Introduction
In simple terms, flow chemistry, or continuous processing, is the reaction of two or more chemicals within a “pipe” or continuous reactor moving at a constant flow rate in a “plug flow” resulting in the formation of a new product (1).
Flow chemistry or continuous processing has gained significant traction in the last decade with many commercial examples (2) now coming to fruition and, most importantly, with endorsement from pharmaceutical regulatory bodies (3).
Flow chemistry opens a whole new scalable toolbox for organic chemists, enabling the synthesis of chemicals and active pharmaceutical ingredients (APIs) using challenging reaction classes, including those that are typically deemed forbidden or unsafe for batch reactions. These chemistries have become accessible thanks to the intrinsic low volume of flow reactions, coupled with enhanced control and excellent heat and mass transfer. This means that reactions can be safely conducted under continuous processing conditions, significantly minimising the risks associated with traditional batch processes. As highlighted in Figure 1, flow chemistry offers a myriad of benefits. Environmentally, it helps minimise waste generation and enhances safety. It also enables the exploration of new or challenging functional group exchanges; this is particularly advantageous in scenarios involving high pressure, high energy, oxidations, or photochemical transformations, where traditional methods might fall short.
The transition to flow, however, involves a significant cultural change and education across chemists, analysts, chemical engineers, quality staff and operators alike, as most mindsets are traditionally focused on batch systems (4).
Technology access in CDMOs
In the current landscape of the US, EU, and UK, CDMOs are faced with several challenges, including higher salary and energy costs, as well as increased scrutiny over safety and environmental standards. To remain competitive under these conditions, it is essential to adopt, or at the very least have access to, technologies that can provide a strategic advantage, and flow chemistry stands out as a promising solution in this regard.
The complexity of chemical modalities is on the rise, necessitating more intricate synthesis and the ability to streamline supply chains. Continuous flow chemistry can unlock new synthesis routes that were previously unfeasible, allowing access to new molecules with the required volume supply, often within shorter timelines. This capability can significantly enhance operational efficiency and competitiveness.
Moreover, continuous flow chemistry offers a way to combat the aforementioned challenges, by simplifying supply chains and enabling more efficient production processes. It creates new possibilities for synthesis, making it an invaluable tool for staying ahead in the industry.
Figure 2 highlights selected examples of the specialist expertise at Almac, though capabilities are not limited to these examples. This figure highlights the breadth and depth of expertise in flow chemistry and underscores the potential benefits of further developing this area within our organisation.
Overcoming challenges migrating to flow chemistry
Process Engineering
When considering development of a chemistry for flow, reaction engineering principles should be considered from an early stage to understand the reaction kinetics, thermos and fluid dynamics. Chemical engineers and organic chemists should collaborate from the reaction familiarisation stage to consider the following aspects: (See Table 1).
During this development period, the right flow reactor can be chosen and designed to fit the right chemistry. It is crucial therefore, that flow chemistry assets are modular and quickly adaptable to try new designs. This saves on ever-valuable time in chemistry development.
Collaboration
Although progress has been gradual, the industry has increasingly shifted—at least in part—towards continuous processing. In Ireland, this transition has been particularly notable, with significant engagement from both industry stakeholders and regulatory bodies.
The Health Products Regulatory Authority (HPRA), for example, has actively participated in several ongoing cGMP-related flow chemistry initiatives within the country. Furthermore, organisations such as BiopharmaChem Ireland and the Solid State Pharmaceutical Cluster (SSPC) have played a pivotal role in fostering collaboration between the Irish industrial and academic communities. These efforts have facilitated knowledge sharing and joint problem-solving in the field of flow chemistry. While challenges remain in validating cGMP flow processes, particularly in areas such as cleaning verification and process control, these obstacles are gradually diminishing.
New technologies
Traditionally, flow chemistry development involves significant material consumption, particularly when high flow rates are required to achieve optimal mixing for certain reaction types. This presents a challenge during early-stage development, where material availability – such as late-stage intermediates in multi-step syntheses – may be limited. Recent advances in reactor design are addressing this issue. For example, novel 3D-printed stainless-steel reactors with tailored internal geometries are being investigated by Almac for their potential to enhance mixing efficiency at smaller scales. These geometries, which are difficult to achieve with conventional machining techniques, offer increased flexibility and efficiency in early development workflows. Ensuring accessible and scalable flow equipment is a key consideration for organisations transitioning to continuous processing. Some facilities have already implemented scale-up infrastructure to support the progression from laboratory development to commercial production, enabling integrated chemical engineering support throughout the development lifecycle.
Quality Assurance by Design
There also needs to be a seamless transition to cGMP manufacture. As projects progress from toxicological investigations into clinical trials, the requirement for cGMP material is paramount. Therefore, having access to cGMP equipment is essential. Almac is currently in the process of implementing cGMP with high pressure flow hydrogenation capabilities.
One of the primary challenges in developing cGMP-compliant flow chemistry processes lies in the significant capital investment required. This includes both the early-stage development of synthetic routes using flow technology, and the subsequent design and construction of commercial-scale equipment; costs that can be difficult to justify compared to established batch reactors. Almac addresses this challenge by offering a modular, flow chemistry rig which can be operated in a non-GMP facility designed for scalability and flexibility. This “plug-and-play” system enables clients to evaluate various reactor technologies, optimise their processes, and build robustness in a cost-effective environment. Once optimised, the same rig can be seamlessly transferred into a cGMP facility, ready for validation and commercial deployment.
Case studies
A key strategic decision for Almac as a CDMO was to focus on development of continuous flow high pressure hydrogenations. With capabilities of up to 300 °C and 100 bar pressure using packed bed reactors and pelletised catalysts, Almac have built significant expertise for a wide range of transformations from alkene saturations to nitro-reductions to reductive deuterations using D2 gas up to 100’s kg scale.
Case 1: High-Pressure Hydrogenation
One particular case study involved an alkene saturation where the customer required ~120 kg of material processed by high pressure hydrogenation as shown in Step C in Figure 3. This reduction was part of a large API project and is highlighted in Figure 3 including Grignard, Biocatalysis and Polymorphism to control physical form.
The initial development work involved defining conditions for the alkene reduction and demonstrated the flow process produced material with superior product quality compared to batch (GC purity flow ≥95.5% vs batch at <90.0%). In addition, flow offered an easier work-up (no need for celite filtration) and significant cost savings due to lower Pd requirements (<1.0% catalyst loading vs batch 10% w/w wet loading). In flow, a robust and reproducible process was developed with a consistent purity profile reported upon upscaling (6 mL development column vs 78 mL pilot production column).
Case 2: Formylation Scale-Up Using Hybrid Batch-Flow Technology
A second successful scale-up example involved producing an aldehyde on a 4,000 L (0.25 metric ton) scale, using low-temperature organometallic chemistry. The process entailed metallation at low temperatures, followed by quenching with ethyl formate to generate the target aldehyde. The reaction has been conducted using Turbo Hauser base (MgDA) and Lithium diisopropylamide (LDA). Due to the rapid reaction kinetics and the need for very low temperatures, this chemistry is challenging to execute under traditional batch conditions. By implementing flow technology, the process achieved an approximate 30% increase in yield, 8% improvement in purity, and a substantial boost in throughput or production rate. While the enhanced yield and throughput contributed to lower production costs, the most significant benefit for the client was the marked improvement in product purity.
A key aspect of this project was the strategic integration of both batch and flow reactors to optimise yield, purity, and throughput. Initial development was conducted using representative laboratory equipment, with the process then transferred to a pilot-scale flow rig.
This enabled a seamless transition to commercial-scale production.
The success of the scale-up was driven by close collaboration between Almac’s flow chemists and flow engineering team, ensuring that the process conditions developed at lab scale were replicated at production scale.
The final flow rig, designed and constructed in-house, exemplifies Almac’s capability to deliver tailored, scalable solutions for complex chemistries (see Figure 6).
Figure 6 above shows Almac’s custom built, non-GMP, manufacturing flow rig. This fully Ex-rated or ATEX system utilises a programmable dosing unit consisting of high-pressure membrane pumps and mass flow controllers connected to a flexible reactor module. Pictured is a ~1 L static mixer reactor module with cryogenic cooling capacity. The ATEX rating of the system allows it to be moved around the production facility and connected to existing plant vessels for feed, quench and down-stream processing.
Platform technology and future flow
Flow processing skids that are modular and flexible offer the greatest adaptability for the successful development of diverse chemistries and are essential for a multi-purpose CDMOs. Having access to in-house engineering is essential for the rapid response to synthetic route and process changes to allow just-in-time modifications of equipment to fit customer needs.
Concluding remarks
There is no doubt that developing new synthetic routes to novel chemicals and APIs through flow chemistry, and maintaining control over these processes, is a top priority for innovators. However, successfully implementing flow chemistry at scale requires both time and investment. In some cases, to meet tight timelines, companies may choose to bypass flow chemistry altogether, opting instead for traditional batch processing or relying on less reliable supply chains.
While this may offer short-term convenience, it introduces significant risks.
As projects move rapidly through clinical trials, it becomes increasingly important not to neglect process control and supply chain robustness. Strong control systems are vital for ensuring long-term success and avoiding unexpected issues that could delay clinical development. Innovators are keen to avoid surprises late in the process that could jeopardize timelines.
Therefore, it is crucial to partner with CDMOs capable of adopting the right technologies to support success. Evaluating your current process and supply chain strategy could be highly beneficial. Consider the potential advantages of gaining control over your API production and integrating flow processing into your operations.
Key considerations when adopting flow processes:
To support the transition of your process to flow chemistry, it is essential to consider the following when selecting an appropriate CDMO:
• Process Development & Demonstration: ensuring the CDMO is equipped to develop and pilot your process using advanced flow chemistry techniques
• Multidisciplinary Expertise: A dedicated flow chemistry team must bring together a wide range of expertise to be successful, including synthetic organic and flow chemists, chemical and process engineers, process safety specialists, automation and control engineers, validation experts, project managers, and experienced technicians.
• Custom Modular Flow Rig: A purpose-built, modular flow system should be available for both demonstration and scalable production.
• End-to-End Flow PRD Execution: Having a CDMO to manage the complete flow process research and development (PRD), scaling from lab to commercial manufacturing further ensures processing success.
• Broad Operating Range: Ideally, systems should operate across a wide temperature and pressure range.
Manufacturing-Ready Infrastructure: Having a flow rig which is fully ATEX-compliant, solvent-compatible, and installed within a dedicated manufacturing environment which can be integrated with batch reactors and product isolation equipment further eases process transition.
References and notes
- (a) Ley, S.V.; Fitzpatrick, D. E.; Ingham, R. J.; Myers, R. M.; Chem. Int. Ed., 2015, 54, 3449-3496; (b) Price, G. A.; Mallik, D., Organ, M. G.; J. Flow Chem., 2017, 7, 82-86. (c) Baumann, M.; Moody, T. S.; Smyth, M.; Wharry, S.; Process Res. Dev., 2020, Article; DOI: 10.1021/acs.oprd.9b00524.
- (a) Gobert, S. R. L.; Kuhn, S.; Braeken, L.; Thomassen, L. C. J., Org. Process Res. Dev. 2017, 21, 531− 542. (b) Britton, J.; Raston, C. L., Chem. Soc. Rev. 2017, 46, 1250−1271. (c) Shukla, C. A.; Kulkarni, A. A., Beilstein J. Org. Chem. 2017, 13, 960−987. (d) Hartman, R. L.; McMullen, J. P.; Jensen, K. F., Angew. Chem., Int. Ed. 2011, 50 (33), 7502−7519.
- (a) https://www.fda.gov/regulatory-information/search-fda-guidance-documents/quality-considerations-continuous-manufacturing (b) L. Lee,T. F. O’Connor,X. Yang, C. N. Cruz, S. Chatterjee, R. D. Madurawe, C. M. V. Moore, L. X. Yu &J. Woodcock, J Pharm Innov. (2015) 10:191–199.
- Rivera, N. R.; Kassim, B.; Grogorov, P.; Wang, H.; Armenante, M; Bu, X.; Lekhal, A.; Variankaval, N.; Process Res. Dev., 2019, 23, 11, 2556-2561; (a) Ley, S.V.; Fitzpatrick, D. E.; Ingham, R. J.; Myers, R. M.; Chem. Int. Ed., 2015, 54, 3449-3496; (b) Price, G. A.; Mallik, D., Organ, M. G.; J. Flow Chem., 2017, 7, 82-86.
Figure 1. Summary of flow chemistry advantages.
Figure 2. Selected examples of chemistries which have transitioned to flow within Almac.
Table 1. Key considerations migrating to flow chemistry.
Figure 3. Application of technologies at Almac to access APIs using flow and Biocatalysis.
Figure 4. Flow diagram of low temperature formylation rig design. Temperature Transmitter (TT), Pressure transmitter (PT), Flow indicator controller (FIC).
Figure 5. Flow mediated lithiation and aldehyde formation.
Figure 6. Modular flow rig at Almac (pictured left), high pressure membrane pumps (centre top left), static mixer reactor system (centre bottom left and centre top right), The flow rig in operation in Almac’s production facility during manufacture (right).
