Risky Business

By Angelo De Palma, Ph.D., Contributing Editor In August, 2002, the U.S. Food and Drug Administration launched the first major overhaul of pharmaceutical current Good Manufacturing Practices (cGMPs) in a quarter-century. Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach outlined the agency's vision for a new approach to manufacturing and compliance based on risk analysis, improved process understanding and quality system methodologies. FDA's use of the "R-word" represents a philosophic shift, an admission, even, that risk management may be used to the industry's advantage, enabling higher quality drugs to be made more efficiently. Industry views this as a healthy development in the evolution of cGMPs. After all, who--in an industry dominated by scientists and engineers--would argue against a policy that encourages science and reason? But two years after FDA announced its directive, many in industry remain unclear about how risk-based validation will accomplish its goals. Pharmaceutical manufacturers' reliance on tried and true methods is, after all, based on the fact that these methods work. Indeed, risk has always guided pharmaceutical firms' compliance with cGMPs--at least to some degree. Over time, however, pharmaceutical manufacturing has become so risk-averse that some companies and inspectors won't tolerate any deviation from standard operating procedure, however minor or distant from mission-critical manufacturing steps. "The compliance we have now is blind compliance," says Ken Leiper, a U.K. based consultant and longtime Glaxo veteran. "We've stopped people from thinking." And simply providing a framework for managing and justifying risk may not prove enough encouragement for passionately risk-averse companies--at least not immediately, says Subbu Vis, senior project manager at Valimation (San Jose, Calif.). The full benefit of risk analysis, with respect to process innovation, may not be apparent for another five or six years, he says. "The situation certainly won't turn around overnight." FDA equates high risk with