Advantages of Continuous Flow Synthesis

By Shawn Conway, Director of Engineering, Cambrex High Point

Continuous flow chemistry has, until recently, largely been a niche problem-solving technology, typically employed when a develope

Continuous flow chemistry has, until recently, largely been a niche problem-solving technology, typically employed when a developed process encounters a hurdle, such as energetic chemistries or issues with capacity that require an alternative solution. However, the technology is a powerful addition to the process toolbox, although its advantages are not yet fully appreciated. Dr Shawn Conway, Engineering R&D Director, Cambrex, describes the possibilities that it can unlock.
Batch production may be the workhorse of the pharmaceutical manufacturing sector, but the economic and technological advantages of Cambrex Shawn Conway 10.2.20.jpgcontinuous flow chemistry are encouraging many active pharmaceutical ingredient (API) manufacturers to give it serious consideration. Continuous manufacturing techniques are not new, but the pharmaceutical sector has only started to explore the possibilitiesthat this technology offers in the past two decades. In theory, any synthetic process could be carried out in continuous mode, but in practice, good candidates for moving away from batch manufacturing will involve a relatively rapid chemical reaction of a type of chemistry that is not readily scalable using current batch processes.
Economic advantages
There are several potential major economic advantages in moving from batch production to continuous flow. First, the equipment is much smaller, which reduces the manufacturing footprint, freeing up additional processing space; and second, the smaller equipment makes key process parameters such as temperature and pH easier to control, which in turn can reduce impurity formation and improve product quality.
Some drugs may be required in only small commercial quantities, either because they are highly potent or because they serve a limited patient population. Small commercial batches can be extremely expensive and inefficient to manufacture in large-scale equipment because of high infrastructure costs and the need for the same verification and cleaning procedures as large runs. A continuous process makes the use of dedicated, or even disposable equipment, for small volumes more feasible.
Additional cost benefits can result from lower inputs: energy consumption and solvent usage will be reduced significantly, or in some cases eliminated entirely, as a result of enhanced control over the process. Furthermore, less waste solvent produced means lower associated disposal costs. Additionally, lower labour requirements and the need for fewer analytical procedures reduce the operating costs, and process efficiencies can increase yield and improve quality. Whereas standard commercial batch equipment can have limitations in terms of temperature or pressure capabilities, performing the process in flow may remove such constraints, enabling more extreme conditions such as elevated temperatures and pressures to be explored with a view to accelerating the process kinetics, while reducing the risk of stability issues.
With most batch processes, critical process parameters are developed and tested throughout the development and validation stages, but quality decisions and material dispositions are often based on offline batch representative testing. In contrast, continuous flow allows for real-time feedback so that potential disruptions can be realized, captured and solved with an appropriate control strategy, avoiding a scenario where an entire batch is put at risk.
Safety considerations
Improved safety is another big driver for continuous flow technology for reactions that are difficult or dangerous to do in batch reactors. As the reactions are carried out on a much smaller scale, energetic chemistries and toxic compounds can be handled with far less risk. Unstable intermediates and final products can also be handled more efficiently, as the rapid timescale of continuous flow reactors minimizes residence times, reducing and potentially eliminating the impact on safety and quality.
Using continuous flow chemistry to handle high-energy products and reagents safely also removes the need for batch operations to be carried out in bunkered production facilities that are expensive to set up and maintain.
Accelerated development
Adopting continuous flow in early-stage drug development can shorten the development phases and reduce the overall time to market. Introducing the process in early clinical development offers opportunities for optimization by choosing the ‘best route’ rather than the one best suited to a facility’s capabilities. As well as a compound typically being obtained in a quicker, cleaner manner, using continuous flow makes it possible to start building a process that can be commercially viable from the outset, reducing the potential multiple iterations of a development cycle as the compound progresses from phase to phase. Continuous flow is scalable from the outset, allowing manufacture to increase quickly from a few hundred grams of a compound to larger quantities by increasing the scale of the equipment, increasing the number of reactor vessels, or by extending the processing time.
Continuous flow allows multiple reactor modules to be linked together, enabling the same equipment and processes to be used at commercial scale as for development or pilot scale. This overcomes the scale-up challenges posed by the variations in equipment design that are often found between facilities or through different phases of process development.
Future development
With continuous processes becoming more widely adopted by the pharmaceutical industry, development work on finding efficient routes for manufacturing greater numbers of APIs is increasing, especially as regulatory agencies are also becoming more supportive of flow chemistry. As companies continue to develop new drugs, especially for niche, targeted indications where only small quantities of API will be required, flow chemistry will increase in importance and become part of the wider toolkit for development and production of medicines in coming years.


A telescoped continuous process installed into a customer’s waCambrex process 10.2.20.jpglk-through hood.