Updating the Toolbox

This article is part of our special focus on "traditional" pharma: The Small Molecule Manufacturer (read more here). You can find more articles from The Small Manufacturer here.

Historically, continuous flow chemistry has been reserved primarily for highly energetic and/or hazardous reactions. In batch mode, these reactions have been limited to small vessels and minimal inventories to produce small quantities in facilities that may require bunkers and isolation in a location away from main manufacturing areas. In this way, if an uncontrollable event should occur during a reaction, the risk to personnel and the surrounding area could be minimized and any damage would be contained. Unfortunately, these facilities are expensive to build and maintain, and the small scale of the reactions limits their cost-effectiveness, with their remoteness adding additional logistical complexity, increasing headcount, time, and ultimately cost. For example, Cambrex has a long history of manufacturing and handling energetic compounds and reagents. The inherent explosive nature of these compounds and reagents meant that large scale production needed to be carried out in bunkered production facilities at a site in Karlskoga, Sweden, dating back to when the site was founded by Alfred Nobel in 1896. 

In pharma, continuous flow chemistry has traditionally been limited to a specific subset of reactions and synthetic processes, driven by efficiency and cost-savings, with nitrations being among one of the most common processes undertaken. One of the biggest obstacles for companies looking to expand development capabilities in continuous flow, however, has been the lack of suitable commercially available equipment, but in recent years this has changed. Driven by the availability of new technologies and equipment, as well as the need to develop drugs faster, more cost-effectively and for smaller patient populations, there has been a growing movement towards replacing batch production with continuous flow operations. A number of large companies have invested in continuous flow operations for API production, as well as formulation, or both. For example, GSK has invested in continuous flow API development capabilities at its facilities in the UK, US and Singapore; while Vertex, Merck Sharp & Dohme, and Johnson & Johnson have invested in continuous flow formulation technology. Novartis, in collaboration with the MIT, has also spoken of its plans to combine continuous flow synthesis and continuous flow formulation.

Cut costs as well as risk

Safety represents a key advantage of continuous flow chemistry, which minimizes exposure and risk, so that energetic chemistries or hazardous reagents can be handled safely as a feasible process option. But there are also economic benefits of converting energetic and hazardous reactions from batch to continuous flow; it reduces the effective volume of a unit operation and enhances control. By enabling these operations to take place in a regular manufacturing plant, they can be linked more directly to other downstream processes, giving the advantage of operational integration.

Looking more closely at cost, the most striking difference between continuous flow and batch production is the comparative investment for a new plant, with the rebuild of a batch facility costing up to four times more than a comparable continuous flow facility. A smaller equipment footprint, which could be less than half that required by a traditional batch operation, and associated infrastructure can also drive capital expenditure down significantly. Handling smaller reaction volumes also means that energy consumption can be cut by implementing continuous flow synthesis, with solvent usage and associated process intensity also being significantly reduced. Additionally, continuous flow requires less labor and may lead to fewer analytical procedures, representing a significant reduction in operating expenditure.

Efficiencies gained from yield and quality improvements can make a further contribution to reducing operating costs. Optimizing the process can reduce lengthy reaction times and extensive work-ups, drastically lowering occupancy requirements and reducing the plant time required for a given process. Continuous flow chemistry can often replace the use of low temperature (-70°C) chemistry, where it is used to reduce the formation of unwanted by-products. As well as reducing the cost of a project, this can also free up capacity for additional production and revenue.

Aside from the obvious advantages of continuous flow that are realized once a compound reaches commercial phases, it should also be pointed out that the overall development phase can also be shortened considerably. Depending on the required volumes for a process as it moves through the different clinical phases, the same equipment used for early development can move through later phase batches, and potentially even into commercialization. Streamlining the traditional batch-based workflow could even eliminate the scale-up phases of the development cycle entirely, saving not only the cost of those batches, but also reducing time to market by months or even years, enabling development investment costs to be recovered sooner.

Simplifying scale up

Even if scale-up phases cannot be eliminated, continuous flow often allows for easier and more cost-effective scale-up. Scaling up a continuous flow process typically does not require the same magnitude of scale increase and, for some compounds, increased throughput can be achieved by simply running longer, or the addition of another reactor of the same size to run in parallel (“scaling out”), thereby reducing validation and investment costs significantly.

When discussing scale-up, controlling temperature is critical to success, and this is particularly true when dealing with exotherms within a reaction. In general, the ratio of heat transfer surface area – commonly the jacket surface area – to the overall reactor volume drops by at least an order of magnitude when a process is scaled up from a laboratory or pilot demonstration batch to a modestly sized production run. This drop in the ratio hinders the ability to remove the excess heat from the reaction mixture, possibly putting the material at risk as it reaches a temperature limit. It can also lead to localized hot spots within the mixture, which can cause non-homogeneity and therefore inconsistency. The practical solution is frequently a reduction in the addition rate of a key reagent. However, this can lead to extended times at reaction conditions that can result in degradation, side reactions or even potentially runaway conditions.

In the scale-up of a flow process, the reduction in the surface area to volume ratio is less significant. For example, a 4-inch diameter tube reactor has approximately the same ratio as a typical 0.5 liter laboratory reactor; more typical tube or pipe reactor diameters will have considerably higher values, ensuring that temperature control and exotherm management can be handled in a straightforward manner. For a flow process that uses stirred vessels or continuous stirred tank reactors (CSTRs) instead of tube reactors, the exotherm impact can also be managed by using smaller reactors in parallel, leveraging throughput and providing the necessary production, while also minimizing the scale-up impact. Similarly, continuous flow can overcome the effects on accelerated reaction kinetics of inefficient mixing in large batch reactors, which can extend reaction times and degrade any process time gains.

Furthermore, after a reaction is completed at elevated conditions the process is typically returned to ambient or near-ambient conditions for quenches, work-ups and subsequent process steps. The large thermal mass in a batch reactor takes a considerable amount of time to adjust, which not only further erodes process time gains, but also exposes the reaction mixture to extreme conditions for an extended period of time.

Finally, higher temperatures may have undesired effects on reaction selectivity, while also significantly increasing the risk profile and potential dangers with solvents being raised to, or above, flash points and reaction mixtures purposely being raised to the point where runaway conditions or over-pressure conditions are a real possibility.

Continuous flow offers a scalable solution to these pitfalls. Smaller instantaneous volumes drastically minimize mixing impacts, and concentration or temperature gradients, and also bring the amount of material that is in an elevated risk status to a much more palatable level. The reduced thermal mass makes the process of temperature quenching orders of magnitude quicker, allowing for a rapid introduction to elevated conditions to drive kinetics, followed by a rapid return to ambient conditions for further processing or to protect the integrity of the products or intermediates that are being formed.

Breaking with tradition

Though overcoming the challenges of scale-up is a major benefit of continuous flow, an even more powerful advantage is its ability to not just simplify a process but to break through traditional process limitations and constraints. Frequently, a process chemist or engineer is forced to accept a less than ideal synthetic route due to infrastructure constraints, resulting in processes that can generate impurities that must be removed. In some cases, flow chemistry can provide an optimized process that reduces these impurities significantly – or even avoids them altogether.

The quality of the final product can also be enhanced in a continuous flow process because there is greater opportunity for control using real-time analysis to monitor quality, rather than waiting to measure a single batch sample. Applying PAT is generally easier in flow than with batch production, as often only temperature probes and flow meters will be needed to ensure that the process remains within the acceptable parameters to achieve product of a known quality. Where necessary, sophisticated PAT probes can be easily integrated into a flow process to allow for rapid detection of deviations. For example, layering in an additional measurement, such as Fourier-transform infrared (FTIR) or Raman spectroscopy, to track a parameter such as reaction conversion can allow real-time adjustments to correct raw material variations or drift that may be happening within the process.

Continuous flow also now makes it possible to use technologies that are technically challenging on a large scale due to infrastructure constraints, such as cryogenic conditions, Grignard reactions, and hydrogenations. Meanwhile, other technologies that are of great interest throughout the industry, notably photochemistry, are not suitable for use in a large batch reactor as a light source cannot fully penetrate the reaction mix with consistency or efficacy. However, with continuous flow, this can be achieved very easily, meaning that this technology can now be scaled up and no longer needs to be regarded as a purely academic exercise.

Every unit operation associated with traditional batch processing has a continuous flow counterpart, and the throughputs and capacities achievable with continuous flow can rival, or often even outperform, traditional batch processes. Until recently viewed mainly as a niche problem-solving technology, continuous flow should now be seen as an option when assessing a synthetic route. Indeed, continuous flow chemistry can be a powerful development tool and the process of choice.