In the pharmaceutical industry, most small molecule production processes are performed in batch reactors. This technology is robust and very well implemented — however, it does have technical limitations. These limitations have to do with the lack of heat exchange and mixing performance, which can lead to safety issues and/or reduced yields and product quality when scaling-up the process.
In 2009, Servier CDMO began to explore alternative manufacturing processes for the production of chemical APIs in order to design processes that fit the optimum chemistry and avoid situations where a lack of technology would limit the industrialization of the best chemistry. Flow chemistry is one such alternative manufacturing approach. In a flow process, chemicals react continuously and the process equipment is designed for very efficient mixing and heat removal, allowing very rapid reactions. Materials are introduced continuously and react on contact with continuous removal of products, with better control of process variables and the reduced likelihood of unwanted side reactions, often resulting in higher selectivities and yields, as well as simpler purification processes. The quality robustness of industrial flow chemistry processes is greater as a result; when well designed, flow reactions are reliable and highly reproducible. Scale up is also often easier.
Only small quantities of reagents, intermediates and products are present at any given time, and thus exposure to toxic or energetic substances is minimized. With this type of equipment, it is possible to perform chemistry that cannot be implemented in batch mode.
The efficiency and increased speed of flow chemistry reactions also mean that it is possible to downsize the equipment needed to produce commercial-scale quantities, resulting in process intensification.
Less solvent is needed and less waste is generated, resulting in a positive environmental impact. Smaller production equipment can also translate to smaller plant sizes and significant reduction of the risk associated with doing chemistry. Capital expenditures and operating costs are often also reduced.
The 2009 decision to explore alternative manufacturing technologies reflects our focus on innovation. Our parent company, internationally recognized pharmaceutical firm Servier, is known as a research-based organization aimed at fulfilling basic human needs and dedicated to the future of healthcare. To that end, 28% of the company’s turnover each year is invested back into primary and industrial R&D.
Process R&D is performed at Servier’s Industrial Research Center, which comprises four departments and 180 employees that support the rest of the company’s activities. The departments — Chemical Development, Analytical Development, Pilot Plant and Innovative Technology — interact with one another on a regular basis. Each new client project is evaluated to determine which areas of expertise will be required to reach the objectives of the project. The relevant experts work as a team under a project manager to develop and implement a roadmap for the project.
At Servier CDMO, our experts in flow chemistry reside within the Innovative Technology Department and work very closely with experts in the Chemical Development Department. Importantly, the Industrial Research Center is located at Servier’s Normandy manufacturing site. As a result, all process R&D activities take place in close proximity to our commercial operations, facilitating close collaboration between all groups involved in process development and commercialization. This gives us the high level of agility necessary to meet customer needs.
The decision to use flow chemistry depends on a number of different factors. Our chemical development experts are aware of the benefits of flow chemistry and consider the use of this technology when designing a synthetic route during initial development. Our flow chemistry experts also review developed synthesis routes to determine if process intensification technology will be beneficial for industrialization of the chemistries used in each step.
This evaluation starts with a review of the chemistry on paper. For extreme reaction conditions — temperature or pressure — mixing depends on reactions, fast chemistry that involves very reactive reagents or intermediates — all are potential candidates.
For instance, a reaction that must be performed over two hours at a very low temperature (-80 °C) because it is very exothermic may be suitable for intensification at 0°C for 15 seconds. One example is reactions with reactive intermediates such as organometallic compounds, which typically can be run at room temperature in less than a minute, preventing degradation, improving the yield and selectivity and reducing the cost. Nitration reactions are often attractive targets for intensification because they can be dangerous when performed under batch processing conditions, but typically proceed in high yield with significant reduction of the hazards when run under continuous processing conditions.
Any potential steps in a synthetic route that have been identified as candidates for process intensification are then performed in lab-scale equipment to determine if the product can be obtained in the desired yield and selectivity under industrializable flow chemistry conditions. At Servier CDMO, we look for intensified reactions to be completed in less than five minutes. Flow chemistry reactions can proceed for longer times (i.e., hours), but reactions that are completed in less than five minutes are more practical for commercialization. This is because the size of the equipment needed for the production of commercial quantities remains sufficiently small, to afford the economic, quality and other benefits associated with flow chemistry.
The process equipment used by Servier CDMO for its flow chemistry reactions is based on a plug-flow or continuous stirring tank design. We initially considered microreactors but found them to have limitations with respect to the industrialization of flow chemistry reactions. The reactors (100 to 400 mL) used for investigation of flow-chemistry processes allow for excellent mixing, rapid cooling/heating and, as importantly, careful control of these and other process parameters. Their design is also readily transferable to the industrial scale (20-50 L), allowing us to more easily commercialize optimum processes.
We currently have one dedicated, industrialized flow chemistry process. The reaction is perfomed in a 50 L reactor. The oxidation reaction provides a key intermediate for an API manufactured by Servier. The batch process was a candidate for process intensification because it requires the use of a reagent that cannot be handled safely in a batch manner. This is also because the needed level of selectivity could not be achieved under batch conditions. Both of these concerns were addressed by switching to a continuous process. It is interesting to note that the workup for this reaction is performed continuously. Approximately 200 tonnes/year of this intermediate are produced annually.
The dream for process intensification is to achieve end-to-end continuous manufacturing. Ideally, each step of a synthesis route would be run using continuous processes and linked together, such that initial reagents are input at one end and API is isolated at the other. Even beyond that, the ultimate goal is to link continuous API manufacturing with continuous drug product production. Presently, in a typical API synthetic route comprising 10 different chemical reactions, perhaps one or two steps will be amenable to process intensification using current technology. There are often issues with converting batch work-up methods — liquid/liquid extractions, distillations, phase separations, filtrations, crystallizations, etc. — to continuous operations. Hybrid processes are of great interest, where conventional and intensified technologies are combined; the most important thing is to be able to use the best chemistry, in which case technology must not be a limitation.
Chemistry is our core business, but at Servier CDMO we have also implemented one continuous purification technology on pilot scale: simulated moving bed (SMB) technology. SMB is a continuous chromatography method that enables API purification at the level of tons per year. This downsized equipment is coupled with continuous evaporators; the result is a reduction in the volume of valuable stationary phases and solvents required for separations.
In order to expand our capabilities and work toward the goal of achieving end-to-end continuous processing, we have initiated a collaboration with leading flow chemistry expert Professor Steven Ley of Cambridge University in the UK. Through this partnership, we will be exploring the process intensification of many different types of chemical reactions. This is in order to determine effective approaches to continuous processing, which will allow us to switch from batch mode to flow chemistry for a wider array of synthetic steps.
Expertise in flow chemistry allows Servier CDMO to provide our customers with a combination of the best chemistry and best technology, which translates to a significant competitive advantage. Not every batch reaction can be transferred to flow chemistry, but with our ability to evaluate the potential for process intensification during the early phases of process development, we are positioned to develop the best routes using the best technology and provide the most optimum solutions to our customers.
Stéphane Laurent graduated from a French chemical engineer school in 1995 and further developed his R&D skills in the United States, conducting researchs on carbene chemistry for his MSc. Stéphane joined Servier and was in charge of process industrialization for more than 15 years. Since 2014, he has been in charge of the innovative technology department that works on intensified technologies.