US Food and Drug Administration officials have been establishing a host of initiatives that efficiently use increasingly limited resources to ensure the regulatory compliance of drug manufacturing facilities in the United States and abroad. During the past year, the agency implemented a risk-based approach for determining which facilities to inspect first. The agency long ago abandoned hopes of meeting its goal of visiting every drug-production site within two years. Instead, it now seeks to identify the manufacturers and processes most likely to raise safety and product-quality concerns and, thus, merit more frequent oversight.
Both FDA and industry must "change their whole way of thinking" about future manufacturing and compliance operations, noted Joe Famulare, acting deputy director of the Office of Compliance (OC) in the Center for Drug Evaluation and Research (CDER). FDA wants to give "ownership of quality" to industry, he explained at the PDA–FDA Joint Regulatory Conference in Washington last September. Instead of worrying about what data and operations FDA wants, manufacturers should examine what they must do to demonstrate process understanding of their products.
To this end, FDA's risk-based approach to compliance aims to adjust the level of regulatory scrutiny to the public health risk of a drug. FDA's pharmaceutical inspection program has been stressed by the need to monitor a growing number of manufacturing facilities, including more foreign establishments, that are producing more diverse and complex drugs. The fulfillment of these responsibilities, however, is complicated by "resource challenges," commented John Gardner, director of OC's Division of Compliance Risk Management and Surveillance.
In addition to determining which operations and which products are riskier and require closer scrutiny, FDA has implemented a number of initiatives to make inspections and drug-quality monitoring more efficient, including:
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- Applying risk-analysis models to the selection of samples of specific drugs and product classes for laboratory testing and for identifying companies that warrant review of their adverse-event reporting systems.
- Integrating preapproval (PAI) and good manufacturing practices (GMPs) inspections to reduce redundant site visits. In the past, most domestic drug inspections related to new drug approvals. Now, the agency may skip a PAI if a plant recently has passed a quality-system inspection. To clarify when a PAI is necessary, FDA is updating preapproval inspection procedures for CDER and for the Center for Biologics Evaluation and Research (CBER).
- Expanding systems-based inspections to emphasize how the manufacturing quality system is central to demonstrating a manufacturer's control over a production process. This approach calls for the inspection of a facility's quality system and one or two other major operations (e.g., production, laboratory, equipment, raw material control, packaging).
- Promoting cooperation and information exchange with foreign regulatory authorities to tap other investigators' inspection reports and avoid less-critical foreign-site visits.
- Training a Pharmaceutical Inspectorate (PI) to evaluate drug manufacturing facilities, particularly those that adopt innovative production and quality-control systems. FDA has certified about 45 field officers for their expertise in understanding quality systems and risk-based approaches, and more are in training. This expert group has a better understanding of drug-development data and thus should be more capable of evaluating quality-by-design systems that the agency is encouraging companies to establish.
- Updating the Team Biologics program, which has provided the basic model for the PI for drugs. FDA conducted a broad reassessment of Team Biologics two years ago as part of its GMP Modernization initiative. The reassessment recommended continuing this program for overseeing biotechnology manufacturers, including blood facilities, vaccine makers, and biotechnology therapies now regulated by CDER. A Team Biologics Operations Group that includes officials from CBER, CDER, and the Office of Regulatory Affairs has developed a Quality-Management System to improve Team Biologics operations and establish criteria to assess the impact of the Team Biologics program on industry. To this end, the Pharmaceutical Quality Research Institute conducted an on-line survey of manufacturer opinions of Team Biologics's effectiveness. The results are being evaluated, even though few responded to the survey.