Preventing Development Bottlenecks---It's All In The Timing

Successful pharmaceuticals come of age much as humans do. Discovery is all about wonder and excitement. Painful, plodding development teaches valuable lessons and is then eclipsed by the euphoria of approval and scaleup. Each stage, from the synthesis of milligrams to grams, to the manufacture of hundreds of grams to tons, adds an order of magnitude to the complexity, investment and commitment required to launch a drug.

When should you, as manufacturing experts, be involved in a pharmaceutical development program? The answer will depend on your organization's resources and its experience and comfort level with similar manufacturing processes. However, early is typically better.

Because of the high attrition rate for Phase I/II medications, for most products it would be a "monumental waste of time" for manufacturing to get involved during Phase I, according to Peter Green, Michigan-based VP of pharmaceutical sciences for Pfizer Inc. (New York City). "If everyone gets off track and starts worrying too early about manufacturing, R&D can actually be delayed," says Eric Musser, chief technical officer at Atlanta-based software supplier Ross Systems.

However, most observers agree that manufacturing should get involved in the development process as soon as possible" before drugs enter human trials, or once developers begin discussing dosage forms, says Tarun Patel, Ph.D., vice president of technical operations for Cardinal Health, Somerset, N.J. "Too often, dosage form decisions are made by marketing or scientific personnel who have only a vague notion of what it takes to make the new product on a large scale."

When a dosage form is altered, Patel points out, recipe changes often require new machinery and equipment. "A change as simple as a different color tablet could make an existing machine vision system obsolete," he says. Manufacturing helps distinguish between the frivolous and the necessary changes, whether they're easy or difficult.

Can manufacturing ever be called in too early? Patel thinks not, provided production's involvement is appropriate for a particular stage of development. "It's never too early to begin the discussion and technology transfer."

Late is always more expensive than early, agrees Dr. Michael Breggar, national leader, life sciences regulatory at Deloitte, Philadelphia. "If you start something early, the worst thing that happens is you have too much information. When you're late, you often spend a lot of time catching up."

Because of regulatory issues and high material requirements, Phase III studies form a natural boundary between development and manufacturing. Counting backwards from the anticipated start of Phase III trials, companies can more or less estimate when they need to start thinking about a robust, transferable process, new capacity and human resources, and vendor/supplier relationships to support a product launch.

However, timing is everything. By Phase III, a process is more or less set, notes Warren Levy, Ph.D., CEO of Unigene Laboratories, Fairfield, N.J.. However, if two to three years of development are required, the real dividing line comes much sooner, during early clinical trials or even late in preclinicals. "Unfortunately many companies wait until much later to address critical manufacturing concerns," he says.

Chemical, Manufacturing and Controls (CMC) approvals often compete with clinical trials as the rate-limiting development step. Companies would do well not to dismiss CMC as a mere "engineering project," according to Michael Glembourtt, vice president of business development at Nektar Therapeutics, San Carlos, Calif. "Nonstandard products or drugs that require a device or unusual delivery system often entail substantial manufacturing equipment development. In those situations the CMC section may run neck-and neck with clinical studies."

Nektar, which is developing inhalable insulin with Pfizer, only works on "unusual" drugs, which explains Glembourtt's partiality to very early manufacturing involvement. Nektar's other formulation/delivery technology, PEGylation, chemically modifies drugs with polyethylene glycol residues to improve the pharmacokinetics and absorption. "We wouldn't be involved if standard formulations, dosage forms, or delivery methods were appropriate," Glembourtt admits.

"There are many horror stories of sponsors struggling to satisfy demand for approved drugs," says Pfizer VP Green. Sometimes products simply sell better than anticipated, but even that situation should not arise, says Green. "Usually material shortfalls occur because the interface between development and manufacturing wasn't properly handled, or the process wasn't robust enough. Even if you've sorted out your manufacturing problems, you've already developed a bad reputation and most likely someone else has grabbed your market." Pfizer emphasizes early manufacturing group involvement through a process it calls "codevelopment."

By the end of Phase II, Pfizer has a pretty good idea how its product is doing, which is when manufacturing is summoned. "There are cases where we call them earlier," says Green, "especially if the product involves some kind of technical complexity, for example a device-based drug or novel delivery system. But if we're working on a tablet with no special chemistry or formulation, we may go a bit beyond late Phase II."

Pfizer employs manufacturing-development teams consisting of two or three people from R&D and five or six manufacturing specialists. The team is initially headed by R&D, but leadership gradually transfers to manufacturing. The research/development group generates a dossier describing the product and process, preliminary expectations for demand and economic forecasts.