U.S. Food and Drug Administration (FDA) caught many drug makers by surprise when it announced in late August a broad-ranging initiative to overhaul how it regulates pharmaceutical manufacturing operations.
The announcement comes at a time when a significant number of major drug makers have struggled to meet the FDA's current Good Manufacturing Practices (cGMP) standards. For example, Schering-Plough in May agreed in a consent decree to pay $500 million for shortcomings identified in inspections of its plants in Puerto Rico and New Jersey. Eli Lilly, Abbott Laboratories and Wyeth are among other drug makers that have recently had to delay or withdraw new drug introductions because of FDA inspection problems at their factories.
Administration officials are quick to point out that the new initiative is not a response to the spate of enforcement actions announced in recent months. Rather, officials say, the current cGMPs have worked quite well to protect the public health--and this initiative is intended to make them even more effective.
"FDA's regulatory and quality control systems for pharmaceutical products have become a gold standard for the world," says FDA deputy commissioner Lester Crawford.`"Any system can be improved upon, however, and with this risk-based, highly integrative cGMP initiative we intend to do just that. We know we can make a good system better. Publicizing this blueprint for action is just the first step."
"For years, the FDA and industry have engaged in an ongoing dialogue on cGMP standards and agree that they're pretty good--even if there were a few rough edges," adds Jeff Trewhitt, spokesman for the Pharmaceutical Research and Manufacturers Assn. (PhRMA). "But now, instead of periodic, ongoing conversations, there will simply be a more organized, consistent review with industry feedback."
Indeed, pharmaceutical cGMPs have continued to evolve since Congress first mandated the application of quality assurance and control principles to drug manufacturing 40 years ago. (After all, the "c" does stand for "current.") But the last top-to-bottom review of the requirements occurred almost 25 years ago.
"The time has come to step back and evaluate the currency of both the cGMP program and the pre-market review of chemistry and manufacturing issues," FDA's Crawford says.
But other industry observers see the timing as more than just a coincidence. "Some senior FDA officials must have been asking themselves, 'Why are these well-financed companies continuing to have basic GMP problems?'" contends Gordon Richman, vice president of strategic consulting and general counsel for EduQuest, an FDA regulatory consulting firm in Hyattstown, Md.
Pharmaceutical manufacturers, meanwhile, have just begun to interpret the FDA's ambitiously titled guidance document, Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach. "It's really too early to tell just what it will mean," says David Adler, a senior engineering consultant for Eli Lilly in Indianapolis. Other pharmaceutical manufacturers contacted for this story were similarly reluctant to speculate on specific implications of the initiative.
A long-term push
The initiative outlines immediate, near and longer-term steps that FDA believes will take two years to fully unfold. "This is a long-term, science-driven process that will take time to develop and implement," says Crawford.
FDA also stresses that enforcement of existing cGMPs will continue during this review process and that it will continue to work with other regulatory bodies worldwide in developing standards applicable to the increasingly global pharmaceutical industry.
On the technical side, FDA outlines three overarching concepts that will guide the reevaluation process: advances in risk management science, advances in quality management science and advances in pharmaceutical science and manufacturing technology.
In broad strokes, the three stated goals of the initiative are to:
Inspection consistency addressed
One immediate step applauded by drug makers is the reinstatement of a centralized review process for all warning letter recommendations, which should go a long way toward addressing industry concerns about inconsistent standards enforcement.
Warning letters, which in the early 1990s replaced the former two-tiered system of "regulatory" letters issued for more serious offenses and "adverse finding" letters for notification of less serious infractions, can significantly disrupt operations until cited problems are corrected. In 1991, in the name of enforcement expediency, the FDA had delegated more authority to field offices and reduced requirements for headquarters review. This resulted, drug makers claimed, in warning letters that were often inconsistent from inspector to inspector and from region to region.
These inconsistencies likely arose from the necessarily general wording of the cGMP standards, which, by their nature, have to remain flexible and applicable to a wide variety of products and processes. And while the FDA does not anticipate that new regulations will be more prescriptive, it has acknowledged the need to develop more detailed guidance documents so that its expectations are better understood.
"Industry clearly needs more rigorous guidance documents that spell out, for example, how the regulations should be interpreted for an aseptic processing application," says an FDA official. "The regulations themselves may need to be revised, but we don't want to reduce their flexibility."
Risk management underlies all
The term "a risk-based approach" made it into the title of the FDA's guidance document, so it's clear that FDA intends to extend its growing reliance on risk management techniques to its oversight of manufacturing facilities.
The movement toward risk-based techniques acknowledges both the explosion in the number of medical products available as well as the increasingly strapped resources of the FDA itself.
Under current standards, for example, the FDA is supposed to inspect a toothpaste plant every two years, the frequency as for plants making prescription drugs. "Well, we don't have the resources to do that," said Janet Woodcock, director of the FDA's drug division, in a recent New York Times article. "We think the drugs that are injected into people's veins should have a higher priority than toothpaste."
Make way for new science and technology
To a certain extent, cGMPs have been continually adapted to ongoing advances in pharmaceutical science and manufacturing technology. But the pace of change has been so great over the past 20 years that the FDA believes it necessary to fundamentally reexamine how it can help drug makers to exploit new technologies without raising unnecessary regulatory roadblocks.
"FDA understands that the industry is becoming more and more reliant on technology," explains EduQuest's Richman. "Things are changing rapidly and they need to restructure accordingly."
There obviously are costs associated with improving manufacturing processes "there's the equipment itself, plus the cost of having the changes approved," adds an FDA official. "The idea is to grow the FDA's understanding of manufacturing technologies and the underlying science so that we can expand the universe of changes that could be implemented without an involved approval process."
The agency is especially bullish on the promise of process analytical technologies to tighten quality control during the manufacturing process. Moving analytical procedures out of the quality assurance lab and putting them directly on line or at line would improve the ability of manufacturers to quickly correct out-of-tolerance conditions--and reduce the possibility of off-spec material being produced at all.
Of course, eliminating off-spec production in the first place reduces the chance that substandard products can slip through final quality testing. Real-time analytical data would also help to improve understanding of the underlying science, FDA officials contend.
A quality systems approach
Last but not least among the initiative's core principles is a stated orientation toward "integrated quality systems." And while much of the FDA's current enforcement principles are based on quality systems concepts, this announcement "lays a public foundation for moving forward in this direction," Richman says. "The focus is shifting from not just what went wrong, but to a higher level evaluation of 'How healthy is the system?'"
According to FDA, its compliance programs already are structured "not to pick at individual nits, but rather to identify systemic failures to detect and correct manufacturing deficiencies."
Richman, for one, believes that the pharmaceutical industry is in for a rude awakening as it is baptized into quality control principles that have become second nature to other industries.
"Historically, pharmaceutical companies have had such high profit margins that they've never had to be efficient," Richman says. "They haven't been driven to major improvements in predictability as other industries have.
"There needs to be a significant self-evaluation of their quality system practices. Many companies have a binder documenting their quality approach, but that's not how they run their businesses on a day-to-day basis."Ultimately, this initiative could prove to be very beneficial to the pharmaceutical industry," he concludes, "but in the short term it has the potential to cause more pain."