The continuous flow process is a manufacturing technology widely used in the petrochemical industry for over a century. However, it has gained significant attention in the pharmaceutical and fine chemical sectors only since the 2000s. The adoption of flow chemistry in the pharmaceutical industry has been comparatively slower due to its inherent complexity, unlike the petrochemical industry, which focuses on the mass production of a limited variety of products.

Nevertheless, the growing global demand for pharmaceuticals has highlighted the need for efficient and cost-effective manufacturing technologies. These include safer methods for handling hazardous or explosive chemical reactions that are more environmentally friendly and require lower energy and Product Mass Intensity (PMI) versus traditional batch processes. Consequently, the pharmaceutical industry is adopting continuous processes for developing Drug Substances (DS) and Drug Products (DP).

Recent trends in flow chemistry

A continuous flow process offers several advantages over traditional batch processes, enabling reactions to occur within narrower temperature ranges with efficient thermal control. This leads to higher-quality pharmaceutical products with improved impurity profiles. Since the continuous flow process allows real-time monitoring and control over the manufacturing process, it is also recommended by the FDA. Since the approval of Vertex Pharmaceutical’s Orkambi® in 2024, several drug products such as Prezista®, Verzenio®, and Daurismo™ have received FDA approval using the flow technology. Notably, GSK’s Dolutegravir (DTG) received FDA approval in 2019 using a continuous flow process for drug substance manufacturing.

The continuous flow process is extensively applied in high-temperature and high-pressure (HTHP) reactions, hazardous reactions, photochemistry, electrochemistry, metal-catalyzed reactions, and flash chemistry due to its superior mass and heat transfer capabilities compared to batch processes.

Yuhan’s study on over 2,200 patents on continuous flow processes in the fine chemical and pharmaceutical industries issued between 2010 and 2021 showed that 944 patents (42%) were associated with heterogeneous metal catalysis reactions. This was followed by Hazardous chemistry with 724 patents (33%), high-temperature and high-pressure reactions with 179 patents (8%), and gaseous reactions with 172 patents (8%).

In the past 5 years, Yuhan CDMO has received numerous customer requests for process development using a continuous flow process. Particularly for plug flow reactions in hazardous and organometallic chemistry, and packed-bed type reactions in heterogeneous hydrogenation reactions. Specifically, fluorination, halogenation, cyanation, and nitration reactions in Hazardous chemistry, and lithiation and Grignard reactions in Organometallic chemistry. For heterogeneous hydrogenation, reactions such as nitro reduction, pyridine reduction, and olefin reduction were commonly requested. This trend indicates that heterogeneous metal catalysis and hazardous chemistry are the primary areas of focus for the application of continuous flow processes.

There also has been an increased number of inquiries from various customers regarding continuous flow processes for photochemistry. It allows uniform transmission of a light source to reactants via tubing, which is notably challenging in traditional batch processes.

Metal catalysis and hazardous chemistry

A heterogeneous metal catalyst reaction using a packed-bed reactor offers high catalyst efficiency, enabling long-term reuse of the catalyst. This technology also allows safe operation at high temperatures and pressure, conditions that are challenging to achieve in traditional batch processes. Additionally, it simplifies post-reaction procedures by eliminating the need for catalyst separation allowing application to large-scale production.

Continuous flow process development involves several stages: feasibility study, process development and optimization study, and scale-up study. In the feasibility study phase, the applicability of a flow process is evaluated by screening process parameters such as catalyst type, solvents, reaction temperature, and pressure. Once the catalyst type is set, catalyst particle size and reaction condition are evaluated. Then, process development and optimization are conducted through the Design of Experiments (DoE) and lab scale-up experiments to assess the repeatability and robustness of the process.

When scaling up from a small-scale laboratory process to increase productivity, the most critical aspects to consider are pressure drop and reactivity, as these factors are significantly influenced by the types of catalyst carriers, particle size, and catalytic activity. Additionally, it is critical to develop a system that accurately predicts heat transfer and heat release through efficient design, in particular for reactions where solid, liquid, and gas phases coexist.

In the laboratory environment, commercially available small-scale screening equipment and lab scale-up equipment can be utilized. However, at the production scale, each manufacturer must design and customize their equipment to meet specific needs, limiting its adoption to a few companies possessing the technology and facility.

Flow chemistry is used across various processes and reactions. In hazardous chemistry, where the raw materials, intermediates, or chemical substances are prone to decomposition or explosion, or cause runaway reactions due to exothermic properties, heat conduction is crucial for controlling mixing and heat generation. For extremely rapid reactions such as those in Organolithium or Grignard reaction, speed and mixing are tightly linked with reaction conversion and by-product formation. In a micro-scale flow system, where the flow is laminar, mixing can be controlled by adjusting the flow rate of reactants. Conversely, in mesoscale systems where the flow is turbulent, mixing efficiency can be enhanced by using various mixers. A basic method for evaluating mixing effects is the 4th Bourne reaction and simulation programs. They can be used together to assess the mixing power of mixers. The efficiency of mixing and heat conduction becomes more critical at production scales, where reaction volumes are much larger than in laboratory settings.

Challenges and advantages

A continuous flow process must overcome several engineering challenges such as mixing and heat transfer when scaling up to a large production scale. During scale-up, increasing the reactor size significantly impacts mixing efficiency within the reactor, requiring predictive simulation programs to model, evaluate, and validate the internal flow dynamics and mixing efficiency. Alternatively, a numbering-up approach can be employed, where conditions from the pilot system are replicated in a larger-scale flow system to increase production capability.

Additionally, since the reactants pass through narrow, tube-shaped reactors, clogging issues must be addressed during the development phase. Several precautions can be taken to prevent clogging, such as selecting solvents with high solubility and adjusting reactant concentrations, flow rates, or reaction temperature. If solvent selection and concentration adjustments impact the reaction condition, engineering solutions like widening the reactor’s inner dimensions or introducing a by-pass line to circumvent clogs, are combined with implementing a cleaning process. However, these measures may not resolve all the fundamental limitations of the continuous flow process.

To utilize solid reactants in a continuous process, Continuous Stirred Tank Reactors (CSTRs) are actively being evaluated. CSTRs are especially advantageous for reactions with slurries or products that precipitate as solids. They are commonly used as Mixed Suspension and Mixed Product Removal (MSMPR) in the crystallization process as they offer valuable alternatives to conventional flow process setups.

Continuous flow technology has been frequently highlighted in various literatures and media for its numerous advantages. Notably, it enhances safety by conducting reactions with rapid heat release or high explosion risks in smaller volume units. Continuous flow chemistry enhances reaction selectivity and prevents runaway reactions through more precise temperature control, as the surface area to volume ratio is greater than in traditional batch processes.

Additionally, continuous flow technology offers distinct advantages in High-temperature, High-Pressure (HTHP) reactions and enhances reactant mixing efficiency which facilitates reaction conversions that batch processes could not have accomplished. Furthermore, it is considered a unique alternative solution for overcoming permeability issues commonly encountered in large-scale photochemistry, microwave, and electrochemistry.

Despite its numerous advantages, the continuous flow process faces several practical challenges before being widely adopted. One major hurdle is the psychological resistance among chemists and engineers to transition from traditional flasks and vessels used for centuries to unfamiliar tube reactors. There may be a lack of technical understanding of the equipment and materials necessary for effective flow reactions which can hinder adoption. Also, significant capital expenditure requirements and uncertainties associated with scaling up flow reaction systems may limit the adaptation.

Furthermore, the continuous flow process has limitations in the work-up and drying processes. Hence many processes still rely on hybrid methods, where work-up, separation, and drying stages are performed in the batch system rather than a fully integrated continuous flow system. To overcome these technical limitations, many researchers and companies are actively researching to integrate continuous processes into work-up, crystallization, filtration, and drying processes.

For instance, MIT has demonstrated a system capable of performing continuous manufacturing from dug substance reactions to final drug product manufacturing using robotics. Since 2010, there has been a rapid increase in interest from companies that aim to implement automated flow systems as a key component of future manufacturing facilities to enhance productivity, reduce costs, and improve quality.

Yuhan CDMO’s plan

The continuous flow process is recognized as a transformative innovation with the potential to revolutionize the future of the pharmaceutical and fine chemical industries due to its advantages in energy efficiency, waste reduction, safety improvements, and increased productivity.

Since 2019, Yuhan CDMO has been developing packed bed reactions using tubular reactors and heterogeneous catalysts for hazardous chemistries such as organometallic reactions and nitration. Yuhan has also expanded its capabilities to Continuous Stirred Tank Reactors (CSTR) and plans to incorporate photochemistry. By 2025, the company aims to introduce cGMP-compliant packed bed and plug flow reactor systems at the pilot scale to meet customer needs. With its slogan, “To deliver superior quality drug substances and services to help humanity thrive,” Yuhan strives to maximize customer satisfaction by achieving an automated continuous flow chemistry system that produces APIs and intermediates more safely, economically, and environmentally friendly.

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