New Methods for the PAT Toolbox

Instrument suppliers are moving a growing number of analytical techniques out of the lab and onto the manufacturing floor. As healthcare economics change, drugmakers that once rejected process analytics are embracing it as they look to reduce costs.

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By Angelo De Palma, Ph.D., Contributing Editor

Top drugmakers have always sought--at least in principle--some sort of process analytic capability. However, vendors and manufacturers agree that without FDA's prodding, nothing remotely like the current push toward process analytical technology (PAT) would ever get off the ground. "Manufacturing was always viewed as drug discovery's ugly stepchild," says Andrew Malcolmson, director of business development at Malvern Process Systems (Southborough, Mass.).

As a developer of particle size measurement equipment, Malvern has offered in-line laser diffraction analyzers for thirteen years, with more than 400 installations worldwide. "But until recently pharmaceutical companies wouldn't touch them," says Malcolmson.

Now, as healthcare economics change, drugmakers that had once rejected the idea of process analytics are embracing it as they look for new ways to reduce manufacturing costs. FDA's endorsement of analytics provides a much greater incentive.

Not only is the Agency advocating PAT, but it's also suggesting that users take a systems approach to implementation. "PAT is not just in-line analyzers, it's about process understanding," explains Chris Watts, Ph.D., one of FDA's PAT point people at the Center for Drug Evaluation and Research (CDER). "PAT is about designing, understanding, and controlling operations," he says. "It's a thought process."

So far, pharmaceutical manufacturers' responses to FDA's PAT initiative range from doubtful to enthusiastic. Watts dismisses doubters' concerns. "PAT is receiving top-down support, right from the Commissioner," he promises. Companies should no longer be thinking strictly in terms of process validation, he adds. "Rather, they will have active controls on the process and validate those controls," he says.

Light Induced Fluoresence, used to determine powder blend uniformity, will soon be available commercially. Shown here, the technique is used to analyze blending and tableting operations in a CAMP pilot facility.

More Knowledge Required

Despite FDA's pronouncements and the urgings of process analytics experts, a knowledge gap remains among manufacturers regarding PAT and its goals, says G. Patrick Stahly, Ph.D., chief operating officer at SSCI, a consulting and analytical services provider in West Lafayette, Ind. A key goal is quality by design. Another often-stated goal is deeper process understanding. However, a good grasp of process fundamentals is essential at the offset of any PAT project, Stahly says. "Manufacturers need to understand which process factors are critical to obtaining quality product and then control and/or monitor those factors."

SSCI provides services for studying solid materials' crystallization and polymorph behavior. The company employs the usual spectroscopic tools for monitoring nucleation, crystal growth rates, and polymorph composition--understanding which factors are critical to crystallization, picking the right modality for monitoring them, and deploying that technology within the process. "Unless you understand the process, all the monitoring in world won't do you any good," he says.

The (Un)usual Suspects

FDA's open-mindedness about specific analytics may be liberating, but presents processors with choices they may not be used to making. On the technology front, several PAT-worthy technologies already are established, particularly infrared (IR) and near-infrared (NIR) spectroscopies. Materials processors have used IR/NIR, usually through fiberoptic probes, since at least the late 1980s.

Although use of IR/NIR is expected to grow, alternative process analytic developments are emerging from techniques that are less familiar to bench organic chemists, plus methods that haven't hit big-time real-time analytics markets (box).

Ionics (Boulder, Colo.) has been offering process analytics, under the rubric "Process Analytical Instrumentation," for about twenty years. The firm's specialty, total organic carbon (TOC) measurement, is employed in wastewater, semiconductor, and chemical industries in real-time but in pharmaceuticals only remotely, off-line. "Pharmaceuticals are lab-centric," explains Nissan Cohen, environmental marketing manager. "Back in 1993, when we began in this business, pharmaceutical companies didn't even want to look at on-line or in-line analyzers."

So Ionics found a way to turn an off-line test into a "fail-safe on-line method," according to Cohen. Fitting an existing process with a TOC analyzer requires a quarter-inch takeoff line and "an electrical box," although, according to Cohen "pharmaceutical manufacturers will make a bigger project out of it because of their need for installation qualification, operation qualification, and performance qualification."

Ionics also developed a methodology it calls EWPS, for Exponentially Weighted Process Statistics, which provides a data filter based on the age of the information. For example, a measurement taken every second will be considered extremely relevant to current process conditions, but one taken an hour ago will be considered much less relevant. "The more frequent the information, the more reliable it is for controlling processes."

Raman Makes Inroads

Like most instrument companies active in pharmaceutical PAT today, Kaiser Optical Systems' (Ann Arbor, Mich.) activity in process analytics predates FDA's interest by many years. Kaiser claims to have built the first Raman process analyzer in 1993.

Although less used than IR and NMR, in a process setting Raman does some things quite well. Unlike IR techniques, Raman is non-invasive, requires no sample preparation, and may be combined with microscopy for studying small particles or differentiating among crystalline polymorphs. Raman also complements IR: Where the latter detects changes in molecular dipole moment, Raman observes changes in polarizability--for example, the symmetric stretch in carbon dioxide. Raman's non-invasive, non-contact analysis makes it ideal for processes where sampling is impossible or inconvenient.

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