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FDA Marks Progress in Improving Manufacturing Rules

Cheryl Thompson

A "tremendous amount of progress" has been made in modernizing how the Food and Drug Administration (FDA) regulates pharmaceutical manufacturing and product quality, the agency's head said today in a teleconference marking the first anniversary of the two-year initiative.

Commissioner Mark B. McClellan said FDA has the opportunity to make drug manufacturing more efficient and improve product safety by incorporating new risk-based management techniques and production technologies into the "so-called good manufacturing practices," which have not been fundamentally updated for a quarter of a century.

In the past two weeks, FDA personnel put the finishing touches on five final or draft guidance documents informing the pharmaceutical industry of the agency's current thinking on certain drug-quality issues.

The draft guidance document on comparability protocols for protein-based pharmaceuticals explains, for example, how a manufacturer can develop a formal FDA-compliant plan for ensuring a product's quality does not decrease when the size of the batch increases and larger-scale equipment must be used. With the comparability plan approved before the need to change arises, the manufacturer could distribute the larger batches sooner than has traditionally been the case.

Officials at the FDA Center for Biologics Evaluation and Research and the Center for Drug Evaluation and Research (CDER) noted later that there have not been any shortages of protein-based pharmaceuticals from the agency only recently compiling its views into a guidance document. Many of the recommendations in the draft guidance document, one of the officials indicated, had been communicated in other ways to the industry over the years.

One of the guidance documents released today acknowledges isolators as valuable equipment, especially during sterility testing, when using aseptic processing to manufacture sterile drug products. This document on a specific part of good manufacturing practices (GMPs) focuses on personnel qualification, cleanroom and process designs, quality control, environmental monitoring, and review of production records when a manufacturer uses aseptic processing, rather than terminal sterilization, to make sterile drug products. 

McClellan said the Office of Regulatory Affairs (ORA) and CDER recently agreed to develop a "pharmaceutical inspectorate" of highly trained personnel to specifically inspect prescription drug manufacturers.

ORA personnel inspect companies that produce, warehouse, import, or transport consumer goods, not just pharmaceuticals, regulated by FDA.

According to the memorandum establishing the inspectorate, 25 members of ORA will undergo special training in fiscal year 2004, and more will be added in subsequent years to reach a total of 50 members by Sept. 30, 2007. The goal is for inspectorate members to spend "a significant portion of their reportable time" inspecting the quality of drug products at domestic and foreign facilities.

So-called preapproval inspections—those conducted before FDA approves the marketing of a pharmaceutical for an indication—will not automatically be undertaken when the product is one of the top 200 drugs prescribed in the United States or an already-approved medication with a narrow therapeutic range, said Joseph Famulare, a division director in the CDER Office of Compliance. He said FDA's experience with those two types of preapproval inspections indicated that the agency could cut back without detrimental effects.

"By eliminating those as mandatory categories for automatic preapproval inspections, that will allow the field officers, on a risk basis, to be able to have more flexibility in [deciding] whether to assign those or not to assign those as preapproval inspections," Famulare said. "So there'll be the ability to focus on higher-risk preapproval inspections when needed or to be able to keep our focus on systematic GMP inspections."

The other guidance documents released today pertain to electronic records and signatures, resolution of disputes over scientific and technical issues, and adoption of state-of-the-art technological advances in pharmaceutical development, production, and quality assurance.

McClellan also announced that FDA has been collaborating with business schools, the National Science Foundation, and private industry to find innovative approaches to drug development and regulation. The agency, he said, has also been working with its counterparts in other nations to improve international standards for drug manufacture.

The one-year progress report on the FDA initiative "Pharmaceutical cGMPs for the 21st Century—A Risk-Based Approach" is available at the agency's Web site.