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Better chemistry: To produce drugs in a continuous-manufacturing method, MIT engineers had to develop several new pieces of equipment, including this reactor, which enabled a faster reaction and eliminated the need for a toxic solvent.

Despite the huge amounts of money that the pharmaceutical industry spends on drug discovery, it is notoriously old-fashioned in how it actually makes its products. Most drugs are made in batch processes, in which the ingredients, often powders, are added in successive and often disconnected steps. The process resembles a bakery more than it does a modern chemistry lab. That could be about to change.

This summer, a team of researchers from MIT and Swiss pharmaceutical company Novartis proved that a continuous production line that integrated several new chemical processes and equipment specially designed for the project could make a higher quality drug faster, and in a less wasteful manner.  This more nimble method may even create more opportunities in early drug discovery. In their continuous-manufacturing process, raw ingredients are fed into a parade of heaters, spinners, extractors, and sensors that relay the intermediates through chemical reactions. At the end, round, coated pills fall out.

Earlier this year, Novartis CEO Joseph Jimenez said that his company plans to build a commercial-scale continuous-manufacturing facility by 2015 (see “The Future of Pharma Is Incredibly Fast”). Other pharmaceutical companies, including Pfizer, the world’s largest, have invested in research to develop their own continuous-manufacturing technologies. But the success of the MIT collaboration suggests that Novartis may be the first to use it for production.  

Moving from the batch method to the continuous method requires new kinds of reactions and equipment. While some segments of a batch process may themselves be called continuous because they are constantly running, the breakthrough in the MIT-Novartis collaboration is that each step of the process is fully integrated. The products of one reaction flow into the next, typically through small-volume tubes. This enables drugmakers to use certain kinds of chemical reactions that aren’t feasible in the large vats used in batch processing, such as those that require higher temperatures or that happen very rapidly. The method could bring new types of molecules into drug discovery.

Making the switch from batch to a fully integrated, continuous production meant that even the way a pill was formed had to be tweaked. The experimental system built at MIT was a jumble of wires, heaters, filters, mixers, and tubes, all enclosed in a 24-foot-long and eight-foot-wide clear plastic case. It could produce a drug that would typically have to be made in multiple facilities. At a few spots, technicians could reach in and adjust equipment or add material, but for the most part, the system was controlled by software that was fed details on temperature, pressure, and other reaction parameters by the many sensors that keep a close eye on the chemistry inside. The MIT system was made to produce one specific drug, but the researchers say the system is adaptable—different pieces of equipment could be swapped in to create a different final product.  

The experimental plant at MIT has been dismantled, and the technology is now being further studied at the Novartis headquarters in Basel, Switzerland. The hope is that the continuous-manufacturing method would be more cost-effective. One benefit could be a significantly reduced time between issuing a manufacturing order for a product and having the finished drug in hand. This would be especially helpful during clinical trials, in which companies have to balance the need for sufficient drugs for upcoming trial stages with the risk that most of those drugs will end up failing. The faster production times promised by the continuous method—at least 10 times speedier in the MIT experimental facility—and the smaller scale of production would be much better suited to the uncertain nature of drug development.

The speedier manufacturing could also reduce the risk that pharmaceutical companies face when bringing a new drug to market. “When you launch a new drug, there’s often a lot of uncertainty in demand. Forecasting is very tough in the business,” says Gary Pisano, a Harvard Business School professor who specializes in life science manufacturing. “If you have a small amount of production and the [drug’s sales] takes off, then you are short, and ramping up will be slow. But if you’ve got a big plant for that drug and if it is not successful, then you are stranded,” he says.

The method could also reduce costs, because continuous facilities can be much smaller and require less energy and fewer raw materials. The smaller amounts of material used in continuous also demand more control over reactions, which, in the end, may ensure a higher quality final product. If you are running a batch process over time and end up with hundreds or thousands of gallons of a chemical at a certain step, you can in some sense “mix away your mistakes,” says MIT chemical engineer Richard Braatz. But the small volumes and fast reactions that typically occur in continuous pharmaceutical manufacturing require that higher product quality requirements be built into the design of the control system.

Yet despite all its benefits, it may be a struggle to bring this new method of drug manufacturing into widespread use. “People have talked a lot about the idea of continuous-flow manufacturing in pharmaceuticals but there’s not been much progress,” says Pisano. “A lot of companies were very conservative about trying anything radically new with their manufacturing,” he says. The batch method, while it has its shortcomings, was tried and true. “Finding a more efficient and effective way to do manufacturing was not high on the priority list,” says Pisano.

This resistance to change is also due to a lack of financial pressure. “For decades, these inefficiencies of batch processing have been masked by large margins earned by blockbuster drug sales, but now the pharmaceutical business model is changing,” says Salvatore Mascia, project manager for the Novartis-MIT Center for Continuous Manufacturing. “The combination of our new technologies with an end-to-end integration strategy will allow production of pharmaceuticals on-demand, with benefits in term of speed, quality, and cost,” he says. As revenues continue to decline for many companies and they move toward more targeted therapies with smaller markets, producers are showing interest in continuous manufacturing.

Allan Myerson, an MIT chemical engineering professor, says the drug industry’s engineers have long understood the potential efficiencies of continuous manufacturing, but never took it seriously because of the relatively small scale at which drugs are produced. “The difference in pharma is that they make so many different products,” says Myerson. “But there is much more economic pressure on pharma now to reduce manufacturing costs.” The MIT-Novartis collaboration demonstrated that companies could use the techniques of continuous manufacturing with only a small facility. “There’s a lot of potential financial as well as environmental benefits,” he says.

In addition to cost savings, continuous manufacturing could also provide benefits in manipulating the chemistry. Take, for example, the ability to use light-dependent reactions, which could give medicinal chemists more options of molecular structures to use when creating new candidate drugs. In batch processing, light cannot efficiently shine through the large volumes of material used, says Tim Jamison, an MIT chemist. The volumes of chemicals used in the team’s continuous system, however, are smaller and flow through tubes that enable a more even light exposure. Other kinds of reactions—those that produce dangerous chemical intermediates or that run very quickly, are more amenable to continuous. “One of the most exciting aspects is that this could open up new families of chemical structures that really aren’t viable currently and therefore expand treatments we have available for various diseases,” says Jamison.

The pilot facility was built to produce one particular compound. Now, the 11 MIT groups involved in the collaboration continue to find new reactions and tools so that other drug compounds can be produced in the automated, continuous-flow manner. “Traditionally, the industry has not been focused on manufacturing, but there’s a lot of momentum now,” says project director and MIT chemical engineer Bernhardt Trout. “We understand we have to make a long-term commitment to get this started.”

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Credit: Novartis-MIT Center for Continuous Manufacturing

Tagged: Biomedicine

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