A Little Knowledge Remains A Dangerous Thing

Companies that participate in "pure research" into process operations gain the knowledge they need to transform them

"Drink deep or taste not the Pierian spring," wrote Alexander Pope nearly 300 years ago. The phrase couldn't be more applicable to pharmaceutical manufacturers today. As the blockbuster drug model fades, and more companies scrutinize their manufacturing operations more closely, a growing number are deploying process analytical technologies (PAT) to gain process enlightenment. Some drug manufacturers such as Pfizer, with its Right First Time initiative, have made deeper process knowledge the cornerstone of corporate programs. Others are just beginning their journeys.

However, even PAT may not be enough. Only fundamental research can unlock the secrets remaining in the age-old mixing, drying and separation processes that PAT monitors. After all, people have been drying solid pharmaceutical ingredients for thousands of years. But, even after all this time, do we fully understand how drying works, on the particle or even the molecular level, and how to control it?

PAT may tell you about the quality of product in a drier, and help you optimize your drying equipment operation. But what if the assumptions you make about the basic drying process are only partly right? What if they're completely wrong? Either way, you won't achieve the most with PAT.

Sometimes, it's necessary to take a step back and look at the fundamentals. Given tight resources, and a necessary focus on customer needs, no pharmaceutical company today could afford to do this type of research in-house.

However, pharmaceutical manufacturers can take part in basic research by joining the Center for Pharmaceutical Process Research (CPPR). This ten-year-old group, funded by the National Science Foundation, is unlocking the mysteries remaining in processes that so many companies still take for granted.

Its members include four universities: Purdue, where the center is headquartered, and the Universities of Connecticut (Storrs), Minnesota, and Puerto Rico. In addition, some 25 companies and, since last year, the FDA, all belong to the Center. Taking a multidisciplinary approach, involving pharmacy, chemical engineering and other disciplines, the Center is working to gain a deeper understanding of basic process operations, learn how to control and optimize them. Along the way, it promises to develop practical tools that will save manufacturing dollars in the future.

CPPR's role is primarily academic, founding director Dane Kildsig says. Its connection to learning centers allows the Center to question the status quo more freely than many industry-funded applied research groups can.

Skeptics tempted to dismiss its work as strictly academic should consider the "Smart Freeze Dryer." Sponsored by the Center and based on the concept of manometric pressure measurement first described by former Purdue professor Steve Nail, now with Eli Lilly, in 1997, the model was further developed by Professor Michael Pikal and Charlie Tang (now with Amgen) at the University of Connecticut. It uses an algorithm and expert system software to allow users to monitor and optimize the lyophilization process. Last year, Center member FTS Systems licensed the process from the University, and is now building it into commercial products, the first of which are expected to be available this Fall.

One major focus at the Center is on pharmaceutical material science, studying the impact of the physical and chemical properties of ingredients on the properties of final drug formulations. Led by associate director Kenneth Morris, researchers are monitoring and controlling granule size and strength in fluid-bed granulation drying, and monitoring changes in crystal form during high-shear granulation and drying. "Modeling the systems so we know what should be monitored, what sensor is best, and what temporal behavior we expect to see, allows us to control the processes in real time to an endpoint as opposed to setting a time and stopping based on that, irrespective of the state of the material," Morris says. Consistent with the spirit and practice of FDA's guidances for PAT and 21st Century GMPs, the projects should allow for more accurate assessment of risk as well as risk mitigation, he says

FDA's involvement also promises to invigorate the Center and to give it a more important role in the future, improving communication and the transfer of knowledge from industry to the Agency and vice versa.

Costs may have prevented some companies from joining, Kildsig admits. Although different levels of membership are available, full annual membership currently costs $35,000. However, given the changes going on in the industry today, the costs of not joining may prove higher. For more information, visit www.cppr.purdue.edu.

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