COVER STORY CHEMISTRY ROOTS Process design reflects laboratory efforts that begin in drug discovery.
BREAKING DOWN BARRIERS Drugmakers are paving the way to more streamlined manufacturing via CULTURE CHANGE in R&D RICK MULLIN, C&EN NORTHEAST NEWS BUREAU
IT MAY COME as a surprise to hear that the pharmaceutical industry stands out as having particularly inefficient manufacturing operations—far less efficient than those in other high-technology sectors, such as computers, or even in mature industries, such as soap and paint. That drug manufacturing is wasteful might seem odd to anyone who assumes that the scientific precision inherent in discovering drugs is reflected in elegant chemical processes that carry through to commercial production. But contract service companies that serve the drug sector, as well as a handful of major drug companies themselves, attest to significant inefficiencies in drug
manufacturing. Given the pharmaceutical sector's drop in profitability since the 1990s, they say, the situation is receiving increased attention. Indeed, new cost-cutting programs across the industry are focused in part on improving manufacturing. Tellingly, three major drugmakers—AstraZeneca, GlaxoSmithKline (GSK), and Pfizer—have joined Britest, a U.K.-based consortium of manufacturers, contract service firms, academic chemical engineers, and equipment suppliers that is studying the problem. All agree that improving manufacturing means more than simply tightening ship at the plant; it means real change in research and business cultures. If the batch-heavy world of WWW.CEN-0NLINE.ORG
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commercial-scale drug production reflects anything, they say, it is a lack of communication between laboratory science and plant engineering. Processes conceived by medicinal chemists to synthesize milligrams of pharmaceutical chemicals pass, basically unchanged, into ton-scale production—the realm of continuous process manufacturing in many other industries. Part of the problem, they say, is a regulatory regime in which making changes becomes more costly and more disruptive the closer a drug candidate moves toward commercial approval. The Food & Drug Administration has, in fact, been a catalyst for change in the pharmaceutical industry with its Process Analytical Tech-
COVER STORY
nology (PAT) program, a quality regime that expedites process and manufacturing adjustments to plants operating under the agency's current Good Manufacturing Practices guidelines. Many of the industry's inefficiencies stem from a "batch-manufacturing culture" deeply rooted in the chemistry of pharmaceutical manufacturing. "There is a tradition of using standard, lab-scale batch processing," says Michael Matlosz, project director of Impulse, a Nancy, Francebased consortium of manufacturers and equipment suppliers studying alternative process design. "This leads to very high inventories, very large amounts of side products, large inventories of solvents, and inefficient use of energy." AS A RESULT, Matlosz says, the drug industry manufactures at a capital utilization rate of about 10-15%, compared with 95% in petrochemicals and other industries employing continuous processes. "This is because you're spending most of your time storing your reactants some place, putting them into stirred tanks, and taking them out of stirred tanks," Matlosz says. "It is a major issue in fine and specialty chemicals, but particularly big in pharmaceuticals." Impulse is developing "process intensification" strategies aimed at deploying microcomponent reactors, thin-film contactors, heat exchangers, and other technologies to boost plant efficiency. These strategies, Matlosz says, may lead to fundamental change in manufacturing: a shift
TOOLBOX The Britest way to efficiency is embodied in a six-step planning process: 1. Project Definition & Evaluation: Ensure a shared understanding of project objectives from both a research and a business standpoint. 2. Process Structure Analysis: Assess the feasibility of chemistry through development, identifying likely process adjustments and associated costs. 3. Duty Definition & Equipment Selection: Match process engineering to required chemistry, gauging necessary heat-, mass-, and momentumtransfer needs; identify compatible equipment. 4. Experimental Plan: Optimize the number of experiments needed to assess process design capabilities. 5. Risk Appraisal: Review risks associated with materials and plant equipment involved in the plan. 6. Project Definition Statement: Finalize plan with detailed production targets for handoff to engineering.
from batch to continuous processing. Britest, the U.K.-based consortium, takes a more conceptual cut at the problem, developing analytical and procedural guidelines for process development intended to improve coordination among discovery chemistry, process development,
and engineering, according to Sue Fleet, chief executive officer. The consortium's goal is to break down a debilitating cultural barrier in the industry. "Companies have different cultures, but by and large, people work in groups," she says. The Britest tools, she says, are designed to bring these groups together to understand the process as well as the business imperatives. "Part of what we are doing is developing better ways of sharing knowledge we already have," Fleet says. "Some is about identifying areas where we have a fundamental lack of understanding." Elaine Martin, an industrial statistician at the University of Newcastle, in England, points to a need for better management of the data-rich environment of chemical production. "Can we get information out of the data, turn it into knowledge, and use that in scale-up? Can we keep learning from experience with other products that have gone through the life cycle and transfer what we've learned through statistical methods to new products?" FDA's PAT initiative is also focused on statistical analysis, and the program has been a key motivator among drugmakers, according to Martin. Significantly, FDA is prodding drug companies to share information once assumed to be proprietary, she says. "Companies are becoming open to discussions of common problems such as new ways of doing crystallization. They aren't discussing their entire processes," she says.
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