LONZA
COVER STORY
FLOW THROUGH A gas-
liquid neutralization reaction occurs from left to right in the millimeter-sized channels of a reactor plate.
END-TO-END CHEMISTRY After a slow start, pharmaceutical and fine chemicals manufacturers are scaling up CONTINUOUS PROCESSES for production ANN M. THAYER, C&EN HOUSTON
A MODERN PHARMACEUTICAL manufac-
turing plant looks a lot like a classical chemistry lab. As has been the case for more than a century, most drugs that come out of these factories are made via stepwise reactions, purifications, and final product formulation. In a handful of plants, however, continuousflow processes are starting to creep in. Continuous processing offers several advantages over start-and-stop batch production. A continuous-flow reactor requires less space and less investment. It can provide better control over reaction conditions and productivity. And, equally important to the lab chemist and the plant engineer, continuous methods can often be used to rapidly scale up reactions, including ones that involve hazardous reagents. Even regulators are encouraging. Coupled with real-time monitoring and control of product variability, continuous manufacturing has the potential to “not only meet current expectations, but to really give enhanced product quality over what some of the current batch technology provides,” says Christine Moore, acting director of the Food & Drug Administration’s Office of New Drug Quality Assessment.
Although continuous processing isn’t mainstream in drug production, many people working in the area see it as inevitable. To make the shift, academic researchers, equipment suppliers, and end users are creating needed tools. Some are even looking beyond converting single reaction steps to achieving ambitious end-to-end processes that flow from raw materials to final pill. But making the switch has been slow. Although DSM, Lonza, and other fine chemicals firms are developing equipment and processes, and pharma companies such as GlaxoSmithKline and Novartis are putting systems in place, the new technology competes against entrenched batch capacity. Even when corporate resistance is overcome, continuous processes have yet to test the regulatory waters in any great number. Mind-set has made the move toward continuous processing easier for some than for others. Jaeyon Yoon, vice president of marketing at SK Life Science, the
contract manufacturing business of South Korean petrochemical producer SK, says it was easy for his firm. “When we started 15 to 20 years ago, our team was originally SK engineers and chemists,” he explains. They began making pharmaceutical chemicals with the continuous bulk chemical processes with which they were familiar. They started with flow hydrogenations using fixed-bed catalysts. Today, SK operates a wide range of continuous-flow chemistries, as well as distillations, extractions, and crystallizations, from the lab to commercial scale. In deciding whether to use a flow or a batch process, SK scientists weigh economics, timing, and the suitability for a specific chemistry, Yoon explains. About 60–70% of what SK runs are still batch reactions. Another sign of the technology’s value, Yoon says, is the conclusion by the American Chemical Society Green Chemistry Institute’s Pharmaceutical Roundtable that continuous processing is the
“Some of the larger players are even ready to invest double-digit millions of euros.” CEN.ACS.ORG
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leading green engineering research area. To assess how the technology is being practiced, the group surveyed its members—12 major drug firms and two manufacturing services providers—on the level of adoption (Org. Process Res. Dev. 2012, DOI: 10.1021/op300159y) and on business drivers (Org. Process Res. Dev. 2013, DOI: 10.1021/ op400245s). Most large pharma companies have formed groups to develop and implement continuous processing and serve as internal advocates, the surveys found. NEVERTHELESS, there is a general lack
of experience in using the technology and reviewing it with regulators. For example, Yoon says SK must work to educate customers on how its processes work and how it will “manage a project, deliver a product with the right quality, and meet regulatory requirements.” Although continuous processes are cost-competitive, drug manufacturers are risk-averse and thus apt to stick with familiar batch methods, says James R. Bruno, president of the consulting firm Chemical & Pharmaceutical Solutions. The high at-
DSM
COVER STORY
PARALLEL BANK DSM uses
Chemtrix flow reactors made of EKasic silicon carbide in a ton-per-hour pharmaceutical production plant.
trition rate in drug development makes companies reluctant to invest in new technology, especially if they view it as unnecessary because of existing batch capacity. “The biggest thing holding us back is that we have assets in the ground,” Bruno says. Pharma firms are typically reluctant to change processes for approved products. Thus, industry watchers expect companies to adopt continuous reactions mostly for
new products or possibly to lower the cost of making generic drugs. To capture this business, “just about every major contract manufacturing organization (CMO) has some kind of a program in place to look at continuous-flow chemistry,” Bruno says. At Chemtrix, a Dutch flow-chemistry equipment supplier, CMO customers have far exceeded pharma customers over the past 18 months, according to Charlotte
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