May the flow be with you

In a recent survey of major pharma companies, most anticipated a shift to flow of up to 25% of the total portfolio in the next 15 years.1 Moreover, the US FDA has released guidance promoting continuous manufacturing processes with the aim of improving product quality, which is the main underlying cause of drug shortages and recalls.2 Flow offers a number of important advantages over batch in terms of the quality, safety, agility, sustainability and speed of the overall process. 

Focus on safety 

Compared to batch, the reaction volumes in flow chemistry are much lower and inherently represent a lower safety risk upon the unlikely event of a runaway reaction. Furthermore, heat-transfer in continuous flow installations is several orders of magnitude greater. Consequently, the heat generated upon chemical reaction is dissipated swiftly, keeping manufacturing temperatures within safe operating conditions. Another advantage is the opportunity to combine various process streams at any point of the chemical reaction. This permits the generation of unstable intermediates and in situ-prepared hazardous reagents, which are immediately consumed upon combination with a subsequent process stream before by-products can be produced.

Focus on quality 

Regulators require APIs to meet high quality standards and manufacturers must implement control strategies at each stage of production. The unrivalled control of the reaction profile in flow translates into consistent purity and quality in the target material.

In batch, the heat transfer surface area usually falls by an order of magnitude on scaling from laboratory to pilot. Consequently, the ability to remove excess heat is hampered and the reaction mixture can generate local hot spots, ultimately leading to unwanted side reactions and degradation of the target material. The fall when scaling up in flow is less severe as the initial surface-area-to volume ratio is much larger. A common issue impacting product quality in scaling batch processes is inefficient mixing. Mass transfer declines and, whilst several engineering and modelling tools can optimise mixing performance, the many parameters impacting the latter make predictions uncertain. In contrast, mixing in plug-flow (tubular) reactors is more straightforward and mass transfer can more easily be kept constant at different scales.

The benefits of superior reaction control are exemplified in a recent example where Ajinomoto Bio Pharma optimised the selectivity of a reaction with a polyunsaturated starting material. Conducting the reaction for a shorter time at higher temperature followed by rapid cooling of the mixture reduced the generation of overreaction by products in which multiple double bonds are modified.

Continuous flow chemistry set-ups are particularly suited to automation and quality by-design principles. In-line process monitoring and process analytical (PAT) tools can instantly detect process deviations and automatically divert any non conforming material without affecting the rest of the batch. 

Moreover, flow equipment is designed to manage process needs, whereas in batch the chemistry is often customised to fit the available plant. In multipurpose pharmaceutical equipment, contamination is managed by stringent changeover procedures. Given the fit-for-purpose design of the continuous process equipment and the relatively low cost for the reactive parts in the set-up, dedicated or single-use coils and reactors can be used, eliminating contamination hazards.

Finally, multi-stage continuous processes can circumvent the need to store synthetic intermediates, avoiding degradation and other stability issues. The net working capital required for multi-stage continuous processes is also lower than for batch processes. 

Focus on sustainable manufacturing

Continuous processing is a key technology for green chemistry. The superior mixing and heat transfer enables chemical reactions to be carried out in more concentrated ways or even without solvent, minimising waste.3 Continuous flow processes often show greater productivity and can further decrease solvent consumption by applying in-line extraction techniques that typically operate with less solvent.

In addition, continuous flow chemistry expands the chemical toolbox with higher temperature and pressure windows. The broadened processing window, together with the decreased risk from hazardous reagents, enables shorter synthetic reaction schemes and improves the purity and yield of certain reactions. In addition, flow processes have lower production costs due to the smaller footprint and decreased energy consumption.

 Continuous flow also makes it possible to use alternative forms of energy to promote chemical reaction, such as electricity and light. Scale-up remained an engineering hurdle but Creaflow’s and Ajinomoto Bio-Pharma Services recently co-developed multi-purpose HANU's photoreactor has overcome this.

Focus on speed

Continuous manufacturing can significantly contribute to speeding up product development. Depending on the required volumes, a continuous flow installation can be used to make larger amounts simply by running the set-up for longer, a process often called scaling-out.

 Furthermore, the scale-up of continuous processes is often straightforward and both footprint and capital expenditures are lower than batch. As a consequence, commissioning a novel continuous flow reactor train is markedly faster than that of a new batch chemistry unit.

A paradigm shift

In a recent webinar, ‘The Paradigm Shift to Continuous Flow Processes: A Holistic View’, Dr Bert Metten (pictured), technology development manager at Ajinomoto, explored Ajinomoto Bio-Pharma’s proven expertise and capabilities in handling dangerous chemistries.

Recently, the team was able to demonstrate its experience with challenging chemistries related to scale-up using diazomethane, an extremely sensitive and volatile chemical that is used in producing the precursor for a client’s cyclopropanated product.

The primary challenge—establishing a sustainable, economically competitive manufacturing process for the product—made this an ideal candidate for translation from batch to flow. While the chemical steps to the diazomethane precursor were relatively simple on paper, there were a few inherent issues with optimising the process with continuous flow.

The project, which began in 2014, involved a three-step process: two based on an existing diazomethane procedure and the third for in situ diazomethane generation and cyclopropanation. It was highly complex for many reasons related to the hazards of the chemistry, analytics, waste streams and reactor vessels, among others.

Finally, scale-up to production (28x pilot scale) in a dedicated set-up was realised in 2020. Ultimately, Ajinomoto was able to demonstrate that transitioning to continuous flow afforded a far more selective reaction. This enabled the team to push reaction conditions in order to achieve optimal results, reducing diazomethane precursor consumption by 20%, precious metal catalyst usage by 25%, and base and solvent amounts by 50%. Based on the latest results from the customer’s commercial plant, we were able to improve the cost of goods, reducing costs by 10-25% and waste treatment costs by 46%.