May the flow be with you
While batch remains the standard in the pharmaceutical industry, a clear increase in continuous flow processes has emerged over the past decade with the commercialisation of preparative flow reactor units.
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-tovolume 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 byproducts in which multiple double bonds are modified.
Continuous flow chemistry set-ups are particularly suited to automation and qualityby-design principles. In-line process monitoring and process analytical( PAT) tools can instantly detect process deviations and automatically divert any nonconforming 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
36 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981