Steady Progress Toward Continuous Flow API Synthesis

Continuous processing for the production of key building blocks and intermediates for small-molecule APIs is no longer viewed as a technology of the future. Most pharmaceutical companies with in-house manufacturing use flow chemistry to some extent, and smaller companies that outsource production expect their contract-manufacturing partners to have continuous-flow systems available. Advances in microreactor technology for commercial-scale production and implementation of continuous downstream processes will ultimately enable the complete continuous synthesis of complex organic molecules required for small-molecule API manufacturing. Widespread adoption, however, will occur slowly as the industry shifts from the infrastructure in place today to smaller, modular, and flexible facilities.

Many technical advantages
“Continuous flow synthesis is a great alternative to traditional batch synthesis/production when it comes to demanding chemistries such as hazardous reactions or potentially challenging conditions like high pressure and temperature,” observes Dominique Roberge, head of continuous flow/microreactor technology business development at Lonza Custom Manufacturing. In addition, continuous flow processing provides many technical advantages over traditional batch methods, including speed of development, process reliability and product quality, maximization of process safety when employing hazardous chemistries, and minimization of investment during product development, according to Peter Poechlauer, principle scientist at DSM Fine Chemicals. For Jörg Schrickel, new business development manager for CABB, the more consistent quality that is achieved with continuous manufacturing, particularly for sensitive products, is of significance.

“There are, in fact, some products that cannot be produced in large batch processes due to the thermodynamic nature of the reactions involved. Under continuous flow conditions, however, because only small quantities of reagents and products are present at any given time, these issues can be avoided,” Schrickel adds.

Another advantage is the improved environmental footprint of continuous processes. Poechlauer points to reduced raw material consumption and waste generation as two key benefits. CABB increases the sustainability of its continuous processes for the production of acid chlorides and derivatives by recycling off-gases (referred to by the company as its “verbund and recycling system”). “As a result, our building blocks have very low process mass intensity (PMI) and environmental factors (E-factors),” says Schrickel.

Slow but steady adoption
Despite the obvious technical advantages of continuous flow processing, companies are adopting the technology steadily, but slowly, and in a strictly opportunistic way, applying elements of continuous processing technologies when they pay off immediately,” states Poechlauer (1). “The technology is not developed to a certain degree of maturity and then waits to be applied, but is developed for and in close connection with a certain production process,” he adds.

Flow chemistry is often considered as an option when exploring new chemical routes, increasing yield, lowering the cost of goods, and generating IP, according to Roberge. “One of the main drivers for the implementation of flow chemistry is, however, to perform a reaction that cannot be done with traditional batch production, such as those involving azide intermediates or oxidation using oxygen,” he notes. Currently, the drivers for adoption are academia and institutes and providers of continuous flow equipment who are looking for innovation and often work together with the pharmaceutical industry to solve specific problems, according to Schrickel.

The main issue is the large existing batch manufacturing infrastructure. “If a company gets trapped in the question ‘use existing or build new?’, it will use the existing equipment in the present business environment,” states Poechlauer. Continuous equipment like microreactors are added when needed, and the existing vessels modified to serve other purposes, such as hold-up tanks used to define the batch for regulatory purposes. “We expect most pharmaceutical syntheses will continue to be a mix of continuous and batch manufacturing operations, which also enables manufacturers to build in inventory buffer zones,” observes Poechlauer.

In one recent example, researchers at GlaxoSmithKline found that for the large-scale manufacture of potassium bromomethyltrifluoroborate, a key raw material for a Suzuki−Miyaura coupling reaction (2), a hybrid approach involving the use of both continuous and batch processing where most appropriate was successful in achieving the project goals, according to Toby Broom, a chemist with GlaxoSmithKline R&D.

Current perspective
“The pharmaceutical industry is very much interested in continuous processes, and a lot of activity is underway within most pharmaceutical companies related to the development of continuous processes. However, we do see continuous processes being more relevant for the next generation of APIs,” says Schrickel. Lonza believes that at least the top 20 pharmaceutical companies have flow systems within their assets at this point in time, with some of the larger players calling continuous processing a disruptive or breakthrough technology, according to Roberge. At the same time, small to mid-size pharma and biotech companies often evaluate flow technology through outsourcing. “As a result, contract manufacturers that have flow processes in place are better positioned to engage in partnerships and collaboration discussions with these early start-ups,” Roberge comments.

As the internal advocate groups within pharmaceutical companies push for the development of continuous processes, continuous processing will be applied in a growing number of processes, but in an evolutionary way, rather than a revolutionary one, as people come to accept the technology as mainstream rather than “experts only” territory, according to Poechlauer. In addition, he notes that with large pharmaceutical houses focusing on new leads rather than on process development, custom manufacturing organizations continue to play an important role in this field.

Support from the authorities for continuous processing has also been crucial in furthering its acceptance by small-molecule API manufacturers. “The industry and FDA are in constant dialogue on continuous processing,” Poechlauer says.

Advances in continuous commercial production
One of the biggest issues for continuous flow chemistry has been scaling up to commercial production levels, because most early equipment for flow chemistry was designed for the laboratory. According to Poechlauer, however, chemical manufacturers and pharmaceutical companies have been working with microreactor manufacturers to address this issue, and pilot- and small commercial-scale equipment is now available, often by “numbering up” and running several microreactors in parallel. “One advantage of this approach is that modular designs that can be fitted to the specific needs of different reactions are possible,” he says.

This advantage was taken into consideration when DSM installed its commercial-scale microreactor suite. “We are very interested in microreactor technology and continuous processing because, in some cases, it makes it easy to scale up reactions that can’t easily be done otherwise due to the nature of the raw materials or the kinetics of the reaction,” says Poechlauer.

Lonza has designed a new type of production facility concept called the “Factory of Tomorrow” in which FlowPlate microreactors of various sizes are incorporated into the company’s development and manufacturing plants. “Flow processes lead to high intensification that radically reduces the size of a reactor and its footprint,” Roberge states. The range of FlowPlate equipment allows for production of a few grams of product in the lab setting and up to 5-ton campaigns for later-stage projects. “In such an environment, flexibility and versatility is needed to combine novel process conditions at high temperature and pressure, which can be difficult to achieve in a classical plant setting. Continuous manufacturing can significantly improve process efficiency with a reduced footprint, therefore reducing overall material consumption,” he observes.

In addition to addressing scale-up issues, advances have also been achieved in expanding flow chemistry beyond liquid systems, which are the traditional and most simple systems for continuous processing, according to Schrickel. “Much progress has been made with respect to the development of technology for the continuous processing of liquid/solid and multi-phase systems,” he explains. Lonza, for example, is developing microreactor plates with its partner Ehrfeld Mikrotechnik BTS, a Bayer Technology Services company, that will enable multi-phase reactions. Schrickel believes these advances will be important for the further application of continuous processes in API production.

Poechlauer does add that there are uncertainties about scale-up, and managing intellectual property issues must be done carefully, given that in many cases new process chemistry is involved.

Flowing downstream
More recently the focus has been on integrating continuous downstream processes with continuous flow synthesis. “Most downstream processes can be easily adapted to run continuously; extractions, phase separations, and distillations are actually more effective when done continuously,” says Poechlauer. On the other hand, he notes that solids handling processes, such as filtration and crystallization, present some difficulties. There are solutions being introduced to the market, however, such as belt filters and spray-drying, and Poechlauer expects others will follow.

Lonza, in fact, is currently extending the application of continuous flow technology to address continuous work-up unit operations such as distillation, according to Roberge. “The objective is the continuous operation of a complete mini-plant within the manufacturing unit ‘Factory of Tomorrow,’ which will allow its use for larger-scale manufacture,” explains Roberge.  

Intense future
Research and development of continuous processes will continue and grow, first on specific, isolated topics, because there might not always be a solution that will enable a complete continuous process or at least a process without bottlenecks. To switch to continuous processes, companies will have to gain all of the possible benefits that the technology offers, and sustainability will be one of the key aspects, asserts Schrickel.

Poechlauer also believes that continuous processes will ultimately lead to simplified distributed manufacturing (on-site, on-demand) in modular container plants as well as enable application of “personalized medicines.” He also notes that the use of disposable devices in the manufacture of highly potent compounds will be beneficial to the further development of continuous processes for these challenging compounds.

“Our partners in the pharmaceutical industry are in a transition stage and are moving toward integrated solutions. Laboratory chemists consider the environmental consequences of raw materials and processes when developing synthetic routes. Drug manufacturers are also forming closer collaborations with suppliers to explore new technologies and concepts, such as continuous processing and the use of microreactors. Such relationships will help demonstrate the benefits of this approach and ultimately lead to adoption of process intensification when it is the most effective solution,” Poechlauer concludes.

At the same time, continuous processes will require new equipment and perhaps dedicated production lines for each API, according to Schrickel. “Pharmaceutical companies may insource the entire manufacturing of their APIs or force their outsourcing partners to install dedicated continuous plants. In either case, the adoption of continuous processes may result in a radical change in the pharmaceutical and outsourcing industry,” he asserts.

References
1. P. Poechlauer et al., Org. Proc. Res. Dev., 17 (12), 1472-1478 (2013).
2. T. Broom et al., Org. Process Res. Dev. Article ASAP, DOI: 10.1021/op400090a Publication Date (Web): June 10, 2013.

About the Author
Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.