An FDA emphasis on process analytical technology could help industry update some manufacturing practices that have not changed in decades
Patrick McGee
Senior Editor
The German petrochemical industry pioneered the use of online analyzers for process control in the mid-1940s, and the US petrochemical industry followed suit in the late 1950s and early 1960s. It wasn’t until the late 1970s and early 1980s, however, that pharmaceutical companies began to consider using such technologies to streamline their manufacturing processes. But they were concerned that the US Food and Drug Administration (FDA) would require them to write substantial amounts of clearance documents if they wanted to use new tools and processes.
“The companies were frustrated by it, and the regulators themselves were frustrated because I think they had expectations for pharmaceutical companies to be using
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innovative modern processing techniques,” says Brian Davies, director of process analytical technology for Thermo Electron Corp., Madison, Wis. “They just haven’t been able to do that. The tablet process that people use to make tablets today is roughly the same one as they used 50 years ago.” That will change because of a new effort on the part of the FDA to emphasize process analytical technology (PAT).
“PAT itself is 60 years old in terms of other industries using it, and it’s been 20 or more years that it’s been used in pharmaceutical-related industries, so it’s not new,” says Mel Koch, PhD, director of the Center for Process Analytical Chemistry (CPAC) at the University of Washington, Seattle. “The new concept is the FDA realizing that its emphasis on using PAT will actually improve processing, cost, quality, and so forth.” The FDA defines PAT as “a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.”
Defining “analytical”
The agency also notes that the term “analytical” in PAT should be viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner. Technologies that can be used alone or in combination for PAT include:
• Multivariate data acquisition and analysis tools.
• Modern process analyzers or process analytical chemistry tools.
• Process and endpoint monitoring and control tools.
• Continuous improvement and knowledge management tools.
In most manufacturing plants, quality control scientists remove samples of drugs from the manufacturing line, take them to a lab, test them, and then document their findings for the FDA. But PAT allows these measurements to be made online and in real time, allowing manufacturers to know about quality problems immediately. It can take 60 to 90 days to manufacture a batch of tablets and put them on the market, according to research done by G. K. Raju, PhD, executive director of the Pharmaceutical Manufacturing Initiative at the Massachusetts Institute of Technology, Cambridge, Mass. The research also shows that using online PAT methods can decrease cycle time 10-fold.
Rick Cooley, formerly of Eli Lilly & Co., Indianapolis, has first-hand experience with the impact that PAT can make on pharmaceutical manufacturing. In 1981, Cooley was moved from the company’s analytical development division to begin working in PAT. His first project? The design and implementation of online HPLC analyzers for closed-loop control of chromatographic purification processes in the production of Humulin, the company’s biosynthetic insulin.
“The biosynthetic insulin area was a new process at Lilly at the time,” says Cooley, who is now manager of the process analytic center of excellence at Dionex Corp., Sunnyvale, Calif., a manufacturer of tools that can be used in PAT. “The manager of the plant realized very early on that the cycle time, which was pretty much dictated by offline analysis in the quality control lab, was going to make it very difficult to meet market demand with the product.” The manager had read of other industries using online analyzers to reduce cycle time, and Lilly decided to integrate them into the production process for Humulin.
FDA efforts pay off
Cooley credits the FDA efforts with drawing attention to PAT and the pharmaceutical manufacturing process in general. “It started out with process analytics but that rapidly expanded to become more generic in nature and people have really started talking about . . . trying to get the pharmaceutical industry’s technology up to speed with more of the other high-tech manufacturing industries,” he says. “I don’t really see any huge shift in technology that was the result of this initiative. For the most part, this has not been a driver of technology; it’s been more discussing how existing technologies could be used and transferring that technology into the process area.”
Ongoing work is focusing on miniaturizing traditional analytical equipment so it can be used in manufacturing processes. CPAC, which has members from 35 different organizations, including several large pharmaceutical manufacturers, is the home of the New Sample and Sensor Initiative (NeSSI), says Koch. NeSSI is an international ad hoc group with more than 250 members devoted to modularizing and miniaturizing process analyzer sample system components.
Companies such as Swagelok Co., Solon, Ohio, and Parker Hannifin Corp., Cleveland, borrowed from work they were doing in the semiconductor industry to monitor gases to come up with a standard which is now being used in increasing numbers in chemical industries. In addition to interfacing with the process and the analytical instrument, the new standard became a platform for mounting miniature analytical instruments, Koch says. “That’s where we are now, where pharma and even biotech is going to gain from these platforms that could end up being a base for most tools that exist in an analytical lab.”
Davies says Thermo Electron Corp., which is the biggest manufacturer of analytical systems, also provides some of the informatics and services needed to support PAT.
Monitoring processes
Davies says one of Thermo Electron’s divisions makes process mass spectrometers and is already selling into the manufacturing process for active pharmaceutical ingredients, typically companies that are making their drug product by deep fermentation. The systems monitor how the fermentation is proceeding, how the various bugs and bacteria that are making the product are behaving, how they are growing, whether they are producing it at an optimum rate, and when the best time for them to be harvested is. “These things sit online. They’re plugged permanently into the manufacturing process, and they draw gases out of these systems 24 hours a day and seven days a week. They analyze them and they compare them with what should be going on in the process to make sure the process is under control, and then they’ll give guidance to the manufacturing folks on what to do in the process.”
Initiating the cultural changes in the way people think and work is not always easy, however. Some of the larger pharmaceutical companies such as Pfizer, Merck, AstraZeneca, and GlaxoSmithKline have been early and enthusiastic embracers of PAT, says Davies. “What’s taking some time to come along behind that are the smaller pharma players, the smaller sized manufacturing guys, and of course, the generics.”
Cooley says these trends will lead to much broader use of analyzers and other tools across the industry, and to quality control labs being transformed from centralized, offline entities that are focused on a central organization. “It will get to where analyzers are more distributed and either will reside in direct contact with the process, or more distributed in control rooms where the samples are being generated and where data can be generated much more quickly and used for feedback control of the process.”
Filed Under: Drug Discovery