) slip-up on asthma inhalers. In 1999 and 2000, the company recalled 59 million units because it couldn't prove that the inhalers contained the active ingredient. The Food & Drug Administration, meanwhile, has found hundreds of quality violations at other companies. The woes are a symptom of a deeper problem: factory processes so antiquated that companies typically can't even pinpoint the causes of snafus. "Manufacturing has been the poor stepchild of the pharmaceutical industry," says Jeffrey T. Macher of Georgetown University's McDonough School of Business.
Now, that stepchild is getting the attention it deserves. Macher and his colleague Jackson A. Nickerson of Washington University's Olin School of Business are leading an effort to find and correct flaws in drug-manufacturing practices and in FDA regulations. The FDA itself is altering its rules, hoping to foster more innovation in factories. And companies such as Pfizer Inc. (PFE
) and Abbott Laboratories (ABT
) are spending tens of millions a year to install new technology and processes in plants.
The potential economic gains of a quality boost are huge: "Everyone has said that costs could decline by up to 50%," Nickerson says. That would save scores of billions of dollars. The new approach would also make manufacturing more flexible, making it easier for companies to produce the personalized treatments that are expected to become common in the future.
It won't happen quickly, though. "There is a tremendous cultural change that we all have to go through," says Dr. Janet Woodcock, FDA deputy commissioner. Drug manufacturing has always been more art than science. The traditional approach: figure out by trial and error how to do each of many steps, from mixing to drying to coating tablets. Then, after each step, take samples and test to see if they meet specifications. The testing alone can take days or weeks.
Moreover, there are inevitable variations in the ingredients and in the processes. That causes many drug lots to fail the tests, wasting time and money. Once a batch develops a problem, "the cycle time -- which might normally be 30 days -- can easily double just doing the investigation. And the lot just sits in inventory," explains Pfizer's manufacturing quality chief, Gerry Migliaccio. And more often than not, the cause of the problems can't be found -- or fixed.
Drugmakers are now tackling these issues with new approaches, such as process analytical technology (PAT). Instead of putting a drug lot on hold to test it after each step, the idea is to peer into the process itself and measure what's going on -- as it's happening. It is possible, for instance, to shine a laser through a window in a blender. The constituents absorb or reflect the light differently, creating a spectrograph that can tell operators if the ingredients are mixing properly. A host of other technologies, such as Raman spectroscopy and chemical imaging, can help determine the distribution of the active ingredients in a pill or the size of the granules.EARLY STAGES. Monitoring processes in real time offers the hope of preventing problems in the first place -- or coming up with solutions. Quality problems at Abbott were so bad that the FDA hammered the company with a total of $200 million in fines and shut down a Lake County (Ill.) diagnostics plant for four years. Now, with new technology and processes, Abbott can pinpoint the root causes of problems 90% of the time, compared with 50% before, and do so in an average of three months instead of six months to two years. "The biggest bang for the buck has been in investigation improvements, where we figure out what happened and fix it more quickly," says Michael G. Beatrice, vice-president for regulatory and quality sciences.
GlaxoSmithKline PLC (GSK
) recently got approval for a test of microbial contamination that yields results in hours, not 8 to 14 days. And Pfizer is investing more than $10 million a year in PAT. "The magic is increased understanding of the process," says Migliaccio.
The enhanced knowledge also translates into smarter regulation. Instead of being the quality backstop for industry, FDA inspectors can switch to ensuring that companies are running their processes correctly. Plus, the agency can more quickly approve changes in processes. "Before, the industry didn't have a conceptual framework about what the problems might be," explains Woodcock, "so we had a lot of citations for failure to adequately investigate."
This revolution in drug manufacturing is still in its early stages. There are big gaps, for example, in understanding the basic physics of powders. But slowly, drugmaking is being transformed from an art into a science. By John Carey in Washington, with Michael Arndt in Chicago