Process Development/Flow Chemistry
Successful implementation of continuous flow processes
By Prof. Tom Moody (VP Technology Development and Commercialisation), Dr Megan Smyth (Senior Flow Chemist), Dr Scott Wharry (Custom and Flow Chemistry Manager), Almac Sciences and Dr Charlotte Wiles(CEO), Chemtrix BV.
Almac Sciences and Chemtrix discuss the importance of collaboration of multidisciplinary teams to successfully deliver robust continuous flow processes from lab scale to manufacture.
n paper, flow chemistry is an extremely
straightforward concept- “simply pump reagents through a narrow coil or channel to react and collect the product at the outlet”. However, as any flow chemist can testify, a number of common challenges may be encountered. This article highlights some of the pitfalls and how to successfully transition an idea from paper to proof of concept and beyond to production scale.
Drivers and opportunities
Flow processes are inherently safer due to the use of lower reaction volumes, better temperature control and the ability to access higher pressures with controlled risk. The technology offers solutions to industrial priority areas including development of cleaner, less consumptive, more efficient and safer chemical processes. The advantages of continuous flow have been well documented,and are summarised in Figure 1. A key driver towards the adoption of flow processes for most CDMOs is maintaining a competitive edge by efficiently accessing challenging reaction classes on scales larger than are typically achievable using traditional batch processing. With the benefits of flow chemistry well recognized, one question that may arise is: “why are more processes not performed continuously?” The answer is multifaceted and includes a lack of knowledge and experience within companies, equipment availability and,
operation integration. In addition, endorsement of the technology by the FDA brings on board QA colleagues at an earlier stage than for comparative batch processes. So how to get experience? The increasing volume of flow publications (Figure 2) and manufacturing process showcases is driving knowledge transfer. Partnering is also key, working together with academic and industrial partners to learn from each other and access training / hands on experience to accelerate uptake. As flow chemistry matures and is no longer limited by the number of industrially relevant examples, CDMOs are becoming faster at using in-house platforms to access wide-ranging chemistries required by their clients.
Business case & When to use flow? It can of course be a challenge to justify additional CAPEX when perfectly functional multi-purpose batch vessels are already installed. For many CDMOs, the move to implement continuous processing requires critical evaluation and demonstration of numerous advantages over existing batch capabilities.
As the pharmaceutical Figure 1: There are a number of strategic drivers for the adoption of continuous flow by CDMOs
importantly, the lack of an internal drive to make flow processes a reality.
Hurdles and challenges
The hurdles and challenges to implementing flow chemistry, or any new technology for that matter, can be split into technical or cultural barriers – each leading to a pitfall. With experience, these pitfalls can be used to define working practices that mitigate project risk.
Experience& Knowledge: The first challenge for any new technology is having trained and experienced staff within an organisation. This means achieving competencies beyond using the new techniques and becoming experts in leveraging the associated technical and commercial benefits it can bring. Critical to change is an openness within the team to try something new in order to succeed! “But this is how we have always done it”
or “we don’t do [insert chemistry] here” blocks the development of technical solutions and commercial implementation. The success of continuous process (re-)development is reliant on a multi-disciplined project team, with chemical and chemical engineering input at an early stage to ensure informed synthetic routes are available for evaluation, together with their impact on the selection of appropriate flow architecture and unit
industry continues to develop more sophisticated and highly effective drug targets, the volume requirements of APIs (and their building blocks) have consequently decreased. This paradigm shift makes it more challenging to secure major financial investment for novel technologies. Couple this with the fact that the adoption of any new technology can be hindered by the ambitious timeline deliveries set by the industry, it takes time to implement and reap the rewards of change.
The adoption of flow processing within CDMO’s is undoubtedly driven by economics, with return on investment (ROI) necessary within timelines that make the project viable. One approach is not to tie ROI to a single production campaign, but to a platform
Process Development/Flow Chemistry
Figure 2: The number of flow chemistry publications per year is on the increase.
As the pharmaceutical industry continues to develop more sophisticated and highly effective drug targets, the volume requirements of APIs (and their building blocks) have consequently decreased. This paradigm shift makes it more challenging to secure major financial investment for novel technologies.
technology by developing a toolbox approach where flow is used for specific process types routinely in preference to batch, the result being modular infrastructure that can be flexible towards the production scale and chemical needs of multiple clients. When looking at the business case more broadly, flow offers
value through production cost savings (OPEX), environmental advantages such as waste reduction, reduced safety concerns and, critically, access to novel or highly challenging functional group interchanges. This brings opportunities to CDMOs likely to be limited by hydrogenation pressure and temperature extremes, cryogenic vessel size/ cooling capacity and overall capacity. As a result, the use of continuous flow can add value to a CDMO’s business by unlocking access to new molecules, along with volume supply in shorter timelines.
Clogging & Fouling: It would be wrong to talk about pitfalls without covering fouling. Despite many advances in flow chemistry, one of the biggest hurdles encountered by any flow chemist at the start is reactor fouling and potential blockages. Whilst it is often thought that homogeneous solutions are a prerequisite for flow, it is important to separate this need based on the use of a static vs. dynamic flow reactor and towards the choice of feed dosing system (ie choice of pumps). Reactor fouling can occur for several reasons: solubility of intermediates / by-products; incompatibilities with materials of
construction; stagnant zones in mixing elements / connectors / regulators; and moisture ingress via the dosing system. It can also be due to impurities present in solvents, as shown recently with the reports of Poly-THF in commercially available THF resulting in reactor clogging. It is essential that the root cause of potential fouling events is evaluated at lab scale so that appropriate measures can be put in place to prevent or mitigate risk on scale-up. Such measures centre on appropriate hardware selection in terms of materials of construction, flow path geometries and dosing line design, but can also include feed quality and stability assessments.
The prevention and resolution of clogging issues can be supported by appropriate analytical methods. Process Analytical Technology (PAT)
facilitates in-line, real-time monitoring of a process, finding particular value as a system ‘health check’ for manufacturing campaigns.
Continuous flow as a collaborative industry As CDMOs build flow capabilities internally (or externally through partnership) there are cultural changes to overcome, as most of
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