Process Analytical Technologies 101

Part of a Larger Picture
Nearly every pharmaceutical regulatory expert has his or her pet PAT caveat. Most advise that process analytics requires a plan, entails a learning curve, and that no one technique will serve all processes equally well.

Process analytics alone won't resolve every process or product inconsistency. Fully half of all the process variations that lead to rejected batches can be traced to variations in raw material, says Chris Ambrozic of Umetrics. Excipients, he points out, introduce tremendous variation into the formulation and dissolution properties of final drug product. "When we start projects with clients, we won't proceed unless the actual QA testing of raw materials is included. You could drive a bus sideways through some companies' raw material specs."

Manufacturers who expect process analytics to give them black/white, yes/no answers right out of the box are deluding themselves, warns Nancy Mathis, Ph.D., CEO of Mathis Instruments (Fredericton, New Brunswick). "Most deployments require that you correlate instrument readouts with known measurements before even attempting to interpret the resulting tons of instrumental data." In other words plan, check against off-line measurements, and keep your fingers crossed.

PAT requires short-term investments in instrumentation, consulting services, internal human resources, down-time for existing processes, or development delays for new ones. Companies adopting process analytics must embrace FDA's brave new world of risk-based compliance and validation.

Within that world, one would expect that the most risk-averse manufacturers, especially contractors and manufacturers with tight capacities, would be the last to adopt process analytics. However, the contract manufacturer Patheon (Mississauga, Ont.), views PAT as an opportunity to streamline operations, improve quality, and offer related services. "Problems begin during development," says Anil Kane, Ph.D., associate director for formulations development, "especially when processes are transferred without fully understanding them, which leads to quality issues."

Last but not least, PAT begs for changes in an organization's quality philosophy. Despite nearly universal recognition of PAT's benefits, today's manufacturing paradigm is still skewed towards finished product testing. "Process analytics," Kane observes, "offers the hope of designing quality in."

PAT the Pfizer Way

As one of the most PAT-savvy manufacturers, Pfizer (New York) relies on core spectroscopic process analytics (infrared, near-infrared, ultraviolet/visible, fluorescence, mass, and Raman), plus high-performance liquid chromatography (HPLC), rapid microbial testing, gas chromatography (GC), and spectroscopic imaging. Another Pfizer favorite is focused beam reflectance (FMBR), which uses laser light reflection to monitor particle characteristics. Pfizer also employs on-line HPLC and GC, but does not consider these core applications.

Pfizer constantly seeks analytic ideas from food, semiconductor, aerospace, and chemical industries to apply to pharmaceutical manufacturing. "Virtually anything goes," says Norman Winskill, Ph.D., Pfizer vice president of global manufacturing services.

For example the company borrowed acoustic analysis, useful in granulation and tablet pressing, from the materials processing industry. Spectroscopic imaging of solids, another Pfizer specialty borrowed from materials analysis, uses spectroscopy plus a camera to obtain complete spectra of defined areas and assemble those spectra into a spectral image.

Vendors are fair game for PAT collaborations, particularly when on- or in-line analytics require extensive equipment modifications. "We'll even work with several vendors on the same technology, like NIR, depending on the application and the suitability of their instruments," Winskill says.

Pfizer's reliance on core technologies reflects, in part, what is available in on-line or in-line format, but as vendors recognize FDA's seriousness about process analytics, availability has become a moving target. "It's amazing how fast technology is advancing," Winskill observes.

As one of the industry's process analytics leaders, Pfizer has maintained a dedicated PAT effort for more than two decades. "Initially, we developed PAT applications to improve process understanding and control of fermentation processes," Winskill says. "About fifteen years ago we started to apply those same techniques to [small molecule] pharmaceutical manufacturing."

PAT has become one of the cornerstones of Pfizer's "Right First Time" (RFT) program (Pharmaceutical Manufacturing, June 2004, p. 37). "Externally, as we increase process understanding and show we're in control of our processes, we would expect that FDA will consider Pfizer operations to be low-risk, and under its risk-based GMP initiative give us less scrutiny and more leeway to implement continuous change ourselves," Winskill says.

"Doing things right just because regulators want you to is not the right attitude, Winskill adds. "If you do it for the right business reasons you should be in compliance anyway. We would have adopted PAT with or without FDA because it's the right thing to do, an important component of our RFT program. As long as companies and FDA understand PAT in light of that risk-based approach, compliance issues should not get out of hand," he says.

PAT's real objective is to create an environment which encourages creativity and innovation in pharmaceutical manufacturing, Winskill says. "For whatever reason, the pharmaceutical industry has been slow to adopt innovative manufacturing techniques and real or perceived regulatory hurdles are at least one contributing factor. Both FDA and industry--certainly Pfizer--want to change that."

Is Your Process Data PAT-able?