A Mercury Chelator

The effort to develop the compound as a mercury poisoning therapy accelerated in 2010 when the company received notification from FDA that it couldn’t market NBMI as a nutritional supplement until it underwent the full drug approval process. CTI determined that the fastest track would be to pursue approval by the European Medicines Agency prior to submitting to FDA. It has filed an Investigaional Medicinal Product Dossier with EMA—the equivalent of a New Drug Application with FDA—and hopes to begin clinical trials later this year in Sweden.

Preparing for trials meant a shift to production that complies with current Good Manufacturing Practices (cGMP), which is well within PCI’s purview. But it also meant going back to the drawing board on process design and the addition of a battery of analytical testing.

Preparing for submission to EMA and FDA meant really digging into the molecule, according to Edward S. Price, PCI’s chief executive officer. “It was not well understood what the FDA was going to require for a compound such as this,” he says. “The main starting material is cysteamine hydrochloride, which is basically an amino acid and found naturally. So it has attributes that could qualify it as a natural product.” But there is also a lot of chemistry involved in its manufacture. “The project has had a number of technical challenges.”

The primary challenge was the removal of impurities to a level that meets cGMP standards. PCI needed to identify, extract, and analyze impurities that were close in composition to the product itself, Price says. Purification was complicated by dimers and trimers of NBMI that were formed in preparing the analytical batches.

In the face of these challenges, PCI’s analytical group took the catbird seat.

“Analytical and synthesis have to work hand in hand,” Price says. “You don’t know if your synthesis guys are doing a good job if you can’t see what they’re doing.” PCI has significantly boosted its analytical chemistry staff over the past four years, Price says, and the firm now has nearly as many analytical chemists—about 20—as process chemists.

Mehdi Yazdi, director of analytical chemistry at PCI, who joined the company in 2011, says the firm’s work for small clients such as CTI is picking up. “Since I have been here, we’ve revamped the whole analytical department,” Yazdi says. PCI has replaced nuclear magnetic resonance testing with high-performance liquid chromatography, he notes, a shift that proved crucial in developing NBMI to FDA standards.

Haley says he has been impressed with PCI’s responsiveness on a project that has provided the contract manufacturer with only sporadic work so far. He is hoping, as is Price, that demand for the compound will increase.

Given FDA’s ramp-up in safety demands, the road PCI took on clinical quality is increasingly being traveled, according to Price. He notes that regulators in recent years have banned 300 drugs commonly used 40 years ago. Notices to nutritional supplement suppliers requiring them to attain full drug approval, such as the one received by Haley’s company, are becoming more common, he says.

Meanwhile, back at the University of Kentucky, Atwood says he is pleased with developments at CTI. He also notes that NBMI’s use in environmental remediation is still being pursued by a firm called Covalent Research Technologies. An initial attempt to use NBMI in the removal of mercury from flue gas in synthetic fuel plants did not result in cost-effective technology, but Covalent retains the license for NBMI and is working on a water filtration system for the removal of mercury and arsenic(III).