Going Small, Thinking Big

    Nov. 18, 2004
    Microreactors and micro-scale equipment enable faster, continuous reactions, and are starting to make their mark in pharmaceutical manufacturing.
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    By Paul Thomas, Managing Editor

    Plenty of drug makers today are thinking small. Real small. In the neverending pursuit of a better route to certain intermediates and active pharmaceutical ingredients (APIs) and more streamlined operations, drug companies are turning to microreactor technology.

    Microreactors are essentially small flow channels, or systems of channels, where reactions may occur. Myriad other microchannel devices exist to handle additional unit operations. The concept behind them is not new, but these devices are now cheaper and easier to come by, and many firms are jumping on the micro-bandwagon. They are looking to perform common pharmaceutical reactions—hydrogenations, oxidations, substitutions, even Wittig and Passerini reactions—in miniaturized continuous flow.

    Microreactors have several distinct advantages. Due in large part to their high surface-to-volume ratios and small channel dimensions, they are highly efficient for mixing, mass transfer, and heat transfer. These factors can lead to greater selectivity and higher yields. It also makes them attractive for highly exothermic reactions or those involving hazardous materials that would normally generate large amounts of unwanted by-products. And they are fast. The channel dimensions result in rapid diffusive mixing at the molecular scale (no need for stirring) while operations can be scaled up (by running many microreactors in parallel) to make them viable for large-scale manufacturing.

    For all of these reasons, microreactors and microprocessing equipment have garnered interest from proponents of broader industry trends such as lean manufacturing, high-throughput technologies (HTT), and personalized medicines. And, not surprisingly, they have been embraced by those who think the industry is too batch-dependent. In fact, microreactors can perform reactions and get results often not possible in batch reactors.

    A brief example: Researchers at the New Jersey Center for MicroChemical Systems (NJCMCS) at the Stevens Institute of Technology (Hoboken, N.J.) have illustrated the benefits of microreactions by comparing a standard catalytic hydrogenation using a 100-liter batch reactor versus the same reaction in a continuous flow microreactor. They found that the microreactor outperformed batch in terms of safety — less H2 at lower pressures — heat extraction, and selectivity. While the batch cycle was several hours, the residence time of the microreactor was a matter of minutes. The researchers did identify challenges to consider in using microreactors — how to mix most effectively, handle pressure, and optimize yield — that indicate they are still coming to grips with the nuances of the technology.

    Drug Companies on Alert

    Drug companies are playing it close to the vest about the extent of their interest in, and use of, microreactors. What is certain is that the technology has proven itself and is making the transition from R&D and pilot projects to full-scale commercial processing.

    “If any of the major pharma companies is not doing something with microreaction technology, then they are following it very closely so that they can jump in when the time is right,” says Ronald Besser of the NJCMCS. The Center is working with several pharmaceutical companies, including Bristol-Myers Squibb (New York, N.Y.), to develop commercial applications using microreactors.

    Several other industry heavyweights have announced strong commitments to microreactor and microchannel technology in the past few months.

    • In October, Bayer Technology Services (BTS; Leverkusen, Germany) announced a buyout of Ehrfeld Mikrotechnik (Wendelsheim, Germany), the start-up manufacturing firm of microreactor guru Wolfgang Ehrfeld.
    • In September, Boehringer Ingelheim (Ingelheim, Germany) purchased another manufacturer, STEAG microParts, from STEAG AG (Essen, Germany).
    • And in August, Clariant Pharmaceuticals, Inc. (Muttenz, Switzerland) established the Clariant Competence Centre for Microreactor Technology at its Frankfurt location to further develop the technology — for niche applications at first, though a company spokesperson estimates that eventually 15 to 20 percent of all synthetic processes at the plant could be done by microreactors.
    Another firm to have gotten on board is GlaxoSmithKline. At its Harlow, U.K. site, GSK has invested in and partnered with the British firm Syrris, Inc. (Herts, U.K.), a maker of modular, continuous flow microreaction systems which can be tailored for multiple purposes. The symbiotic relationship between a major pharma and a fledgling manufacturer is typical of the micro landscape today. “They have provided the science, we have provided the engineering,” says Richard Gray, Syrris’s commercial director.From Microreactor to Plant-in-a-BoxThe miniaturization trend began in the laboratory, driven by the need to expand and quickly analyze sample libraries, but it has since moved on to manufacturing. In part because the technology is fairly new, and hasn’t really been standardized yet, people tend to use the term microreactor rather loosely. In its simplest form, it is a small reactor — with channel dimensions in the neighborhood of one micron to 500 microns or even one millimeter in diameter. It can work in concert with any number of similar reactors and devices on one or several unit operations, initially for performing lab functions with the potential to be scalable for manufacturing.Microreactors can be made of stainless steel, Hastelloy, ceramics, silicon, or glass (which has the added benefit of providing a window to the reaction). They are arranged on wafer-like plates which can be stacked, allowing for ever-increasing reaction volume. Microreactors have the potential to be a “disposable” technology, as the plates themselves are becoming cheaper and can be replaced and upgraded fairly simply without retrofitting an entire system.The broadening array of microdevices available — including miniature mixers, pumps, pressure gauges, mass flow controllers, and heat exchangers — opens the door for miniaturized multi-step operations or, for that matter, entire drug-making processes via what some are calling a “toolkit,” “toolbox,” or even “plant-in-a-box,” a modular microchemical system small enough to fit on a bench top. (A related term, “lab-on-a-chip,” refers to microreactor systems aimed more at analysis rather than manufacturing.)Manufacturers like Syrris, MicroChemical Systems, Inc. (Hull, U.K.), and Cellular Process Chemistry (CPC), Inc. (Cambridge, Mass.) are leading the charge in modular systems. Drug firms are also experimenting with running many such reactor systems in concert for ever-increasing throughput — often called numbering up rather than scaling up. The ability to number up also means that the transition from R&D to more large-scale production is a matter of adding more reactors until the optimal output is achieved.
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    This microreactor system from CPC, Inc., has been used in a Clariant Pharmaceuticals’ pilot plant. The prospect of bringing research, chemical development and process development back together is what much of the excitement is about, says Dr. Thomas Schwalbe, CEO and founder of CPC. One reactor getting a lot of attention is his company’s CYTOS Lab System. An array of CYTOS systems were used in developing a pilot plant with Clariant Pharmaceuticals, up and running since 2001, for the continuous-flow production of organic pigments. The success of that project in fine chemicals convinced many in pharmaceuticals of microreactors’ commercial viability.CPC is now working with Sigma-Aldrich (Buchs, Switzerland) and other firms on more mainstream pharmaceutical applications. In addition, it has started another company, Synthacon, in eastern Germany, to provide CYTOS-based continuous chemical manufacturing. Synthacon will be onstream in early 2005, Schwalbe says, with the potential to generate hundreds or even thousands of tons of product annually.While the jury is still out on the plant-in-a-box concept — does going micro really add value at each step in the process? — few are arguing against the potential of microreaction technology to transform the industry in due time, to bring it one giant step closer to low-cost, high-quality, continuous flow drug manufacturing. Specific ApplicationsMicroreactors and microchannel devices are showing their worth in a variety of ways, though without much coordination or standardization as of yet.Dr. Xini Zhang and researchers from Johnson & Johnson Pharmaceutical Research and Development (Raritan, N.J.) performed several reactions typically hazardous in batch using microreactor systems by CPC, Inc. Microreactors offered an easy, safe and fast alternative to batch. They performed a ring expansion with ethyl diazoacetate (EDA), for instance, by reacting EDA with N-Boc-4-piperidone, typically a highly exothermic reaction. The microreaction went off without a hitch, with an 89% yield and just a 1.8 minute residence time. Ninety-one grams of the product was generated within an hour.Velocys, Inc. (Plain City, Ohio), a spin-off from Battelle specializing in customized microchannel systems and solutions, is making inroads in pharmaceuticals after working primarily with the commodity chemical industry. Pharma firms have sought help with three particular applications: the formation of high-performance emulsions; gas-liquid processing for hydrogenations and oxidations; and continuous production of materials in catalytic reactors, says Laura Silva, manager of business development.In the latter application, the firm attaches catalysts to a chemical tether, which is then attached to the microchannel reactor — ranging from 50 microns to one millimeter in diameter. Throughout the reaction the catalyst stays immobilized to the walls of the microchannel, and thus requires no later separation step. Besides the higher productivity and better yield of the reaction itself, there are time and cost savings.Sigma-Aldrich has been testing CPC’s CYTOS system for a variety of applications. In one example, the company dramatically reduced the reaction time for a fairly standard condensation — of 2-trimethlysilylethanol and p-nitrophenyl chloroformate to produce 2-(trimethylsilyl)ethyl 4-nitrophenyl carbonate — from 14 hours in a conventional reactor to 18.4 minutes in a microreactor.According to Dr. Fabian Wahl, the company’s manager of R&D in Europe, 800 of the some 2,000 lab compounds that the company produces could be done with microreactors. In addition, Wahl says, many new compounds become possible using microreactors.Bye Bye Batch?In their own small way, microreactors are spurring the gradual shift from batch to continuous processing. Experts agree, however, that batch will always be better in some cases. What is more likely is an integration of the two, with differing unit operations performed at the micro or macro level.Getting started in microreactors requires caution (see "Micro Managing," below), as the technology has its limitations and bugs to be worked out. “For clean reactions, with high purity and mild temperatures — where everything is perfect — microreactor technology lends itself to that very well,” says Clyde Payne, CEO of the emerging technology consulting firm The Catalyst Group (Spring House, Penn.). “You can idealize the conditions. But for reactions that are complex or have impure starting materials, with a lot of by-products, the product can gum up the system.”
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    The AFRICA microreactor by Syrris, Inc. illustrates the modular system concept for drug discovery and development. Courtesy of Syrris, Inc.

    The tendency to clog, in fact, seems to be the one consistent knock against microreactors. Manufacturers are working on solutions. Syrris’s Gray, for example, notes that the company’s AFRICA system is designed to detect the presence of precipitates before blockage occurs. Yet the sheer dynamics of performing reactions on the micro scale will give rise to problems not encountered on a large scale. They can be difficult to clean, for instance, and may be unable to work with many gases or insoluble reagents. As the systems are numbered up, reaction behavior can change and control becomes more difficult.J&J's Zhang suggests another limitation. “The reaction has to be relatively fast,” she notes. “If it doesn’t complete within a half-hour or so, it becomes less practical. The throughput is so low that you can only make small amounts of product.”Nevertheless, Zhang is excited by the potential of microreactors. “As we have moved from an evaluation phase of the technology to some successful applications in some real-life situations, interest in the microreactor technology is increasing in the other parts of our development organization,” she says.Even if the bugs and limitations are addressed, microreactors will need some time to really catch on. “It will be five to 10 years before I see them being more potentially mainstream,” says Payne. One reason, he says, is that the technology has not matured yet for its optimal applications.“The barrier in the laboratory to acceptance is fairly low,” says Dr. Anton Nagy, head of Integrated Lab Solutions, a turnkey engineering consulting firm in Berlin. “If you tell guys in the processing plant, ‘This will blow your batch reactor away,’ you get a lot of resistance. They love their batch reactors.”Moreover, Nagy says, it is nearly impossible to simply exchange a batch reactor with a microreactor without having to completely retrofit the feed section and downstream processing operations. “The cost implications and down-time required to do this are substantial and this often impedes implementation,” he says.Nagy says the microreactor community shares the blame for the slow acceptance, because it has been too ambitious at times, always thinking small. “They always thought that smaller was sexier,” he says. Rather, Nagy believes microreactors should be made “as small as possible, but as big as necessary.” As an example, he says that there are many instances in which a microreactor is advantageous, but in which miniaturized pumps, pressure transducers, and mass flow controllers and other peripheral components provide no additional benefit but add substantially to implementation costs.CPC, Inc. figures to be a bellwether firm, in its role as equipment vendor and contract manufacturer (through Synthacon). CEO Schwalbe, who recently moved the company’s headquarters to Cambridge, Mass., to take advantage of research synergies in the Boston area, is betting the timing is right for widespread acceptance of microreaction technology. “The market has just passed the point where the technology’s early adapters have finally confirmed that it is highly worthwhile,” he says.
    Micro Managing

    Dr. Anton Nagy, head of the engineering consulting firm Integrated Lab Solutions (Berlin), offers up some suggestions for companies looking to get their feet wet in microreactor technology.

    • When introducing microreaction technology, aim for applications that target a business-relevant process and have a high probability of success. A success with a demonstrated economic benefit builds momentum to implement the technology.

    • The input of process engineering and technology assessment people is essential and involving them early on speeds implementation at the production level.

    • Consider projects that, when successful at the laboratory bench-scale, easily translate to the process scale. Take the limitations of microreactors at the process scale (throughput, pressure drop, etc) into consideration before choosing the R&D application.

    • Remember that high value-added products, done in low to moderate throughputs, will benefit the greatest.

    • There is currently too much focus on heat-exchanger microreactors. Look at vaporizers and multiphase systems that benefit from high surface-to-volume ratios.

    • Keep in mind that microreactors are particularly powerful for demonstrating a process’s maximum potential, making them valuable for benchmarking the performance of components.

    • Work with microreaction components that are easily manufactured in large numbers. A close and open relationship with a dedicated microcomponent supplier is key to success.

    • Numbering up only makes sense to a point. Process control and commercial benefit can eventually be compromised.
    MAJOR PLAYERS IN MICRO

    The following firms are some, certainly not all, of those pioneering microreactor technology and microfluidics:

    CPC, Inc. (Cambridge, Mass.), www.cpc-net.com — CPC’s CYTOS Lab System and other offerings have had proven successes in multi-step operations.

    Ehrfeld Mikrotechnik BTS (Wendelsheim, Germany), www.ehrfeld.com — The start-up by Dr. Wolfgang Ehrfeld, recently purchased by Bayer Technology Services. The company currently offers a variety of products from various manufacturers.

    Epigem Limited, Inc. (Redcar, U.K.), www.epigem.com — Produces microfluidic chips and the Fluence microfluidic system, a “starter pack” for experimentation in microreaction and analysis.

    FZK (Forschungszentrum Karlsruhe; Karlsruhe, Germany), www.fzk.de — The manufacturing arm of a research center producing, among other things, microchannel devices and ceramic microreactors.

    IMM (Institute for Mikrotechnik Mainz; Mainz, Germany), www.imm-mainz.de — A groundbreaking research institute which produces microreactors and many other miniaturized devices.

    MicroChemical Systems Ltd. (Hull, U.K.), www.microchemicalsystems.co.uk — Started by microchemical pioneer Dr. Stephen Haswell. Offers a variety of microfluidics products and services for high-throughput chemistry and screening.

    Mikroglas Chemtech GmbH (Mainz, Germany), www.mikroglas.de — Specializes in glass and other microreactors, micromixers, and heat exchangers.

    Syrris, Inc. (Herts, U.K.), www.syrris.com — Its AFRICA modular systems can be tailored to any number of manufacturing needs.

    Velocys, Inc. (Plain City, Ohio), www.velocys.com — Customizes a variety of microreactors and devices for industry. Just beginning to focus on pharmaceuticals.


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