Streamlining early phase drug development with continuous flow technologies

The pharmaceutical industry is witnessing a shift as small molecule drugs become increasingly complex and potent.​

Advances in medicinal chemistry are driving the development of more sophisticated compounds, often with highly targeted mechanisms of action. These innovations, while promising, are also pushing the boundaries of traditional drug development, particularly in the early phases, where the need for rapid iteration and flexibility is critical.

At the same time, there is growing pressure to shorten development timelines and reduce costs, while maintaining high standards of quality and safety. These trends are making early-phase drug development more challenging, as existing processes can be too rigid and slow to keep pace with the demands of modern drug discovery.

Batch manufacturing, the traditional method used for early-phase production, can become a bottleneck in this evolving landscape. Designed for larger-scale, simpler compounds, batch processes are slow, requiring time-intensive setup, validation, and scale-up between production runs. This stop-start nature creates inefficiencies, making it difficult to meet the demands for speed and agility for certain early development projects.

Going with the flow​

Increasingly, early phase drug developers are looking to use continuous flow processes to avoid some of the limitations of batch processing. Continuous flow processing in pharmaceuticals is a manufacturing method where chemical reactions occur in a continuous, steady stream rather than in separate batches.

Reactants are continuously introduced into the system, and products are constantly removed, allowing for an uninterrupted process at least for a certain period of time. This approach contrasts with traditional batch processing, where reactions occur in discrete steps and production is halted between batches.

Continuous flow systems enable better control over hazardous reactions by operating in smaller volumes, reducing risks. Improved heat and mass transfer allows for faster, more consistent reactions with higher product quality. The ability to manage operation at higher pressures, which enhances gas solubility and reaction rates, makes these systems ideal for processes involving gaseous reactants.

The use of continuous processes also supports cost and resource efficiency by eliminating downtime and minimising solvent and energy use. Additionally, continuous flow is adaptable to complex, multistep syntheses, making it a valuable approach for modern pharmaceutical manufacturing.

Continuous flow is preferred over batch processing when higher safety is required for handling hazardous or reactive chemicals, when rapid heat and mass transfer are essential for efficient reactions, for processes requiring high scalability and consistent product quality, or when reducing waste, downtime, and production costs is a priority, particularly in complex, multi-step chemical syntheses.

This is not to say that one of these distinct methods is superior to the other but that each has its specific use cases. Batch production will remain appropriate if the objective of production is volume often driven by slow reactions, whereas when process intensification is paramount then this is where continuous flow holds an advantage.

Mini-mono plant technology​

At Lonza Small Molecules, the continuous flow process is integrated into early phase development, allowing for optimisation of chemical processes from pre-clinical work all the way to Phase III. As part of its work with continuous flow, the company has successfully completed over 50 customer projects and has contributed to the publication of more than 50 peer-reviewed articles.

One such publication was released on the potential of ‘mini-monoplant’ technology, utilising continuous flow to create dedicated, intensified pharmaceutical processes from early lab-scale to commercial production.¹​ The conceptual paper covered a vision of how continuous manufacturing could operate in the future, as well as what potential advantages could be delivered. The authors explained that the concept of the mini-monoplant is a small, dedicated production facility that focuses on making a single product.

The ‘mini’ in the name refers to the intensification of the product, through the continuous processing, use of advanced reactor technology and small factory footprint; and the ‘mono’ refers to the dedication of the facility, which is catered for a single product, independent of being batch or flow, with high automation, and real time release testing.

The focus on one product allows for quicker and cheaper production, which suits companies that need to respond rapidly to market demands. The aim of the mini-monoplant is to facilitate the processing of more complex, potent, lower-demand, and specialised drugs that require an accelerated timeline to reach the market, and have uncertainty in their demand.

The authors noted three key advantages to mini-monoplant production:

• The ability to develop best-in-class processes at the lab scale, where novel synthesis routes will improve the safety, sustainability, and yield
• To accelerate development and time to market through a streamlined scale-up to factory-based production facilities. The lab-scale process becomes the production setup, which may be developed further and, when required, scaled up using established geometrical scale-up methodologies
• An overall reduction in capital and operating expenditures when the mini-monoplant is ultimately built and dedicated to continuous production of a single product – increasing productivity while reducing the factory footprint and avoiding changeover steps typical to multipurpose plant production

This conceptual paper was published in 2020. Lonza has released a mini-monoplant for a customer in 2022. In this case a Grignard reagent is produced under very concentrated conditions leading to high exotherms.

Figure 1 shows the reactor setup build in a modular fashion. The reaction is first conducted in a microreactor (FlowPlate® technology) to cope with the heat and aged in a coil reactor to gain volume and residence time.

Figure 1. Examples of fundamental continuous reaction technologies​​

The importance of know-how 

Lonza Small Molecules has built its expertise in continuous flow manufacturing over a number of years. This experience allows for the quick resolution of key flow issues, including plugging and long-term stability, without timelines being impacted.

At Lonza Small Molecules, a dedicated team is ready to work with clients on their continuous flow plans, and the company holds four laboratories exclusively for this type of project. In terms of the equipment used, the team possesses various reactor technologies, including plate, shell and tube, coil, and electro-chemical.

Beyond Lonza Small Molecule’s experience with continuous flow manufacturing, there are other elements of its service that can help clients to successfully navigate their early phase development, particularly when dealing with complex APIs.

One such service is Lonza’s AI-enabled Route Scouting, which uses AI to innovate and design the best synthetic routes. Computer-assisted synthesis planning tools leverage predictive and analytical cheminformatics to identify optimal synthesis routes.

AI-powered technologies enable in silico retrosynthesis, supply chain analysis, and process R&D evaluations using extensive datasets. This allows for the automated generation and comparison of multiple synthesis pathways, enhancing efficiency and decision-making in the development process.

When combined as a complete package, Lonza Small Molecule’s offers a way to manage risk and investments through the team’s technical expertise, facility capabilities, and engineering solutions. The end result is a manufacturing process that fits with the evolving needs of drug developers to deliver consistent scale up with improved safety, sustainability, and yield.

References​

1.​ Doyle BJ.; et al. Mini-Monoplant Technology for Pharmaceutical Manufacturing ​Organic Process Research & Development 2020 24 (10), 2169-2182.