Life-saving pharmaceutical drugs sometimes run out faster than manufactures can renew supplies. Now, researchers have developed a refrigerator-sized machine that could make such shortages a thing of the past. Instead of making drugs in huge batches, the device is able to synthesize—one by one and as they are needed—thousands of doses per day of a variety of pharmaceuticals. Such machines could someday help pharmaceutical companies meet unexpected surges in demand and help health officials respond to disasters and medical emergencies worldwide by producing medicines when and where they are needed.
The process of making drugs is normally long and involved. Chemists and engineers must not only figure out the suite of chemical reactions needed to produce their desired compounds, but they must also purify them, add inactive ingredients to stabilize them, and have the mixtures pass approval by regulators. This process can take years. One upshot is that pharmaceutical companies tend to make their drug compounds in large batches, stockpiling the starting materials in sites around the world. Such batch manufacturing works well for big-market drugs with a steady demand like Lipitor and Sudafed. But the process often isn’t economical for making so-called orphan drugs that are needed only in rare cases, such as a compound called bis-choline tetrathiomolybdate that is currently being studied to treat Wilson disease, a rare heredity disease that leads to the accumulation of toxic levels of copper in the body. Moreover, if major production facilities go offline, supplies of even more common drugs can dry up quickly. According the U.S. Food and Drug Administration, there are dozens of such shortages at any given time.
To avoid such problems, researchers have been working to develop automated chemical syntheses using a setup called “flow chemistry.” Rather than running reactions in batches one after the other, flow chemists pass starting compounds through thin, snaking tubes and carry out the needed series of reactions one after the other as the compounds travel down the molecular assembly line. Such continuous manufacturing can speed the production of thousands of doses of a drug from months to days and eliminate the risk of intermediate compounds undergoing unwanted reactions as they wait for the next synthetic step to be carried out.
Two years ago, for example, researchers led by chemist Timothy Jamison and chemical engineers Klavs Jensen and Allan Myerson at the Massachusetts Institute of Technology (MIT) in Cambridge unveiled a boxcar-sized flow-chemistry setup that produced large amounts of a blood pressure medicine called aliskiren hemifumarate. Such setups could be useful for drug companies to better control the production of their medicines. But the apparatus was too large and cumbersome to be moved around to different locations with ease.
For their current experiment, the MIT researchers set out to shrink their apparatus and make it more versatile. They designed new compact flow chemistry setups to carry out the dozen or more steps needed to synthesize different drugs and formulate them as medicines. The result, reported today in Science, is a refrigerator-sized apparatus that can be reconfigured to produce any one of four different liquid medicines, an antihistamine, an anesthetic, an antidepressant, and an antianxiety drug.
Such relatively portable flow-chemistry setups could dramatically improve efforts to ensure medicines are available around the world when needed, says Tyler McQuade, a chemist and program director of the Battlefield Medicines program at the Defense Advanced Research Projects Agency in Arlington, Virginia. “This is an excellent first step.” None of the four medicines produced in the current experiment are particularly large or complex molecules, McQuade adds. But he notes that there are hundreds of other drugs with a similar level of complexity that might be produced with such a setup. That could allow large pharmacies to ramp up production of drugs in response to surging demand.
In the future, drug synthesizers could also make it cheaper and easier to produce drugs when only small volumes are needed, McQuade and others say, such as in clinical trials and to combat rare diseases, such as cystic fibrosis and narcolepsy. Portable drug synthesizers could be vital in combating localized outbreaks of diseases such as influenza, in which demand for a particular drug spikes, says Martin Burke, a chemist at the University of Illinois, Urbana-Champaign. “It’s hard to predict when an outbreak will occur,” Burke says. Drug synthesizers “can increase or decrease production of medicines when there is a need.”