By Paul Thomas, Senior Editor
(Note: This is the second of four summaries of talks given at a continuous manufacturing symposium at AAPS 2010 in New Orleans. The first can be found here.)
Last week at AAPS 2010 in New Orleans, Brian Marquardt, PhD, of the University of Washington’s Applied Physics Laboratory, discussed his group’s latest work in developing, and adopting, continuous microreactor technology for the synthesis of drug substances. The key focus of Marquardt’s work is the understanding of analytical sampling for online applications, and applying analytics directly to continuous processes—“for better understanding, better control, and ultimately better product quality.”
Marquardt reminded the audience of the benefits of using advanced flow reactors for drug synthesis. (Note: He prefers “flow reactor” to “microreactor”, joking: “I don’t like to use the term microreactor . . . when I do, people think that you can’t actually see them, whereas in fact you can see them quite well!”) There are many benefits, but foremost among them perhaps is the ability to easily increase production volumes. “If we can get to production, can we eliminate chemical engineering production problems related to scaling up batch systems? Can we increase production through the use of many parallel microreactors to achieve volume? If we can make 10 tons per year on one system, we can make 100 tons per year by putting these reactors side by side. It is scale out versus scale up.”
Marquardt also discussed how continuous flow reactors lend themselves to improved and expedited analytics. He described his team’s efforts to do simple kinetic studies to determine the impact of temperature on a reaction. In batch mode, seven different studies were performed and required roughly a week’s time. In continuous mode, the same information was obtained in roughly 150 minutes using real-time Raman data. “We can graph, in real-time, how Raman peaks change at different temperatures and understand the optimal temperature for the reaction.” Using other measurements and data, Marquardt and colleagues use “continuous analytics” to run design experiments continuously. The main point: “Continuous reactors with analytics allow for fast optimization of design space.”
Challenges remain the use of advanced flow reactors, he acknowledged. They include:
- Education. Within academia, very little pharmaceutical chemistry is taught regarding continuous processes, and instead still emphasizes batch.
- Sampling and screening. “We can’t just take our large analytics from our production facilities and bring those to bear on a small channel,” Marquardt said. “We need to develop analytics for the scale of continuous processes. Once that’s done, we’re able to produce massive amounts of data.”
- Analytical characterization. “Once we have all these components [to characterize a reaction, such as Raman, NIR, FTIR, and so on], which one do we pick?”
- Data handling. Challenges range from sensor “fusing” to multi-sensor modeling
- Process modeling and feedback control
- Process optimization, or the pursuit of “feed forward” control. “Process optimization is not feedback!” he stressed. “We understand if we feed quality materials in that we can actually predict product quality, not actually chase product quality.”
Marquardt also touched upon the ongoing work at the University of Washington to further NeSSI, the New Sensor/Sampling Initiative, a cross-industry effort to develop standardized, “Lego-like” flow components, from sensors to electrical and communication devices, to allow for “plug-and-play” integration of multiple devices. (NeSSI is sponsored by the University’s Center for Process Analytical Chemistry.) “We’re able to populate the sensors we need by expanding in length, whereas we can’t expand by applying more sensors to the top of a traditional reactor,” he said.
Marquardt ended his talk by summarizing pilot projects that his group is currently conducting with FDA using various new technologies on the market, including the Corning Advanced-Flow LF continuous flow system and analytical devices such as the Mettler Toledo React-IR, the Thermo C2V Fast Micro GC. (Here’s a video from earlier this year of Corning’s Bill Seiderman demonstrating the reactor.) “We will do simple chemistries—our focus is on model development, process optimization and, eventually, continuous process control.” While current projects center around glass flow reactors, future work will also involve Hastalloy and fluoropolymer reactors to increase the amount of chemistries that can be tested.
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