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Continuous API manufacturing: flow chemistry and the pharmaceutical sector

Flow chemistry is a technique ideally suited for large-scale manufacturing. It not only makes producing large quantities of a given product more efficient and controllable, but it is also a solution that can be bespoke and entirely tailored to the specific needs of a reaction.

flow reactor used in pharmaceutical manufacturing
Coflore ATR Reactor

Where is flow chemistry used?

Flow chemistry has been a well-established technique for decades. It entered the market as an alternative to batch manufacturing, driven by the need for larger-scale production. It created opportunities to commercialise products in high demand within industrial environments.

However, it was quickly discovered that batch reactions are not feasible in some instances. For example, meeting the requirements for heat and mass transfer is a challenge when scaling chemical syntheses, particularly when batch manufacturing is employed. The nature of flow manufacturing makes scaleup from lab to pilot, and full production, much simpler. As a result of this, flow chemistry started to gain traction and acceptance as the manufacturing mode of choice.

Key applications of continuous flow now include hydrogenation, oxidation, halogenation, nitration, diazotisation, and many other reactions that involve a mixture of materials. Initially only used for liquids and gasses, flow technology has now improved to accommodate reactions that require solid handling capabilities too.

After championing green chemistry, automation, biocatalysis and a variety of high-temperature or high-pressure reactions, which were once difficult or impossible to achieve in batch mode, flow chemistry has garnered considerable attention and recognition.

Pushing the boundaries of chemical technology

Flow chemistry was predominantly used in sectors such as petrochemical and chemical R&D, but it is now expanding into new arenas, chiefly pharmaceutical manufacturing. Flow chemists have been working hard to provide access to ‘impossible chemistry’, and the result? Continuous pharmaceutical manufacturing!

The very nature of flow chemistry enables strict control of reaction parameters. Its’ use of a small reactor tank means less reaction occurs at any given time. The mixing, temperature and overall reaction time can also be tailored depending on the safety risk of the reaction performed.

Pharmaceutical and biopharmaceutical companies around the globe are now utilising continuous flow to design new chemistry that not only provides better results and improved safety but is also amenable to rapid development, discovery and optimised scaling. Commercially, this is helping market leaders meet their product demands and aiding smaller national companies to reduce their time to market.

A new solution for Active Pharmaceutical Ingredients (APIs)

Broadly speaking, active pharmaceutical ingredients (APIs) are the component of a drug formulation which is responsible for its activity. APIs can be categorised into two types: synthetic and natural. Synthetic, or chemical, APIs currently occupy the largest part of the pharmaceutical market, with many variations of small molecule drugs commercially available and in development pipelines.

APIs can and are currently being synthesised by flow chemistry, by conducting the synthesis of reagents in a flow reactor, whereby the compounds are produced continuously. Once the chemical reaction has occurred, the product (which is typically a liquid or solution) can be passed through further reactions for completion of the process or even an observation tube for further assessment.

For many years there has been a struggle with moving lab-scale API reactions to large industrial-scale synthesis. This is because reaction parameters need to be strictly monitored and maintained in order to create an optimal reaction. The conditions required for continuous API manufacturing are easily achievable because flow is entirely controlled, from the heat and mass transfers to the tubing coils and separators.

The reproducibility of these synthetic transformations is reliant on the use of a single reactor tank, with a continuous stream of reagents pumped in, where conditions are replicated.

Enabling continuous API manufacturing

The reactions that take place to form API compounds are inherently high risk, which means the reaction volume must be kept low. Flow technology enables the continuous delivery of the target compound with a reduced residence time and improved productivity all whilst practising safer chemistry by isolating the reaction to a singular, small tank.

Subsequent reactions can follow from the initial reaction to develop an end-to-end API flow process synthesis. The first stages can involve formation, with latter stages such as substitution reactions and final coupling reactions ultimately producing a synthetic, chemical, API.

In batch manufacturing, handling hazardous intermediates was typical in order to move to the next stage of the production process. With a continuous production process, all key steps involved in formulating the desired product can occur within the flow process.

Flow chemistry has created a new alternative for the synthesis of APIs, but we are still a long way from exploiting the full potential of continuous manufacturing for the pharmaceutical sectors. New applications of flow chemistry within biopharmaceuticals have led to many other companies also transitioning to continuous flow.

Manufacturing Biological APIs in flow

Biopharmaceuticals, or biologics, are complex medicines made by and extracted from living organisms, generally bacteria. Bacteria are the masters of natural flow chemistry, manufacturing highly complex molecules from environmental substrates.

Cultured bacteria can be used to manufacture these natural, biological, APIs in large quantities. Like chemistry, this biological manufacturing requires only the optimal conditions to work. These conditions can be provided in the context of continuous manufacturing just as they can in ‘traditional’ batch manufacturing and deliver similar advantages to flow organic synthesis.

Bringing out the big guns, flow chemists!

The pathway to continuous API manufacturing has only just begun, but it will continue to reveal new applications of flow chemistry. The toughest challenge in adopting flow chemistry in what is otherwise considered ‘non-typical’ sectors, is understanding how flow chemistry works and visibly seeing the advantages of it.

Working with pumps, different reactors and a massive variety of interchangeable components can be daunting. The collaboration that a flow chemistry process requires between chemists, engineers and many other participants is vital to understand which ‘X’ will be compatible with which ‘Y’. This is exactly why working with third-party chemical reactor partners, like us, can aid with integrating a flow process for the desired synthesis.

The key takeaway when introducing your company to continuous flow manufacturing is that it is built on the premise of being able to adapt reactors to the chemistry and not the other way around.

If the pharmaceutical sectors had come to recognise the benefits of continuous manufacturing, many supply chains would have been protected from the consequences of the long and cumbersome batch processes which continue to cause supply chain problems. Flow chemistry is not only the continuous, steady production of products but it is also a means to improving the overall efficiency and effectiveness of the pharmaceutical manufacturing sector.


“One of today's most important tools for modernizing the pharmaceutical industry is a process known as continuous manufacturing”

Director of the FDA’s Centre for Drug Evaluation and Research,

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