The rise of flow chemistry in API development and manufacturing: Navigating challenges with continuous processing
Pharmaceutical manufacturing has long leaned on batch processing as the default approach. However, in recent years, flow chemistry, also known as continuous processing, has emerged as a powerful alternative or complementary method.
Flow chemistry replaces the traditional stop-and-go rhythm of batch processing with a continuous stream of processing. Continuous manufacturing techniques have an extensive history of adoption in fine chemicals and specialty manufacturing, but scaling these techniques for larger-scale API production remains an opportunity.
Numerous drivers, like the need for safer handling of hazardous materials and rising pressures to reduce costs and increase manufacturing efficiency, have contributed to flow chemistry’s growth in the pharmaceutical manufacturing space. With the global flow chemistry market projected to grow by about 11.6% through 2030 , many pharmaceutical organisations are actively seeking ways to integrate continuous processing methods in their development pipelines.
Continuous processing shows great promise in a variety of use cases, but its success depends on understanding where it adds the most value and anticipating potential challenges it may bring. In this blog, we explore what’s driving wider adoption of flow chemistry in the pharmaceutical space, how it compares to batch processes, and what is required to apply flow chemistry most effectively.
The advantages of flow chemistry in pharmaceutical manufacturing
At its core, flow chemistry is about efficiency and control. Let’s take a closer look at some of the core benefits flow chemistry can bring to API manufacturing.
As reaction volumes in continuous processing tend to be smaller, heat and mass transfer are more efficient and tighter control over reaction conditions can be achieved. This control is vital for complex and hazardous transformations.
Furthermore, in the event of any equipment failures, only a small volume of material is lost, rather than an entire batch.
High mass transfer also increases the efficiency of heterogeneous reactions, such as those using a solid catalyst or reacting gases. Reactions with gases and liquids can be further improved by the use of high pressures, increasing gas solubility.
High pressures are easy to achieve in a flow reactor, which means that solvents and reagents can be used at temperatures above their normal boiling points. This opens up a wider range of reaction conditions, such as higher temperatures and different solvents. This, in turn, can allow for faster reactions and more options for impurity control.
As only a limited amount of material is contained in a reactor at any given time, flow reactors can accommodate more hazardous chemistries without risking safety incidents. Working with functional groups such as nitro compounds, azides, cyanides, and diazonium compounds becomes more manageable and less risky.
Once flow reactors have hit steady state, the tight process control over a small reaction space means that product quality remains consistent through an entire flow run, reducing batch-to-batch variation, assuming no deviations occur. This means less intervention and ongoing monitoring required by operators to ensure consistency and affirm quality.
Furthermore, certain flow reactor features, such as the use of fixed bed reactors for heterogeneous catalysts, can aid product purification and support improved quality. Additionally, in high-pressure reactors, low boiling point solvents can be used and easily removed from the product post-reaction.
Flow reactors run consistently with fewer stop-start cycles and less manual intervention, meaning continuous processing can reduce overall operating costs for API manufacturing.
Comparing batch manufacturing and flow chemistry
Flow and batch processing both bring unique advantages to API manufacturing. Each has preferred use cases, and sometimes, batch and flow processes are used together in pharmaceutical manufacturing projects.
Below, we summarise key advantages of each approach:
| Batch manufacturing | Flow chemistry |
|---|---|
| Effective for slurries and poorly soluble reactants and products | Favourable for reactions requiring tight temperature control |
| Well-established regulatory guidelines and industry familiarity | Safer for hazardous or unstable materials |
| Easier to isolate intermediates | Offers reproducibility and control, with less room for error |
| Removes complexity and time inefficiencies associated with engaging in new proposal discussions or change orders for every piece of work. | Accelerated time to market as a result of parallel pathing, in addition to removing complexity and time in efficiencies associated with engaging in new proposal discussions, change orders, etc. at the commencement of a new project/partnership. |
| Well-known and accessible modeling and simulation tools | Supports automation and simpler monitoring |
As both methods bring distinct benefits, the question for pharmaceutical organisations isn’t whether to use batch or flow processes. Instead, it’s about knowing where flow chemistry can be most effective.
Key considerations for continuous processing
Implementing flow chemistry in API development and manufacturing programmes requires more than just an equipment change. Organisations must account for several important considerations.
1. Regulatory considerations
Regulatory frameworks in the pharmaceutical industry have long been built around batch processing, which can make documentation, validation and approval for continuous processes more complex. A partner that offers significant expertise in compliance and quality inspections can help to translate flow processes into GMP-compliant systems and submissions.
2. Infrastructure and scale
Purchasing new equipment is one thing, but it is important to consider that many commercial flow systems are designed for R&D or smaller-scale work. Ensuring that equipment is production-ready often demands custom engineering, specialised reactor design, and consideration for ATEX compliance. A partner that has the expertise to apply and adapt infrastructure can help to streamline adoption.
3. Safety and hazard evaluation
Since flow chemistry can be preferable for reactions involving certain hazardous compounds, comprehensive hazard evaluation capabilities and expertise in handling hazardous materials are critical prerequisites. A manufacturing partner who is already well-versed in hazardous chemistry can ensure that hazardous processes are safely navigated, and that processes developed in the lab will effectively translate to the plant scale.
The future of flow chemistry in pharma: A complementary model
Although flow chemistry will not replace batch processing in the pharmaceutical industry, continuous processing offers opportunities to deliver therapeutics in a more efficient and cost-effective manner.
As technologies mature, more reactions may occur in flow, while batch methods will continue to serve where they are best suited. A partner with expertise in manufacturing best practices and continuous innovation can help organisations understand where flow chemistry can fit into their programmes and complement batch manufacturing to support the highest possible quality and yield.
Supporting flow chemistry at Sterling
At Sterling, we’re helping to drive innovation in API manufacturing approaches with our specialised infrastructure and technical expertise. Our team has expanded its expertise in converting problematic batch chemistry into feasible flow processes, and we have successfully transitioned hazardous and challenging batch processes to the kilo scale in flow.
Through our extensive API manufacturing expertise and collaborative approach, we help customers to understand where flow chemistry can make the greatest impact in their programmes and harness its benefits with confidence.
For more information on our flow chemistry capabilities, speak to a member of our team.
Frequently asked questions on flow chemistry:
Flow chemistry, or continuous processing, is a process where reactions are performed in a continuous stream, rather than batches. Reactants flow through a specialised reactor under controlled conditions.
In batch manufacturing, reactants come together in a reactor in a start-and-stop sequence. Flow chemistry, on the other hand, operates continuously. Material flows into and out of a reactor on a continuous basis, reducing potential material losses and operator involvement.
Flow chemistry’s primary advantages include improved efficiency, enhanced safety, greater consistency in product quality, and cost efficiency. Relative to batch manufacturing, flow chemistry can afford greater control with less operator intervention.
While flow chemistry has been applied at smaller scales in the pharmaceutical industry, it is increasingly being applied at larger scales. Scaling to larger batches may require specialised infrastructure and custom reactor design, as most available equipment is built for smaller scales.
Yes. Today, we are running flow chemistry projects at the lab scale up to the multi-kilo scale, and we have the expertise to adapt our equipment and approach to different project requirements.
If you’re interested in learning more about how we can help with your project, speak to an expert.
