Handle With Care

SMALL PHARMACEUTICAL companies almost always need to hire a chemical manufacturer to get a new drug to market, and in that regard, NicOx's contract with DSM is business as usual. The details of the collaboration, though, are anything but. In two industry firsts, the partners will use a microreactor-based process to make an arthritis drug that is the first in a new class of cyclooxygenase-inhibiting nitric oxide donators.

The drug, naproxcinod, is the nitroxybutyl-substituted form of naproxen, the well-known nonsteroidal anti-inflammatory drug. Containing a nitrate group, the substituted compound is difficult to make. But once ingested, it provides the expected analgesic effect and also slowly releases NO to act as a messenger molecule in the body. NicOx, based in France, expects to file for regulatory approval by midyear.

Microreactors installed at DSM's site in Linz, Austria, will enable the safe and cost-efficient production of large quantities of a nitrated intermediate. Nitration reactions must be handled carefully because they generate products that can violently decompose. Strict control of reaction conditions is needed to make the nitration selective and to allow extraction and neutralization of the desired nitrated product.

In a traditional batch-manufacturing process, these constraints would call for highly dilute and biphasic conditions in specialized safety equipment. Occurring instead in a continuous flow through millimeter-sized channels, the microreactor process transfers heat efficiently and limits the residence times of unstable materials. Working with glass specialist Corning, DSM designed a microreactor system that combines three key process steps—the nitration reaction, neutralization, and workup—and ultimately generates a few hundred tons of product per year.

Within a "few inches" after the starting materials are mixed, the process is already in a safe mode, explains Michael Hartmann, senior vice president for new business development at DSM Pharma Chemicals. "It's very controlled, and you never have a lot of dangerous material around in the first place," he says. "It also is very fast and therefore cleaner, and the yields are better, which contributes to productivity without huge amounts of equipment."

When NicOx sought a manufacturing partner, it wasn't looking for a high-tech answer but rather a supplier that could manage the difficulties of making nitrated products, says Gavin M. Spencer, the French firm's vice president for business development. "Our decision was driven by DSM's capability, flexibility, and ability to meet NicOx's needs."

DSM was willing to take on the project and deliver on the timeline NicOx required, Spencer notes. "They also demonstrated that they had the knowledge and skills in manufacturing to take the process from the small scale we had already developed to the scale we'll need when naproxcinod is on the market."

Moreover, Spencer believes DSM understood NicOx's needs as a small firm preparing to launch its first product. "We don't have unlimited funding and are not able to do everything that a big pharmaceutical firm can do," he says. "DSM has been very responsive and accommodating in dealing with questions and issues as they arise and in progressively structuring our work with them to allow us to achieve what we need."

Hartmann agrees that transparency between the collaborators was important, especially when it came to developing new technology around a new product. The project started with running a traditional small-scale batch process to produce a few kilograms of material. "There definitely were issues with scalability and cost-effectiveness," Hartmann says. "At the very beginning, we saw an opportunity to use microreactors and actively developed a process in the lab."

AFTER AN EXCHANGE of information between project teams and some feasibility work in late 2007, DSM proposed using microreactor technology, at least as a second-generation process, Hartmann says. Along with the safety and processing advantages, he says, NicOx appreciated how quickly large amounts of material could be made available.

When scaling up a microreactor-based process, scientists "number up," or add more identical parallel reactors, rather than reengineering the process to work in larger vessels, Hartmann explains. As a result, "the development efforts and investment are much less," he says. After about six months' work, DSM had a pilot-scale process that could supply hundreds of kilograms.

In November 2008, NicOx reported positive Phase III trial results for treating osteoarthritis with naproxcinod. A week later, DSM and NicOx signed a long-term manufacturing agreement for the active pharmaceutical ingredient. To conserve resources, NicOx ended a supply contract with fine chemicals maker Archimica, which had met its obligations at its Springfield, Mo., site. DSM will now supply commercial quantities of naproxcinod to support product launch.

EXECUTIVES at NicOx and DSM say their close relationship on both technical and business levels helped them move from feasibility studies to large-scale production in about 18 months.

"DSM is turning out to be a very strong partner in addressing the challenges that we come up against as we work toward filing for regulatory approval," Spencer says. "Obviously they are heavily implicated in this work over the next few months to complete the chemistry parts of the dossier and having their site ready for inspection."

DSM's work with microreactors dates back at least a decade, and the company has used them for manufacturing fine chemicals. But DSM believes that the system developed with Corning for naproxcinod will be the first industrial-scale use of microreactors for making a pharmaceutical under current Good Manufacturing Practices.

The Food & Drug Administration should soon get its first look at the new production technology. Hartmann believes the approach will be consistent with agency initiatives encouraging "quality by design" because the precise control of reaction processes translates into control over product quality.

Meanwhile, NicOx is looking for a large drug company partner to help commercialize a drug that has blockbuster potential. The market research firm Datamonitor suggests that the launch of naproxcinod, expected in 2010, will help the market for osteoarthritis drugs grow more than 3% per year to reach $5.5 billion by 2017.

Just six years ago, naproxcinod's future was in doubt. In 2003, NicOx's partner, AstraZeneca, returned the product to NicOx when, despite good safety and efficacy profiles in Phase II trials, it failed to show a desired gastrointestinal benefit compared with existing cyclooxygenase-2 (COX-2) inhibitors, such as Merck & Co.'s Vioxx.

Within about a year, however, Vioxx was withdrawn over concerns about blood pressure and cardiovascular safety. Pfizer's Bextra was taken off the market in 2005. These events were a boon for naproxcinod because the NO it releases helps maintain normal blood pressure and reduce vascular inflammation. If approved, naproxcinod could end up as the only brand name drug to compete with Pfizer's Celebrex, which had sales of about $2.5 billion in 2008.

NicOx's drug development platform involves taking known drugs and grafting NO-donating groups onto them via chemical linkers. This process creates patentable entities that it hopes have improved safety, efficacy, or activity. Among its 10 programs, NicOx is working on NO-donating antihypertensives with Merck and ophthalmology drugs with Pfizer. Naproxcinod may be only the first such drug to emerge, along with a new technology to make it.