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Safety

Effective Manufacturing

FDA Process Guidelines Encourage Efficient Plant Controls

by Rick Mullin
June 19, 2006 | APPEARED IN VOLUME 84, ISSUE 25

As major drug companies comb their operations looking for inefficiencies, they will likely find plenty to work on in their manufacturing facilities. Many firms have not installed systems or adopted practices that have helped other industries streamline production and reduce costs in the plant over the past 10 years.

This state of affairs is partly due to the industry's profitability in the 1990s. "When you have gross margins of 70%, what's to improve?" says Mark Albano, marketing manger for Honeywell Process Solutions in Phoenix. The industry, he adds, is also impeded from making manufacturing improvements because of regulation. Any change to a manufacturing operation that has been validated by the Food & Drug Administration must be revalidated, a process that is costly and time-consuming. In many cases, he says, FDA validation has locked drugmakers into fundamentally inefficient processes.

Janet Woodcock, FDA deputy commissioner for operations, agrees. "Many pharmaceuticals are manufactured in a pretty antique way," she says. "They are not working in a continuous-processing mode with process controls and feedback. Drugs are made in batches; you take one step and test it and store it." This mode of manufacture, she says, has been supported by the FDA validation system.

She says a new program at FDA called Process Analytical Technology (PAT), seeks to circumnavigate the traditional approach by allowing the use of continuous process control systems that measure and assess quality during the manufacturing process rather than between batches (C&EN, May 30, 2005, page 63). The framework specifies the development of manufacturing procedures that can consistently ensure a predefined quality at the end of the manufacturing run, she says. Such procedures would be consistent with the basic tenet of quality-by-design inherent in currently available commercial control systems and could actually reduce quality concerns while improving efficiency.

Among the currently available technologies, PAT will permit multivariate data acquisition and analysis tools, modern process analyzers or process analytical chemistry tools, process and endpoint monitoring and control tools, and continuous improvement and knowledge management software.

Albano says the PAT validation framework prescribes quantitative values rather than run times, allowing blending cycles, for example, to stop when blending is completed to the correct volume and quality. This approach can significantly reduce run times. A classic example is tablet manufacturing, he says. Digital control systems can measure the homogeneity of the mixes in real time, allowing what had been an hourlong process to be completed in 10 minutes. Albano says the pharmaceutical sector has been Honeywell's fastest growing market over the past two years.

Woodcock, who is also heavily involved in FDA programs to boost efficiency in the lab and clinic, sees the focus on manufacturing efficiency as a kind of attitude correction in the drug industry. "Manufacturing managers at pharma companies have told me clearly that they are thought of as the poor stepchild, that the glamour end of the industry that drives innovation is R&D," she says. "Basically, manufacturing was told, 'Just make it and don't get us into trouble.' "

FDA is hoping a recalibrated validation system will give the manufacturing department leeway to innovate. However, Scott Lundstrom, vice president of research at health care industry analyst Health Industry Insights, cautions that more work needs to be done by regulators to get the program off the ground. "FDA has not given much guidance on how to implement systems under PAT," he says, and the Critical Path Initiative, FDA's program to modernize and improve drug R&D, is "very light on specifics" regarding manufacturing systems. Helen Winkle, director of the office of pharmaceutical science at FDA's Center for Drug Evaluation & Research, says that while FDA offers only general guidance, standards bodies such as the American Society for Testing & Materials have or are developing more explicit PAT guidelines.

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