An Inside Look at FDA On-Site
Segal, Marian, FDA Consumer
There are nearly 15,000 establishments in the United States that manufacture, test, pack, and label drug products for humans. The Federal Food, Drug, and Cosmetic Act requires FDA to inspect each of these facilities at least once every two years. In addition, 800 to 1,000 foreign facilities are periodically inspected.
Agency investigators, working from field offices in some 160 locations throughout the country, completed 3,142 domestic inspections in 2,618 human drug establishments in the fiscal year that ended Sept. 30, 1993. Another 223 inspections were done at 213 foreign establishments.
During that year, the agency took a number of legal actions to correct deficiencies for failure to meet drug manufacturing and product standards. These included one prosecution, two injunctions, 15 seizures, and 408 warning letters. FDA also monitored recalls involving 406 drug products in various dosage forms.
An inspection can last from one or two days to several weeks, depending on its purpose and scope. There are three primary types of inspections: preapproval, postapproval, and surveillance good manufacturing practice (GMP) inspections.
Preapproval inspections are often initiated by the Center for Drug Evaluation find Research at FDA headquarters. While the center is reviewing a new drug application or abbreviated new drug application, it requests that the field office inspect the drug manufacturing facilities.
This inspection represents a significant step in the drug review process. The investigators must determine if the data submitted in the firm's application are authentic and accurate and if the plant is in compliance with current good manufacturing practice regulations. The district office recommends approval or disapproval of the application, based on its findings.
After the center approves an application and the firm is ready to start marketing the drug, FDA conducts a postapproval inspection, intended to evaluate the firm's validation studies. Validation refers to FDA's requirement that the firm show it can consistently manufacture a drug product within tight parameters from batch to batch, day to day, year to year. The investigators also verify that the firm has not changed its manufacturing, labeling, or quality control testing for that drug without filing a supplement to its application, and that the firm has not exceeded a tenfold "scale-up" in production.
"Scaling up" is the process of increasing the batch size for commercial manufacture. "For commercial production, FDA allows firms to manufacture their product in batches ten times larger than those produced for clinical or bioequivalency testing," Kirk Sooter, investigator with the agency's Morgantown, W.Va., resident post, says. "For example, if tablets were produced in batches of 100,000 during clinical testing, the commercial production batch cannot exceed 1 million tablets."
The investigators collect samples at both preapproval and postapproval inspections for analyses that will compare the composition of the product against known standards. The drug's chemical "fingerpfint" must match the standard pattern for the compound. Samples are also collected to verify that the firm's laboratory methods are proper and consistent with the drug application.
Finally, a GMP, or "routine," inspection evaluates the firm's entire operations. Although pre- and postapproval inspections include examination of the firm's manufacturing practices, they are product specific. GMP inspections, on the other hand, involve a comprehensive review of the firm's manufacturing operations.
When FDA's Sarah Brown and Kirk Sooter arrive to inspect Barre-National Inc., a Baltimore drug manufacturer, they show their credentials and issue a written "Notice of Inspection" to the firm's quality assurance manager. A full inspection may take weeks, while a visit to look at one or two specific things may take only an afternoon. An inspection team may comprise several people, including analysts, chemists, microbiologists, and investigators. …