Are Microreactors Practical for Large-Scale Production?

Although continuous processing is applied in other manufacturing industries, it is not widely used in the pharmaceutical industry, which relies on batch manufacturing. But the US Food and Drug Administration’s quality-by-design initiative and the possibility of improving production economics and process control are encouraging companies to consider continuous processing in pharmaceutical manufacturing. Microreactors, which are based on flow chemistry, can be used to apply continuous processing to the manufacture of active pharmaceutical ingredients. Recent technological advances in microreactor technology are improving the application and scale at which the technology can be applied.

One notable change relates to the equipment’s functionality. At first, various types of microreactors were designed for specific reactions, and chemists had to choose the best microreactor accordingly. During the past several years, however, multipurpose microreactors have emerged that are applicable to a bigger portfolio of reactions than before, says Gregor Wille, specialist for microreactor technology at Sigma Aldrich (St. Louis, MO). A large part of chemists’ work is in multipurpose applications, and the development of multipurpose microreactors represents a paradigm shift, says Wille.

This shift has occurred thanks to a change in the plates within the microreactors. In the past, each mircoreactor had individual plates for mixing, reaction residence time, or temperature control, but newer microreactors use plates that integrate several functions. These new machines are gaining widespread acceptance in the pharmaceutical industry, says Sergio Pissavini, business director of Corning Reaction Technologies (Corning, NY).

Multifunctional plate reactors can be reconfigured easily to suit various reaction requirements, says Martin Jönsson, sales and marketing manager for Alfa Laval Reactor Technology (Lund, Sweden). These devices can be used for liquid–liquid reactions and two-phase liquid reactions. Multifunctional plate reactors also allow operators to determine the ideal equipment parameters during process development.

The types of unit operations that microreactors can perform have also expanded. New machines can isolate and purify the chemical products of reaction mixtures by performing tasks such as phase separations and distillations, according to Peter Poechlauer, principal scientist of DSM (Heerlen, The Netherlands). For example, the inner surfaces of new microreactors combine hydrophilic and lipophilic domains that enable the units to separate phases.

Traditionally, microreactors’ yields have been limited by the size of the machines’ tubes, which affects the flow of ingredients. Operators have tried ad hoc strategies to improve yields, including wrapping small pieces of tubing around a heating or cooling exchanger and stacking grooved reactor plates. But equipment manufacturers such as Corning now offer larger units with wider tubing than before. The larger flow-chemistry reactors still have good surface-to-volume ratios, but offer a flow path with a larger diameter to help improve throughput and yield, says Jeffrey W. Sherman, head of advanced technology development at Mettler-Toledo (Columbus, OH).

Technological improvements have enabled some pharmaceutical companies to begin using microreactors for commercial-scale production. In a joint project, Corning and DSM developed equipment and a production process that safely and cost-efficiently produces the nitrated intermediate required to make naproxcinod. First, the partners successfully achieved current good manufacturing practice standards and then accomplished pilot-scale production. This year, Corning provided DSM with a large-scale reactor that can produce more than 100 tons of product annually, says Pissavini. Corning is now developing reactors for several major companies whose names cannot be disclosed because of customer agreements.

Still, the promise of efficient scale-up of microreactors with consistent, predictable results has not yet been realized, Sherman says. Pharmaceutical companies question whether parallel synthesis (i.e., stacking several microreactors to make large quantities) is pragmatic. The technique requires manufacturers to buy and maintain a lot of equipment. Although parallel synthesis might reduce safety and scale-up problems, it introduces problems such as equipment validation and real-time control. “People are wary of saying that microreactors are the answer,” says Sherman.

Hope for the technology’s future seems justified, however, considering how much technological advances have improved the equipment. And companies such as sanofi aventis (Paris) and Schering-Plough (Kenilworth, NJ) have publicly recognized that microreactors can produce high-quality chemicals cost efficiently and with a low environmental impact, says Pissavini.

A desire to improve product quality, a need for greater process control, and FDA’s promotion of continuous processing may spur greater industry adoption of microreactors. “I think flow chemistry is here to stay and will increasingly play a role alongside batch reactors,” says Sherman.