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Process Analytical Technologies 101

Drugmakers and instrumentation vendors share best PAT practices

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

The U.S. FDA's Process Analytical Technology (PAT) initiative promises to bring pharmaceutical manufacturing into the 21st century by automating real-time measurement, integrating data with control systems, and providing levels of process understanding comparable to those that the chemical and semiconductor industries have enjoyed for decades.

The initiative lags leading companies' efforts in this area by years, and real-time monitoring in other process industries by decades. Large, established manufacturers enjoy a comfortable lead in PAT deployment, but the pharmaceutical industry as a whole has a long way to go.

Strictly speaking, PAT encompasses more than just the adaptation of traditionally laboratory-bound analytical techniques to manufacturing environments,but that's where much of the initiative's emphasis has been placed to date. Today, these PAT installations come in three basic flavors.

• In-line sensors or probes are in direct contact with process materials inside the reactor and transmit signals outside.
  
• On-line analysis diverts process material to a connected analysis loop, analyzes it, and returns it to the vessel.
  
• At-line measurements employ laboratory-type analyzers, but require sampling and sometimes human intervention.

Although FDA mentions specific technologies in its PAT pronouncements, the Agency has not endorsed any analytical method, or attempted to dictate which analytics are appropriate for specific processes or equipment. Rather, FDA expects manufacturers to base PAT decisions on a scientifically-driven, risk-based need to design, analyze, and control manufacturing to improve process understanding. "Any methodology can be applied, as long as it accounts for these three factors," says Nissan Cohen, environmental marketing manager at Ionics Instruments (Boulder, Colo.). "Theoretically, any type of analysis is workable under PAT guidelines."

To Revalidate, or Not?
For already-validated processes, PAT presents drugmakers with something of a dilemma: revalidate an existing process and take on all costs, delays, regulatory uncertainty—and potential benefits—inherent therein, or stick with the safe, fuzzy warmth of an approved process already known to work.

If process understanding is insufficient incentive for testing PAT waters, FDA offers regulatory incentives within its risk-based approach to validation and compliance: Show us the science, the Agency says, and we'll review you fairly and consistently.

Within the risk-based framework, drug manufacturers that are starting out in PAT typically continue using traditional offline analysis alongside process analytics until they can demonstrate equivalence between the two. Once equivalence can be shown, they can cut the cord and reap the benefits.

However, with respect to revalidation, a number of questions remain. Will it be enough to prove that PAT provides equal or better performance than off-line analysis? Will a formal revalidation be necessary, or will demonstrating equivalence serve as the revalidation? "The mechanisms for switching need to be flushed out," says Andrew Malcolmson, director of business development at Malvern Process Systems (Southborough, Mass.).

So far, he says, not many drug manufacturers have worked through this exercise for existing processes. "It's definitely easier to implement PAT for new processes," he says.

Normally, when process engineers decide to use PAT with an existing process, it's for a product or operation that has posed problems in the past,in such cases, the potential benefits of installing PAT clearly outweigh the regulatory uncertainties. Pfizer (New York), a leader in applying pharmaceutical process analytics, has converted dozens of older processes--some developed more than 50 years ago--but believes that any operation within any process is fair game. "Although PAT is certainly much easier to deploy early in development--and we are doing that for new processes--we had to start somewhere, and the logical place was existing processes," says Norman Winskill, Ph.D., Pfizer vice president of global manufacturing services.

From the Ground Up
Time is what distinguishes PAT deployment for new processes vs. retrofits of older lines--new processes have it, while existing ones don't, says Chris Ambrozic, senior consultant at Umetrics, Inc. (Kinnelon, N.J.) Manufacturers are reluctant to shut down profitable lines to retrofit and revalidate, especially if they've just spent five or ten years perfecting a manufacturing process.

The scientific and engineering justifications for PAT are most obvious when process analytics are adopted at the lab bench and scaled upwards, through pilot and production scales. Earlier deployment helps iron out process wrinkles, but, perhaps most importantly, it allows analytics, control, feedback, and data processing functions to be tested on nonessential preclinical batches. "What companies do with PAT data at the back end needs to be discussed during development," says Howard Hartley, manager for engineered systems at Pfaudler (Rochester, N.Y.). "Companies looking for real process optimization, continuous improvement, and statistical process control need to get PAT data into their plant control system," he says. "And they need to do this early on because it's expensive. Just plunking an analyzer out there won't give you the full benefit."