mitigation strategy is to operate at high dilution, keeping all components in solution and reducing the risk of clogging.
However, it also increases solvent consumption and places a greater burden on downstream solvent removal. More importantly, reaction kinetics slow down, reducing the overall efficiency and practicality of the process. In such cases, particularly where reactions are slow or involve heterogeneous systems, batch remains the more viable option.
Continuous work-up
In large-scale production, flow chemistry can also help to increase capacity. This comprises both the chemical transformation and the work-up. While the benefits of continuous quenching, phase separation, distillation or crystallisation may be less immediately apparent, they are essential in handling sensitive compounds and kinetic products. Beyond the throughput gains, these operations support process consistency and control.
The role of continuous stirred tank reactors( CSTRs) is particularly noteworthy in this context. Unlike tubular flow reactors, CSTRs use small vessels rather than coils or tubing. This configuration allows for greater flexibility and can overcome certain limitations of standard flow processes, such as solid formation or longer reaction times above the minute scale.
As CSTRs have been in use for a long time, they are often not explicitly highlighted in the literature. They have received renewed attention over the past five to ten years, particularly as part of hybrid or integrated continuous manufacturing strategies.
Highly potent compounds
Flow chemistry may offer fewer advantages when working with highly potent APIs( HPAPIs). While the chemistry itself may be the same as for conventional APIs, HPAPIs are typically produced in significantly smaller volumes due to their high pharmacological activity. As such, the usual benefits of flow, such as improved scale-up and largevolume handling, are less relevant in this context.
That said, the closed nature of flow systems can offer clear advantages for containment and operator safety, both of which are essential in highpotency manufacturing. Although throughput gains may be modest, flow set-ups can still contribute to improved handling practices in HPAPI manufacturing and support the use of single-use set-ups to reduce the risk of cross-contamination.
However, the added complexity of designing and operating flow set-ups represents an additional effort in development. When combined with the already challenging nature of
HPAPI handling, this can make flow chemistry a less attractive option unless the safety or contamination control benefits clearly outweigh the drawbacks.
Automation & regulatory readiness
Automation remains one of the strongest inherent advantages of continuous processing. Once a system is properly set up, it can operate with minimal intervention; the machinery handles the work. This extends to inline and online analytics, which support consistent product quality and, in some cases, enable real-time release testing( RTRT).
However, automation requires a significant upfront investment, including the validation of analytical methods and control systems. This must be justified by cost savings and the projected lifecycle of the product.
From a regulatory standpoint, there have been encouraging developments over recent years with the release of ICH Q13 representing a major milestone. Regulatory authorities have expressed interest in seeing wider adoption of continuous processes for both drug substances and drug products. However, the industry remains on a learning curve.
On the CDMO side, preparing regulatory filings that incorporate flow chemistry demands close collaboration between development, production, quality assurance and regulatory teams. There is still experience to be gained and supporting infrastructure to be built before flow processing becomes as routine, and as regulatory accepted, as batch manufacturing.
Outlook & summary
Carbogen Amcis has applied flow chemistry selectively, specifically where the greatest gains could be achieved: chemical conversion. The driving forces have included safety, yield and improved process robustness.
In earlier stages, the potential of continuous work-up and purification
34 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981