Manufacturers have objected to CDER's use of plant size as a risk factor. Gardner acknowledged that although a high-production automated facility might be more safe and reliable than a small, obsolete operation, a quality problem with the potential to affect a lot of people carries higher risk. Companies also would like to know the risk scores of their facilities, but FDA has no plans to provide that information, Gardner emphasized, just as the Internal Revenue Service does not tell taxpayers its audit criteria. "Every manufacturer needs to know that it will be inspected, and that the frequency will be determined by risk, by FDA resources, and by the particular policy emphasis at FDA, which may change every year," Gardner pointed out.

Integration and coordination

In addition to setting inspection priorities, FDA aims to avoid redundant site visits by better coordinating GMP and PAIs. The agency recently dropped its mandatory PAI policy and is waiving more PAIs for generic drugs and for manufacturers who receive high marks on GMP inspections and can demonstrate that a facility is in full compliance and shows a state of control.

FDA has had team-based inspections for biologics for several years, and Glavin considers Team Biologics and the Pharmaceutical Inspectorate "the future" of federal inspections. The Team Biologics cadre conducts routine GMP inspections for products regulated by the Center for Biologics Evaluation and Research (CBER), while CBER reviewers head preapproval inspections. ORA is incorporating these elements into new compliance models for drugs and medical products, a trend accelerated by the shift of biotech therapeutics to CDER and reflected in the establishment of the Pharmaceutical Inspectorate.

Seeking information

One problem for FDA in assessing site risk is a lack of information about manufacturer production volume by product and by facility. Companies do not have to provide specific manufacturing data to the agency, and many hesitate to do so for fear of unveiling trade secret information about product formulation, manufacturing process, engineering plans, or other issues. FDA inspectors get a sense of plant volume from site visits, but such information is not precise and may become outdated quickly.

FDA also lacks information about bulk ingredient imports, which now come largely from countries without a long history of information exchange with US regulators. ORA would like to know if manufacturers have quality problems with certain active ingredients or refuse certain shipments; such information, Glavin points out, would inform inspection and sampling decisions. She is contemplating new incentives for manufacturers to share such information with FDA. One idea proposed by generic drug manufacturers is a "Green Lane" for faster processing of drug and bulk ingredient imports for companies that provide information about a foreign producer's quality-control and testing capabilities.

Manufacturers generally support FDA efforts to streamline the frequency and scope of its foreign inspections, which total about 1000 per year. Unfortunately, FDA's program now is only the tip of the iceberg. More than 30 foreign regulatory agencies want to inspect pharmaceutical manufacturing plants, and the number continues to increase, according to Malcolm Holmes, director of global quality assurance at GlaxoSmithKline (Hertfordshire, United Kingdom, http://www.gsk.com/). Industry is building large, sophisticated production facilities that may export products to more than 80 different markets, and inspectors from all over the world are showing up to conduct their own audits.

This kind of "industrial tourism" does little to enhance public health and safety, Holmes complained at the FDLI April meeting. He noted that industry spends some 35,000 employee-hours coping with multiple foreign inspectors, now coming more frequently from Mexico, Argentina, Africa, and Asia. One GlaxoSmithKline site experienced five inspections last year, and all manufacturers are suffering from "inspection overload," Holmes commented.