During the past decade, pharmaceutical manufacturing and quality functions were thrust into an unaccustomed spotlight. After an extended spate of consent decrees, noncompliance and drug quality problems, FDA began to look for root causes and to consider lessons in manufacturing science that regulators and manufacturers might learn from other industries.
At FDA’s Center for Drug Evaluation and Research, the Office of Pharmaceutical Sciences held a series of meetings to analyze these issues. In quick succession the Process Analytical Technology (PAT) team was formed in 2002, the 21st Century cGMP’s were published, outlining a risk-based approach to regulation and compliance, and the PAT Guidance appeared in 2004. During this period, a challenge was issued to drug companies by then-Commissioner Mark McClellan, who was quoted by The Wall Street Journal as saying that the science of drug manufacturing was “behind that of potato chip and soap making.”
Today, drug companies still face quality and compliance problems ranging from supply shortages to consent decrees and warning letters. We asked a number of expert industry observers, including some who had led the call for change last decade, to share their thoughts on how pharmaceutical manufacturing has progressed, and whether anything had actually changed. This is a brief summary of some of what they had to say.
Examining the big picture, experts agree that the “sea change” predicted for drug manufacturing still hasn’t occurred. “McClellan’s quote still resonates today,” says Bikash Chatterjee, President and CTO of Pharmatech Associates, Inc. “Our processes have not demanded the level of sophistication required in other market segments where margins are much tighter, so it’s natural to expect them to evolve at a different rate.”
Although some companies have implemented processes that run at 6 Sigma, the industry overall still operates at the same Sigma level of 2.5 to 3 that it did last decade, says G.K. Raju, Executive Director of the Pharmaceutical Manufacturing Initiative at MIT, and President of Light Pharma, Inc. At FDA’s Science Advisory Board meetings last decade, Mr. Raju documented the high cost of traditional QC and its contributions to pharma’s unusually high cycle times.
“Progress seems to be slow when one looks at reports on shortages, recalls and other quality issues,” says Ajaz Hussain, CSO at Philip Morris International, and former Deputy Director of OPS and head of the PAT Team at FDA. FDA had launched PAT and the 21st Century initiatives, in part, to prevent just these types of problems from recurring. “Efforts towards developing guidelines have been laudable,” he says, “but additional emphasis is needed on certain fundamental aspects of quality such as effective QMS, training, root-cause investigations and setting of specifications based on an analysis of variance.”
However, there are bright spots. More people seem to realize that changing operations is not simply doing some Lean Sigma training, but changing mindsets, says Thomas Friedli, professor at the University of St. Gallen, whose research group has been closely tracking pharmaceutical operational excellence progress for a number of years. “The complexity that drug plants have to master has increased, so a plant that maintains operational performance over the years has in fact improved,” he says. Traditional pharma leads in Lean and Six Sigma efforts, but biopharma is now devoting more resources to operational excellence in manufacturing, and to consolidating isolated improvement activities, Friedli says. Currently, the University of California Berkeley and NSF have launched the Initiative for Research in Biopharmaceutical Operations to study this issue, while, funded by the Sloan Foundation, MIT and Georgetown are exploring related issues and the impact of globalization on regulation and innovation.
Increased Use of Modern Manufacturing Tools
Another positive sign, Raju says, is the fact that more drug companies are applying established industrial engineering tools such as process capability analysis and statistical process control. These methods are specifically called out in FDA’s Process Validation Guidance, says biopharmaceutical consultant James Blackwell, but more companies are realizing their value in catching trend deviations, providing new process insights and driving continuous improvement. “Looking for trends once a year is not cGMP anymore,” he says.
“Today, even generic manufacturers routinely have control charts on the shop floor, a big change from a decade ago,” Chatterjee notes, “while most companies use some kind of scorecard for product performance.” In addition, he says, inline detection, vision systems and barcode readers are common at most facilities. Ten years ago, they were still a novelty. Chatterjee notes the need for greater flexibility, particularly where shift changeovers are concerned. Mergers and acquisitions are driving manufacturing to greater agility, since many companies now must accommodate technologies rapidly, even with limited or no development understanding. He points to flu vaccine manufacturing, and the push to cell-based vaccines, as a success story. A few years ago, there was only one cell-based vaccine pilot. Today there are eight. “The market needed something, and we applied the innovation engine to figure out how to do it,” he says.
FDA enforcement and guidance trends are also having a positive, if painful, impact. For one thing, the Agency’s emphasis on science- and risk-based reviews and inspections will likely change the short-sighted emphasis that some companies give on “delivering quality to the regulator rather than the consumer,” says Gawayne Mahboubian-Jones, manager of Quality be Design at Philip Morris, and a frequent speaker and trainer at FDA staff training workshops.