CASE STUDY
CV Therapeutics: Building A Relationship With Dow
CV Therapeutics reached a major milestone last month when the Food & Drug Administration accepted its New Drug Application (NDA) for ranolazine, a potential treatment for chronic angina that works by partially inhibiting fatty acid oxidation. If approved, the drug will represent the first new class of antianginal therapy in more than 20 years.
The FDA acceptance is the latest in a string of successes for the 12-year-old firm. After acquiring ranolazine from Syntex in 1996, CVT has steadily moved the drug, trade named Ranexa, through the clinical trial process, providing angina sufferers with hope for a new treatment and convincing investors that CVT stock is a good buy.
It’s not important to angina patients or investors that CVT sources the drug’s active ingredient from Dow Chemical. But it’s of great importance to employees like Peter M. Strumph, vice president of operations. Palo Alto, Calif.-based CVT has no commercial production facilities and relies on Dow for ranolazine supply. For Strumph and his colleagues, it is crucial that the facilities where its lead drug is made pass rigorous FDA inspections.
CVT’s relationship with Dow began in 1998. The purchase from Syntex had included ranolazine manufactured for previous clinical trials, and CVT quickly contracted with another third party for supplies to conduct further trials. But as the drug continued to perform, Strumph’s team began to look for a contractor that would be able to carry it through late-phase trials and into commercial production.
CVT is unique in the pharmaceutical world in that its focus is on only one therapeutic area—cardiovascular disease. The company also develops only small-molecule drugs—partly, Strumph notes, because it has more leverage in the competitive small-molecule manufacturing market than it would if it were developing protein-based pharmaceuticals, where a handful of contractors dominate.
In keeping with its small-molecule outsourcing strategy, the company set up four hurdles for prospective manufacturing partners. The first is a successful regulatory/quality track record. “The lack of a good regulatory and quality history—or the impression on our part that a company isn’t willing to continually invest in its quality systems—is a go or no-go criteria,” Strumph says.
The second is an appropriate equipment fit. The third is that a supplier have process development and analytical capabilities. CVT operates a 20-employee chemistry laboratory where it conducts route selection synthesis and bench-scale manufacturing, but Strumph says the firm looks to its vendors for assistance with process development.
The fourth—and perhaps highest—hurdle is that the supplier has successfully navigated the complete process of developing and manufacturing a new pharmaceutical chemical. “We want manufacturers that have worked in clinical development—done process development, documented that process in an NDA, and defended their quality systems in a preapproval inspection,” Strumph says. “Those are all steps we need to go through, and we want to make sure our contract manufacturer has gone through them as well.”
Dow was one of a handful of firms to emerge at the end of this winnowing process and, after subsequent interviews and negotiations, was hired by CVT. Samantha Janisse, CVT associate director for process development and manufacturing, became CVT’s main liaison with Dow, and the multiyear task of process development and production scale-up began.
Although Janisse has a primary counterpart at Dow—Program Manager Jeff Legge—she explains that CVT takes pains to develop and maintain a relationship with multiple points of contact. “We wanted quality control to talk to quality control and process development to talk to process development,” she says.
Ranolazine development took place in three main stages.
The first was a six-month effort that started with transfer of a technical package and ended with production of initial quantities at Dow’s Midland, Mich., site under current Good Manufacturing Practice conditions. The second leg, also about six months, took the molecule through process development to pilot production. The third, nine-month leg included additional development work, commercial scale-up, and manufacturing.
Janisse says the multistep commercial synthesis of ranolazine is “very straightforward,” thanks in part to streamlining efforts by Dow chemists and engineers during the development effort. She adds that Dow’s materials processing expertise was crucial to optimizing the manufacturing process.
Because ranolazine is a fairly high-dosage drug intended for a chronic disease, it must be made at facilities that can handle large-volume manufacturing. Indeed, Dow is conducting the final synthesis step in 4,000-gal reactors, producing metric tons per batch.
Strumph says CVT is open to working with smaller contract manufacturers on future lower-volume products, but he discounts the notion that a smaller contractor better understands or interacts with an emerging company like CVT. “There’s a lot to learn from a big company like Dow,” he says. Janisse adds that the melding of CVT’s creative, small-company culture with Dow’s well-defined, work-process-oriented mind-set can pay dividends for both. “It improves Dow and it improves CVT,” she says.
Strumph advises other contract manufacturers seeking to do business with CVT to openly lay out their regulatory history and present what they can and can’t do. “Through the selection process we find out a lot of information. Small inconsistencies or an over-representation of capabilities take away a level of trust,” he says. “I like when the story stays the same from beginning to end.”
He’s wary of relationships in which contractors provide early-phase synthesis work as a loss-leader for commercial-scale work later on. “We don’t mind paying as we go, because then we can be very clear about defining the development work that we do and the ownership of intellectual property,” Strumph says. “Sponsors that aren’t willing to pay as they go and hold out future commercial business as a carrot can end up with a lot of issues a few years down the road.”
In exchange for a contractor’s honesty and effort, he says CVT will bring people to the project who can work well with others both inside CVT and outside the organization.
“We try to get our manufacturers to share our pride for the science, the clinical results, and the positive impact the drug can have for real patients,” Strumph says. “We endeavor to blur as much as possible any boundaries between the two organizations. You can’t write this into a contract, but it’s as much of a success driver as any technical skill set.”
It’s a lofty goal, but Strumph says he has a very down-to-earth reason for setting it: He wants everyone at the contractor—from the plant operator to the bench chemist to the lawyer negotiating the contract—to see CVT’s project as their number one priority.
“I want all the people involved to feel a sense of ownership in our project,” he says. “In the end, we get better service and a better product.” |
