promised enhanced control over mixing and temperature.
Over time, it became clear that the benefits of continuous processing are not limited to micro-structured systems. Running reactions continuously in slightly larger setups can still deliver many of the same benefits, while avoiding some drawbacks of micro-reactors such as a poor tolerance to solids, high pressure drops and greater device and control complexity or cost.
This insight initiated a gentle shift in the pharmaceutical space, where batch processing using multi-purpose stirred vessels had long been the dominant model, even though continuous processes have existed for over a century. Over the last 20-30 years, some well-established concepts have increasingly been adapted into pharmaceutical development and production on a smaller scale.
In general, the higher the annual production volume of a chemical, the more likely it is to be manufactured continuously – the standard in the production of fuels or fertilisers, for instance. Kilogram production in flow remains relatively rare, although Eli Lilly and others established dedicated fume-hood systems for flow-based production of small quantities of APIs for clinical trials more than ten years ago. 1
Some synthetic techniques, such as ozonolysis, electrochemistry and photochemistry, have also experienced renewed interest, due to their use in lab-scale flow systems. Although these methods are well established, they have traditionally been difficult to apply at larger scales. Flow reactors running for extended periods now offer a practical route to overcoming these barriers.
The development dilemma
In many CDMO-pharma collaborations, the focus is on reaching the next milestone. While this is understandable, it often leads to a dilemma.
As long as a project appears to be progressing towards the desired outcome without the need for significant additional development, both parties tend to stay with the established process. There is little incentive to consider a switch to flow chemistry, especially in the early stages of development where material needs and the likelihood of successful commercialisation are both low, as > 95 % of compounds will ultimately not reach the market.
From a technical perspective, it would be ideal to initiate process optimisations as early as possible, when volumes are low and changes are easier to implement. As an API candidate progresses through preclinical and clinical studies, the CDMO must simultaneously investigate and refine the manufacturing process, gain process understanding, manage impurity profiles and improve control strategies.
However, transitioning to a flow process is more than just an optimisation step. It typically involves a fundamental shift in reaction conditions and a complete change in equipment. The later such a switch is attempted, the more difficult it becomes.
Once a product is approved and commercialised, changing the underlying process presents major regulatory challenges. The original
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