FDA is responsible for the safety and quality of domestic and imported pharmaceutical products under the Federal Food, Drug, and Cosmetic Act. Specifically, FDA’s Center for Drug Evaluation and Research (CDER) establishes standards for the safety, effectiveness, and manufacture of prescription pharmaceutical products and over-the-counter medications. CDER reviews the clinical tests and manufacture of new pharmaceutical products before they can be approved for the U.S. market, and it regulates the manufacture of pharmaceutical products already being sold to ensure that they comply with federal statutes and regulations, including current “good manufacturing practice” (GMP). GMP requirements are federal standards for ensuring that pharmaceutical products are high in quality and produced under sanitary conditions. In addition, CDER enforces the act’s prohibitions against the importation of adulterated, misbranded, and counterfeit pharmaceutical products. CDER regulates the manufacture of pharmaceutical products by requesting that FDA’s Office of Regulatory Affairs (ORA) inspect manufacturers both at home and abroad to ensure that pharmaceuticals are produced in conformance with GMPs. ORA manages investigators located in FDA’s 21 district offices. Approximately 375 investigators and 75 microbiologists and chemists conduct inspections of foreign pharmaceutical manufacturers. ORA’s investigators inspect manufacturers that produce pharmaceuticals in finished form as well as manufacturers that produce the active ingredients used in finished pharmaceutical products. Typically, ORA investigators travel abroad for about 3 weeks at a time during which they inspect approximately three manufacturers. Each inspection ranges from 2 to 5 days in length, depending on the number and types of products inspected. In fiscal year 1996, FDA reviewed the results of 287 inspections of foreign pharmaceutical manufacturers conducted by its investigators in 35 countries (see figure 1). About 70 percent of these inspections were performed in manufacturing facilities that produce the active ingredients used in finished pharmaceutical products. CDER requests that ORA’s investigators conduct inspections for three reasons. First, CDER requests pre-approval inspections to ensure that before a new drug application is approved, the manufacturer of the finished pharmaceutical product as well as each manufacturer supplying a bulk pharmaceutical chemical used in the finished pharmaceutical product comply with GMPs. Each step in the manufacture and processing of a new drug, from the sources of raw materials to final packaging must be approved by FDA. Second, CDER requests postapproval or routine surveillance inspections to periodically assess the quality of marketed pharmaceutical products. During these inspections, investigators verify that manufacturers of finished pharmaceutical products and bulk pharmaceutical chemicals comply with GMPs. Third, CDER requests for-cause inspections when it receives information indicating problems in the manufacture of approved pharmaceutical products. In addition, CDER requests for-cause inspections of manufacturers that were not in compliance with GMPs during previous inspections. In for-cause inspections, FDA investigators determine whether the manufacturer has improved its production processes to comply with GMPs. During an inspection, the ORA investigator examines the pharmaceutical manufacturer’s production processes, product packaging and labeling processes, product contents, warehouse practices, quality control, laboratories, recordkeeping systems, and other manufacturing practices. The investigator reports observations of significant objectionable conditions and practices that do not conform to GMPs on the list-of-observations form, commonly referred to as FDA form 483. At the end of the inspection, the investigator gives a copy of the form 483 to the highest ranking management official present at the manufacturing facility. The investigator also discusses the observations on the form 483 with the firm’s management to ensure that they are aware of any deviations from GMPs that were observed during the inspection and suggests that the manufacturer respond to FDA in writing concerning all actions taken as a result of the observations. Figure 2 shows FDA’s process for managing foreign pharmaceutical inspections. After returning to the district office, the investigator prepares an establishment inspection report that describes the manufacturing operations observed during the inspection and any conditions that may violate federal statutes and regulations. The investigator also recommends whether the manufacturer is acceptable to supply pharmaceutical products to the United States. The investigator’s district office formally endorses the recommendation after reviewing the inspection report to determine if it supports the proposed recommendation. The district office forwards its endorsement along with the investigator’s establishment inspection report and the form 483 to CDER. The foreign inspection team within CDER’s Office of Compliance reviews the documentation and the manufacturer’s written response to FDA about any corrective actions taken. CDER then decides whether the manufacturer complies with GMPs. Inspections of pharmaceutical manufacturers are classified in one of three categories. As table 1 shows, during fiscal year 1996, 238 inspections (or 83 percent) revealed deviations from GMPs. Of these, CDER determined that 46 inspections revealed deviations from GMPs that ranked in the most serious (or “official action indicated”) category. When CDER classifies a foreign pharmaceutical inspection as “official action indicated” (OAI), it sends the manufacturer an enforcement letter. CDER issues two types of enforcement letters: untitled letters and warning letters. CDER issues an untitled letter to a foreign manufacturer when the inspection was conducted as part of its review of a new drug application and the manufacturer has not previously been inspected and accepted to supply approved pharmaceutical products to the United States. The untitled letter notifies the manufacturer that its manufacturing process does not comply with federal statutes and regulations and that failure to take corrective action may result in the disapproval of any new drug application on which the manufacturer is listed. CDER issues a warning letter to a foreign manufacturer when a subsequent inspection of its facility is classified as OAI. Warning letters are issued to manufacturers that are already supplying approved pharmaceutical products to the United States. Warning letters indicate that serious manufacturing deficiencies can and are affecting commercially marketed products. The warning letter notifies the manufacturer of its violation of federal statutes and regulations and that failure to take corrective action may result in further FDA enforcement action. CDER issued 17 untitled letters and 19 warning letters to foreign pharmaceutical manufacturers in fiscal year 1996. If CDER classifies an inspection as OAI and believes the manufacturer’s product is adulterated because it was not produced in compliance with GMPs, CDER can instruct the district offices to cooperate with the U.S. Customs Service in detaining the manufacturer’s product when it is offered for entry into the United States. In such a situation, the warning letter may also threaten to detain the manufacturer’s products at U.S. entry points or notify the manufacturer that detention will occur. Customs, which controls the points where foreign shipments enter the United States, ensures that adulterated pharmaceutical products are either exported from the United States or destroyed. In fiscal year 1996, CDER determined that the pharmaceutical products made by two foreign manufacturers should be detained. FDA’s 1988 internal evaluation found that delays in the submission of final inspection reports by investigators made it difficult for FDA to take prompt enforcement action against foreign manufacturers that did not comply with federal regulations that ensure the safety, purity, and quality of pharmaceutical products. Since then, FDA has taken several actions that have reduced the average time required by investigators to submit foreign inspection reports to headquarters. Despite this improvement, only about a quarter of the warning letters FDA issued in fiscal year 1996 to foreign pharmaceutical manufacturers found to have serious deficiencies met FDA’s timeliness standards. The lack of prompt enforcement action may impair FDA’s ability to prevent foreign manufacturers from exporting contaminated or adulterated pharmaceutical products to the United States. FDA’s 1988 internal evaluation of its foreign inspection program reported that the average length of time required from the completion of an inspection to CDER’s receipt of a final report was slightly more than 3 months. Delays in submitting inspection reports may hinder CDER’s ability to initiate timely enforcement actions to prevent contaminated or adulterated products from entering the United States. To reduce these delays, the evaluation recommended that FDA explore new ways of processing inspection reports. To strengthen its enforcement strategy, FDA revised its timeliness standards for new drug applications in October 1991 by requiring investigators and districts to submit all inspection reports classified as OAI or “voluntary action indicated” (VAI) to CDER within 30 work days of completing inspections. FDA also revised its enforcement policy to require CDER to review OAI inspection reports containing recommendations for warning letters and issue the letters within 15 work days. According to FDA officials, additional changes were made to help investigators submit more timely inspection reports on foreign manufacturers. In the early 1990s, FDA reduced the length of foreign inspection trips from about 6 to 3 weeks as well as the number of inspections an investigator conducted during the trip. The agency also revised inspection requirements for international travel to build time into foreign inspections for investigators to prepare their reports and provided investigators with notebook computers so that they could begin preparing their reports overseas. Although FDA has reduced the average time it takes to submit reports after inspections are completed from slightly more than 3 months to 2, over half of the reports in fiscal year 1996 did not meet FDA’s timeliness standard. Our analysis of 287 foreign inspection reports CDER reviewed during fiscal year 1996 showed that about 42 percent (102) of the inspections that identified GMP deficiencies (either OAI or VAI) were submitted on time or within 30 work days of completing inspections. However, 58 percent (141) of the inspection reports were not timely (see table 2). About half of the inspections with the most serious deficiencies (classified as OAI or requiring official action) were submitted on time and half were not. Most of the OAI inspection reports that were submitted to CDER after the 30-day deadline were submitted within 60 work days. CDER received about one-third of the inspection reports with less serious deficiencies (classified as VAI, allowing foreign manufacturers to voluntarily make corrections) on time; two-thirds were late. FDA reported more recently that its analysis of fiscal year 1997 data showed a modest improvement in the submission times for OAI and VAI inspection reports.