Food and Drug Administration: Improvements Needed in the Foreign Drug Inspection Program
Released: 1998-04-24T00:00:00

Letter

Background

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.

Timeliness of Inspection Reports Has Improved, but Delays in Taking Prompt Enforcement Actions Continue

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 Has Acted to Improve the Timeliness of Enforcement Actions

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.

Inspection Reports Are More Timely, but Many Miss FDA’s Reporting Deadline

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. FDA reported that in its analysis of 230 foreign inspection reports reviewed during fiscal year 1997, about 47 percent (75) of the inspections that identified GMP deficiencies (either OAI or VAI) were submitted on time. However, 53 percent (85) of the inspection reports were not timely.

Our review of inspection reports for China and India showed that regardless of the seriousness of the GMP deficiencies found, CDER did not receive the majority of the inspection reports within the 30-work day requirement. Specifically, 22 of the 36 OAI and VAI inspection reports (61 percent) we reviewed for China and India were not submitted on time.

Although there was no one reason for the late submissions, CDER officials told us that an investigator may return to the United States 3 weeks after conducting his first inspection, making it impossible for him or her to submit an inspection report within 30 work days. Some investigators told us that the paperwork, which includes preparing numerous documents and exhibits to support the deficiencies observed, is time-consuming. In addition, after returning to their district offices, some investigators stated that they are often confronted with competing demands on their time, such as responding to problems with domestic pharmaceutical manufacturers.

FDA Enforcement Actions Still Take Too Long

Although FDA established a 15-work-day standard for issuing warning letters, about one out of four warning letters issued by CDER during fiscal year 1996 was issued on time. The extent of these delays can be significant. For example, CDER took 4 months (80 work days) to issue a warning letter to one Chinese manufacturer inspected in September 1994. In the inspection report, received by CDER 2 months after the inspection, the investigator noted 20 significant deviations from U.S. GMPs and wrote that the manufacturer was incapable of producing the injectable pharmaceutical product for which it was seeking approval. The investigator wrote that “Virtually all of the processing equipment for the first phases of processing is filthy, in extreme state of disrepair, and was removed during this inspection.” Despite the severity of the inspection findings, it was not until March 1995 that CDER sent a warning letter to the manufacturer.

As shown in table 3, it took more than 15 work days to issue 23 of the 30 warning letters sent to foreign pharmaceutical manufacturers. After receiving the inspection reports from investigators, it took CDER between 21 and 148 work days to issue the 23 late warning letters, with an average of 57 work days. According to a CDER official, CDER experienced staffing shortages during the period we examined that delayed the review of incoming foreign inspection reports.

More recently, FDA reported that its analysis of fiscal year 1997 data showed a substantial improvement in the time CDER spent in processing warning letters. FDA reported that 30 percent or 3, of the 10 warning letters issued to foreign pharmaceutical manufacturers during fiscal year 1997 were sent within 15 work days. On average, FDA issued the 10 warning letters in about 24 work days. However, compared with the number of warning letters issued during fiscal year 1996, FDA issued two-thirds fewer warning letters during fiscal year 1997.

Our analysis of inspections conducted in China and India between January 1, 1994, and May 15, 1996, showed that CDER did not issue any of the six warning letters within the agency’s 15-work-day standard. The number of work days from CDER’s receipt of inspection reports to the issuance of these warning letters ranged from 24 to 86 days, with an average of 40 days.

In one case, a February 1994 inspection of a plant in India making an antibacterial agent identified serious problems, including failure to ensure that the proper manufacturing process was followed and inadequate testing of impurities in the product and water used by the plant. The investigator also found that two deficiencies identified during a 1985 FDA inspection had not been fully corrected to meet U.S. quality standards.Given the significance of the deficiencies found during the 1994 inspection, the investigator and his district office recommended that CDER (1) not approve the new drug application, (2) advise FDA district offices to deny entry into the United States of any pharmaceutical products from this manufacturer, and (3) pursue additional enforcement actions against pharmaceutical products from the manufacturer that were already distributed in the United States. Notwithstanding the seriousness of the problems or the recommended enforcement action, it took 2 years for CDER officials to determine that they had not taken any enforcement action against this foreign manufacturer.

While CDER officials agreed with the district recommendation and planned to issue a warning letter, the letter was never sent to this foreign pharmaceutical manufacturer because CDER lost track of it during staffing changes. In March 1996, CDER officials determined that they had allowed this foreign manufacturer to continue shipping already approved bulk pharmaceutical products to the United States, even though the inspection had identified manufacturing problems such as unacceptable impurity testing procedures, no periodic review of the production process, and the failure to investigate product yields that were lower than the specified amount.

In another case, it took CDER about 3 months to issue a warning letter to a foreign pharmaceutical manufacturer operating with 17 serious GMP deficiencies. FDA inspected this foreign manufacturer in April 1995, after receiving several new drug applications listing the manufacturer as a supplier of bulk pharmaceutical chemicals for use in U.S. finished drug products. The investigator found that the manufacturer did not have an appropriate impurity testing system and identified questionable results from impurity testing. The investigator believed that these questionable results represented a deliberate attempt to conceal instances in which the pharmaceutical products contained higher levels of impurities than permitted by U.S. standards. As a result, the investigator and his district office recommended that CDER not approve the new drug applications and that it issue a warning letter to the manufacturer.

Notwithstanding the serious nature of the investigator’s findings, it took ORA about 2 months to submit the inspection report to CDER and another month for CDER to review the report. On August 1, 1995, slightly more than 3 months after the inspection, CDER issued a warning letter stating that it would not approve any applications listing this foreign pharmaceutical manufacturer as a supplier. During the time it took CDER to act on the serious deficiencies and possible fraud identified by the investigator, a U.S. finished-drug manufacturer discovered that several containers labeled as a bulk pharmaceutical chemical product from the same foreign manufacturer contained an herbicide rather than a bulk chemical.

FDA Verifies Corrective Actions in Only About Half the Cases in Which Serious Deficiencies Are Identified

Members of the Congress and industry representatives have been concerned about the consistency of FDA inspections and subsequent enforcement actions taken against domestic and foreign pharmaceutical manufacturers. In FDA’s 1993 internal evaluation, these concerns were attributed to differences in how field investigators and headquarters staff evaluated foreign inspection results and determined the appropriate follow-up activity. Moreover, the internal evaluation acknowledged that there was a perception that FDA relied on foreign facilities to correct manufacturing deficiencies because there were insufficient resources to conduct follow-up inspections to confirm that corrective actions had been implemented.

Our analysis of the foreign inspection reports reviewed during fiscal year 1996 showed that in about half the instances in which field staff concluded that the severity of inspection findings warranted a reinspection, headquarters disagreed. For domestic manufacturers with a history of serious GMP manufacturing problems, FDA typically conducts a reinspection to verify that promised corrective actions have been implemented. However, current FDA policy does not address the need for verifying the corrective actions of foreign pharmaceutical manufacturers in instances in which FDA headquarters downgrades the severity of inspection findings. As a result of downgrading, FDA conducted far fewer reinspections of foreign manufacturers than was recommended by its investigators. Without reinspections, FDA cannot adequately verify that foreign manufacturers have corrected serious deficiencies that could affect the safety, purity, and quality of their pharmaceutical products.

FDA’s 1993 Internal Review Identified Differences in the Evaluation of Inspection Findings That Affected the Frequency of Reinspections

In the 1993 internal discussion paper, FDA managers found that agency headquarters’ personnel downgraded the severity of the manufacturing deficiencies identified in foreign inspections and the need for reinspecting violative foreign manufacturers. However, they stated that FDA did not downgrade the severity of inspection findings for domestic manufacturers that had similar deficiencies. According to the review, this was caused by different FDA units being responsible for reviewing and evaluating inspection results and planning reinspections of foreign and domestic pharmaceutical manufacturers to verify corrective actions. The discussion paper identified several instances in which approval of new drug applications was withheld, based on significant GMP deficiencies discovered during domestic inspections, whereas similar deficiencies found at foreign manufacturing facilities resulted in the approval of applications.

In the discussion paper, FDA managers stated that differences between the evaluations of foreign and domestic inspection results existed for two reasons. First, unlike for domestic inspections, decisions regarding the severity of the manufacturing deficiencies identified during foreign inspections are made by CDER staff rather than by the field investigators who actually conducted the inspections and their district office managers who endorse their recommendations. Second, they indicated that a perception existed that FDA has too few resources to conduct a reinspection of a foreign manufacturer to verify that corrections have been made. According to the review, this leads CDER staff to “trust” a foreign manufacturer to correct serious manufacturing deficiencies. The review described several instances in which significant GMP deficiencies at foreign facilities received little or no enforcement action, while similar deficiencies at domestic facilities resulted in product recalls or application denials.

To correct this problem, the discussion paper recommended that district offices, where the investigators are located, rather than CDER be responsible for evaluating the results of foreign inspections and determining the appropriate enforcement action, including the need for reinspecting the manufacturer. FDA officials disagreed with the assertion that its inspection and enforcement programs were applied disparately to domestic and foreign pharmaceutical manufacturers. Further, they argued that district offices already had this responsibility.

CDER Often Downgrades Investigators’ Recommended Classifications of Inspection Findings

Our analysis of FDA computer data of foreign inspection reports reviewed during fiscal year 1996 showed that CDER and field investigators often disagree on the classification of inspection findings and the severity of the enforcement action that should be taken against foreign pharmaceutical manufacturers when GMP deficiencies are found. For 82 of the 287 foreign inspections reviewed during this period, field investigators concluded that the severity of the GMP deficiencies they observed warranted that CDER initiate official action against the manufacturers. The investigators’ district offices also endorsed their classifications of these inspections and their recommendations for enforcement action before these were forwarded along with the inspection reports and the form 483s to CDER. However, CDER officials downgraded the inspection classifications and recommendations for enforcement action in 41 of these inspections, based on foreign manufacturers’ promises to implement corrective actions. CDER officials decided that rather than OAI, 40 of these inspections should be classified as VAI and 1 should be classified as “no action indicated” (NAI). Conversely, CDER officials upgraded the field investigators’ classifications and recommendations for enforcement action in 11 foreign inspections and classified them OAI rather than VAI.

In instances in which inspections found serious GMP deficiencies but CDER downgraded the inspection classifications, FDA’s procedures allow foreign manufacturers to continue exporting pharmaceutical products to the United States without reinspections to evaluate whether they comply with U.S. quality standards. The classification of an inspection determines to a large degree whether a reinspection is conducted. The OAI classification is the most serious and requires FDA to reinspect the manufacturer to verify that it has improved its production processes to comply with GMPs. When CDER does not accept the investigators’ recommendations and classifies inspections as VAI rather than OAI, foreign manufacturers are allowed to voluntarily correct their deficiencies and respond in writing to FDA about the corrections made. FDA officials have acknowledged that they sometimes base their downgrades of inspection classifications and approvals of new drug applications on foreign manufacturers’ promises to implement corrective actions. They contend that during the next inspection, whenever it may be, FDA confirms that the corrections were made.

Our analysis of FDA computer data of foreign inspection reports reviewed during fiscal year 1997 showed that CDER and field investigators continue to disagree on the classification of inspection findings and the severity of the enforcement action that should be taken against foreign pharmaceutical manufacturers when GMP deficiencies are found. For 49 of the 230 foreign inspections reviewed during this period, field investigators concluded that the severity of the GMP deficiencies they observed warranted that CDER initiate official action against the manufacturers.

However, CDER officials downgraded the inspection classifications and recommendations for enforcement action in 32 of these inspections. CDER officials decided that rather than classify these inspections OAI, 32 of the 49 inspections (65 percent) should be classified VAI. CDER officials also upgraded the field investigators’ classifications and recommendations for enforcement action for two foreign inspections and classified them OAI rather than VAI.

FDA officials believe that in some instances the agency can adequately verify that foreign manufacturers have corrected serious deficiencies without reinspecting them. They said that foreign pharmaceutical manufacturers nearly always respond in writing concerning corrective actions taken as a result of the observations listed on the FDA form 483. They said that these responses typically include copies of the manufacturer’s documentation of the corrective actions taken, such as photographs, laboratory test results, and corrected manufacturing procedures. Consequently, FDA officials said they can evaluate a manufacturer’s corrective actions to ensure the safety, purity, and quality of its pharmaceutical products without conducting a reinspection based on the deficiencies found, the documentation provided, and the manufacturer’s history of implementing corrective action. While we recognize that there may be instances in which documentation could suffice to verify the correction of manufacturing deficiencies, inspections of facilities in China and India that we reviewed give instances in which such documentation may not have been sufficient.

A pre-approval inspection of a bulk drug manufacturer in India found several deficiencies in the procedures used to test impurity levels in the product being manufactured. Although ORA personnel recommended withholding approval of the new drug application until corrective actions had been implemented, CDER changed the final inspection classification based on its review of the manufacturer’s written explanation of the actions it was taking to correct the deficiencies identified during the inspection. CDER did not request a reinspection to verify that the corrective actions had been taken, even though FDA documents raised questions about the trustworthiness of the manufacturer. According to these documents, FDA had been notified several years earlier that this manufacturer had informed the U.S. Department of Commerce that it was no longer making a particular pharmaceutical product, despite evidence that the manufacturer was still shipping the product to the United States.

In another case, FDA conducted a for-cause inspection of a bulk pharmaceutical manufacturer in India to investigate reports that the manufacturer was using chloroform in its manufacturing process (a substance that had been found at higher than acceptable levels in the bulk pharmaceutical chemical). While the investigators found that the manufacturer was no longer using chloroform, they identified other deficiencies in how the company was measuring the impurities present in other bulk drug products that an FDA chemist characterized as “incompetence bordering on fraud.” The investigators recommended from these deficiencies that the manufacturer be considered an unacceptable source of bulk pharmaceutical chemicals. CDER disagreed with this recommendation after reviewing the manufacturer’s response to the investigators’ findings and accepted the manufacturer as a supplier of bulk pharmaceutical chemicals without verifying that it had corrected deficiencies in its impurity testing procedures.

FDA Conducts Infrequent Routine Inspections of Foreign Pharmaceutical Manufacturers

FDA’s 1988 and 1993 internal evaluations found that while FDA routinely conducted surveillance inspections of domestic pharmaceutical manufacturers, foreign manufacturers were typically inspected only when they were listed in new drug applications. The evaluations concluded that this practice, which FDA said was because of limited resources, was unreasonable and unfair to domestic manufacturers. In addition, FDA’s 1993 evaluation concluded that in the absence of reinspections, FDA could not adequately verify that foreign manufacturers corrected deviations from GMPs that had been observed during prior FDA inspections. Both evaluations recommended that FDA increase the frequency of its inspections of foreign manufacturers that supply approved pharmaceutical products to the United States.

FDA has authority to inspect foreign pharmaceutical manufacturers exporting their products to the United States under the Food, Drug, and Cosmetic Act. The purpose of the foreign inspection program is to ensure that internationally manufactured pharmaceutical products meet the same GMP standards for quality, safety, and efficacy that are required of domestic manufacturers. However, FDA is not required to inspect foreign pharmaceutical manufacturing facilities every 2 years as it is required by statute to do for domestic pharmaceutical manufacturers that must be registered with the agency. Enforcing GMP compliance through routine surveillance inspections is FDA’s most comprehensive program for monitoring the quality of marketed pharmaceutical products. FDA also uses routine surveillance inspections to verify that manufacturers have corrected all less-serious GMP deficiencies that were observed in prior FDA inspections. Each year, FDA classifies about 65 percent of its foreign pharmaceutical inspections as VAI, which means that deviations from GMPs were found but they were not serious enough to warrant FDA intervention to ensure that corrections were made. In such instances, manufacturers agree to voluntarily correct any manufacturing procedures that do not comply with U.S. GMPs.

FDA’s foreign inspection program has been predominantly a pre-approval inspection program—that is, most inspections of foreign manufacturers occur only when they are listed in new drug applications, with no routine follow-up thereafter. We found that the majority of FDA’s foreign inspections of pharmaceutical manufacturers were conducted to ensure that before a new drug application was approved, each manufacturer listed as a supplier of a bulk pharmaceutical chemical used in the manufacture of the finished pharmaceutical product had been inspected within the previous 2 years and found to comply with GMPs. During fiscal year 1995, about 80 percent of FDA’s foreign inspections were of pharmaceutical manufacturers listed in new drug applications. The remaining 20 percent consisted of routine surveillance inspections of accepted foreign pharmaceutical manufacturers. Consequently, FDA had few opportunities to verify that foreign pharmaceutical manufacturers had implemented prescribed corrective actions in response to prior inspections where less-serious GMP deviations were observed and were producing pharmaceutical products in compliance with GMPs.

FDA officials could not tell us how often accepted foreign manufacturers are inspected. FDA has inspected about 1,100 pharmaceutical manufacturers since the foreign inspection program began in 1955. For each fiscal year from 1990 through 1996, FDA conducted about 100 routine surveillance inspections of accepted foreign pharmaceutical manufacturers annually. At this rate, assuming that resources for the program remain constant, FDA will inspect each accepted foreign pharmaceutical manufacturer only once every 11 years, provided it is not listed on a new drug application.

Of the 39 inspections we reviewed for pharmaceutical manufacturers in China and India from January 1, 1994, through May 15, 1996, 11 (28 percent) were routine inspections of manufacturers producing approved pharmaceutical products rather than inspections conducted as part of FDA’s review of new drug applications. On average, we found that approximately 4 to 5 years elapsed between routine inspections of manufacturers in China and India producing approved pharmaceutical products for the U.S. market, more than twice FDA’s 2-year inspection requirement for domestic pharmaceutical manufacturers.

FDA Plans to Conduct More Routine Inspections of Foreign Pharmaceutical Manufacturers

In June 1997, FDA’s foreign inspection working group proposed a strategy for scheduling more routine surveillance inspections of accepted foreign pharmaceutical manufacturers. Led by the Deputy Commissioner of Operations, the group was asked to review the program and identify areas for improvement. The working group found that serious deviations from GMPs were identified more often in foreign pre-approval inspections (42 percent), compared with 18 percent at U.S. manufacturers. They concluded that by relying primarily on pre-approval inspections, FDA did not provide the necessary assurance that imported pharmaceutical products were manufactured in compliance with GMPs. The foreign inspection working group proposed that FDA’s foreign inspection program include more routine surveillance inspections and fewer pre-approval inspections. To accomplish this, they suggested that FDA conduct fewer pre-approval inspections of accepted foreign manufacturers. Instead, they recommended that FDA use information from routine surveillance inspections in approving new drug applications in which accepted foreign manufacturers are listed.

Recognizing that FDA does not have sufficient resources for frequent inspections of all foreign manufacturers of pharmaceutical products imported into the United States, the working group proposed using risk-based criteria to prioritize the foreign manufacturers that FDA inspects. FDA’s four-tier surveillance inspection strategy would vary the frequency of routine surveillance inspections depending on the public health risk associated with an accepted foreign manufacturer of an approved pharmaceutical product. Foreign pharmaceutical manufacturers whose prior inspections found serious deviations from GMPs would be placed in tier 1 and inspected annually. Routine surveillance inspections of all other foreign pharmaceutical manufacturers would vary from 3 to 6 years. Foreign manufacturers of pharmaceutical products that pose higher public health risks, such as sterile pharmaceutical products, would be placed in tier 2 and inspected every 3 years. Foreign manufacturers producing 10 or more pharmaceutical products for the U.S. market and those producing nonsterile bulk ingredients used in sterile finished pharmaceutical products would be placed in tier 3 and inspected every 5 years. All other foreign pharmaceutical manufacturers would be placed in tier 4 and inspected every 6 years (see table 4). The working group estimated that when the strategy is fully implemented, 60 percent of FDA’s foreign inspections will be routine surveillance inspections. The remaining 40 percent will be inspections of foreign pharmaceutical manufacturers listed in new drug applications.

FDA began implementing its four-tier surveillance inspection strategy in fiscal year 1997 by including routine surveillance inspections within its pre-approval inspections. FDA reported that 151 of the 230 foreign pharmaceutical inspections conducted during fiscal year 1997 (66 percent) were classified pre-approval and routine surveillance inspections. In addition, FDA planned to conduct routine surveillance inspections of about 150 accepted foreign pharmaceutical manufacturers placed in tiers 1 and 2. This group includes manufacturers that produce sterile pharmaceutical products and manufacturers that had prior inspections that revealed serious deviations from GMPs. FDA reported, however, that it conducted only 60 inspections of these manufacturers. As a result, although FDA conducted more routine surveillance inspections, most foreign pharmaceutical inspections still are limited predominantly to manufacturers listed in new drug applications rather than those considered high risk.

In developing its new four-tier surveillance inspection strategy, however, FDA did not include all foreign pharmaceutical manufacturers that it should consider for a routine surveillance inspection. According to FDA data, about 3,200 foreign manufacturers have submitted information to FDA listing the pharmaceutical products that they intend to export to the United States. However, FDA prioritized for routine surveillance inspections only the 1,100 foreign pharmaceutical manufacturers that it had previously inspected. Consequently, FDA’s scheduling strategy does not account for almost two-thirds of the foreign manufacturers that may be exporting pharmaceutical products to the United States. Moreover, according to the FDA official in charge of developing the surveillance inspection strategy, FDA may never inspect the majority of foreign manufacturers placed in tiers 3 and 4. However, while FDA has recognized that it does not have sufficient resources to routinely inspect all foreign manufacturers of pharmaceutical products imported into the United States, its strategy does not ensure that every foreign manufacturer exporting pharmaceutical products to the United States complies with U.S. quality standards.

Serious Problems Persist in Managing Foreign Inspection Data

Although both FDA’s 1988 and 1993 internal evaluations identified serious problems in its foreign inspection data systems, the agency still lacks a comprehensive, automated system for managing its foreign inspection program. Instead, the information FDA needs to identify the foreign pharmaceutical manufacturers it is responsible for inspecting, manage its foreign inspection workload, and monitor inspection results and enforcement actions is contained in 15 different computer systems, very few of which are integrated. As a result, essential foreign inspection information is not readily accessible to the different FDA units that are responsible for planning, conducting, and reviewing inspections and taking enforcement actions against foreign manufacturers. While FDA’s working group recently proposed several actions that FDA officials hope will correct these data system problems, they have not been implemented.

Lack of Comprehensive Automated Information System Inhibits Effective Management of Foreign Inspection Data

FDA’s 1988 internal evaluation found that its automated field management information system did not contain complete information for 37 percent of the foreign inspections that FDA conducted during fiscal years 1982 through 1987. Specifically, the Program Oriented Data System (PODS) did not contain the results of 673 of the 1,813 foreign inspections that FDA investigators had conducted during this period. Moreover, the system did not contain any data for 251 of these inspections (14 percent). The evaluation attributed the missing inspection results to PODS not being updated after CDER’s review and classification of the inspection reports. The evaluation recommended that FDA revise its procedures for entering foreign inspection data in PODS.

FDA’s 1993 internal evaluation found that essential data on foreign pharmaceutical manufacturers were not readily accessible to agency personnel. The evaluation indicated that comprehensive data for a foreign pharmaceutical manufacturer should include (1) its inspection history, (2) the results of its last FDA inspection, (3) the identification of responsible company personnel, (4) its U.S. agent or representative, (5) the products that it supplied to the United States, and (6) the domestic manufacturers and distributors that it supplied. The evaluation found that comprehensive foreign inspection information could be obtained only by searching multiple computerized databases and FDA headquarters’ files. For example, the evaluation noted several instances in which ORA investigators conducting domestic inspections suspected that U.S. manufacturers had received adulterated bulk pharmaceutical chemicals from foreign manufacturers. However, the investigators’ efforts to substantiate these suppositions were hampered because they could not readily gain access to comprehensive data for foreign pharmaceutical manufacturers. The evaluation recommended that FDA use its field management information system to provide agencywide access to complete data for all foreign manufacturers shipping pharmaceutical products to the United States.

In 1994, FDA began using a new information system to support the foreign inspection program. The Travel and Inspection Planning System (TRIPS) was specifically developed to assist FDA’s foreign inspection planning staff in managing foreign inspection assignments and the program’s budget. TRIPS is also used to monitor whether the inspection report has been completed as well as the results of the inspection. However, TRIPS is accessible to only ORA headquarters staff. As a result, foreign inspection data are not readily accessible to the different FDA units responsible for conducting foreign inspections and reviewing inspection results. FDA plans to make data from TRIPS more broadly available within the agency when it upgrades its field management information system in fiscal year 1998.

TRIPS and PODS have not significantly improved the quality of FDA’s foreign inspection data. Our analysis of data recorded in TRIPS and PODS disclosed that these systems did not contain the results of 111 of the 759 inspections (15 percent) FDA conducted of foreign pharmaceutical manufacturers between January 1, 1994, and May 15, 1996. For 68 of the 111 inspections, the database did not identify the foreign manufacturer that was inspected. TRIPS and PODS also did not include the correct inspection results for 10 of the 39 pharmaceutical manufacturers FDA inspected in China and India during this period. Specifically, the inspection results were missing for two of these manufacturers and were incorrect for eight others. The database errors in recording the results of inspections conducted in China and India occurred because the systems were not updated after CDER staff reviewed and classified the inspection reports. Without complete and accurate data, FDA cannot ensure that all “high-risk” foreign pharmaceutical manufacturers are targeted for more frequent routine surveillance inspections.

We also found that essential foreign inspection data are not readily accessible to the different FDA units responsible for planning and conducting domestic and foreign inspections, and conducting import operations. The information that FDA needs for identifying foreign pharmaceutical manufacturers, verifying their compliance with federal laws and regulations, and screening foreign-produced pharmaceutical products for importation is dispersed among 15 automated databases, most of which do not interface.

FDA’s multiple and unlinked databases inhibit the effective management of the foreign inspection program by impeding the flow of foreign inspection data to agency personnel for use in screening foreign pharmaceutical products offered for entry into the United States. For example, table 5 illustrates how the lack of linkage between 8 of FDA’s 15 databases not being linked impedes the flow of essential foreign inspection data. The first four databases described in the table are used by FDA’s district offices to support import operations. The four other databases described in the table are used by FDA headquarters staff for monitoring foreign pharmaceutical manufacturers’ compliance with federal statutes and regulations. However, because these systems do not interface, comprehensive data about foreign manufacturers are not readily available to FDA district personnel screening imported pharmaceutical products.

Consequently, much of the same data must be retrieved from one automated system to be manually entered into others. Moreover, staff must search multiple data systems to obtain a comprehensive profile of a foreign pharmaceutical manufacturer. FDA also cannot easily match foreign manufacturers that have listed with the agency with their compliance status and the pharmaceutical products that are imported into the United States.

FDA’s foreign inspection working group concluded in June 1997 that the agency continues to be plagued by having too many databases that do not automatically interface. FDA is relying on a new automated field management information system to provide agencywide accessibility to comprehensive foreign inspection data. The Field Accomplishments and Compliance Tracking System is expected to replace approximately 22 computerized databases and support automated interfaces with several existing databases. The first installment of FACTS, which is to include an inventory of foreign and domestic pharmaceutical manufacturers, is scheduled to go on line during fiscal year 1998. FDA also plans to develop additional FACTS components to assist the agency in managing its foreign inspection workload and compliance activities. These components will be included in the second installment of FACTS, which is scheduled for fiscal year 1999.

Incomplete List of Foreign Manufacturers Shipping Drugs to the United States Hinders Inspection Planning

FDA’s 1988 internal evaluation found that the agency did not maintain an inventory of all foreign pharmaceutical manufacturers that were subject to FDA regulation. At that time, the only computerized file of foreign manufacturers shipping pharmaceutical products to the United States was maintained on a personal computer that could be accessed only from within one FDA unit. The file listed the foreign pharmaceutical manufacturers that FDA had inspected and the results of the last inspection. The internal evaluation concluded that this file was inadequate because it did not contain an inspection history for each foreign pharmaceutical manufacturer that had advised FDA that it intended to ship pharmaceutical products to the United States. As a result, FDA could not ensure that it was aware of, and therefore inspecting, all foreign pharmaceutical manufacturers that were under its jurisdiction.

FDA’s 1988 evaluation recommended that the agency develop a comprehensive inventory of all foreign manufacturers shipping pharmaceutical products to the United States that could be used to improve long-range inspection planning and scheduling. To use resources better and increase knowledge agencywide, the evaluation also recommended that this inventory be available on FDA’s automated field information system.

FDA’s 1993 internal evaluation found the same problem. According to the evaluation, the lack of an inventory of the foreign manufacturers that were shipping pharmaceutical products to the United States made it virtually impossible for FDA to inspect foreign manufacturers as frequently as domestic pharmaceutical manufacturers. The evaluation detailed several instances in which a database with a comprehensive history of each establishment’s previous inspections would have assisted in identifying problems in foreign pharmaceutical manufacturers. FDA’s 1993 evaluation recommended that the agency use its automated field information system to develop an accurate and comprehensive inventory of all foreign manufacturers shipping pharmaceutical products to the United States.

It remains difficult for FDA to determine the number of foreign manufacturers shipping pharmaceutical products to the United States that should be considered for periodic inspections. Recently, an FDA official told us that the agency had to search four data systems just to determine the number of foreign manufacturers that should be considered for routine postapproval surveillance inspections. They found that the systems did not include a common data element to permit them to easily identify a foreign manufacturer from system to system. Because the names and addresses of foreign manufacturers are sometimes incomplete or inaccurate, FDA officials found that matching data among the systems was an arduous, manual, and inconclusive effort.

The June 1997 report by FDA’s foreign inspection working group acknowledged that the agency still lacked a complete list of foreign manufacturers that were shipping pharmaceutical products to the United States. According to the report, about 3,200 foreign pharmaceutical firms were listed with FDA as indicating their intent to ship products to the United States. However, FDA internal databases indicated that only about 1,100 pharmaceutical firms had been inspected by the agency. FDA officials could not explain why the remaining 2,100 firms had not been inspected.

The foreign inspection working group proposed two options for developing an official inventory of all foreign manufacturers that ship pharmaceutical products to the United States. One option would be for FDA to seek authority to require foreign pharmaceutical manufacturers to register and update their registration information annually. The other would use data from existing information systems to develop an official establishment inventory of foreign pharmaceutical manufacturers.

FDA’s efforts to reconcile data from several of its databases to more accurately estimate the number of manufacturers that it should consider for inspection under its four-tier inspection strategy should identify all foreign manufacturers that are shipping pharmaceutical products to the United States. When completed by April 1998, FDA should have a comprehensive inventory of all foreign manufacturers shipping pharmaceutical products to the United States. This information could then be used to improve FDA’s planning and scheduling of foreign pharmaceutical inspections.

Conclusions

Since 1955, FDA has inspected foreign pharmaceutical manufacturing facilities to ensure that drug products exported to the United States meet the same standards of safety, purity, and quality required of domestic manufacturers. However, two internal FDA evaluations in the past 10 years identified serious problems with the foreign inspection program that raised questions about FDA’s ability to ensure that American consumers are protected from contaminated or adulterated drug products. FDA has taken some action to address these problems. However, we found indications that certain aspects of the foreign inspection program still need improvement.

FDA continues to experience problems in ensuring that inspection reports are submitted in a timely manner and that necessary enforcement actions are promptly initiated to prevent contaminated and adulterated pharmaceutical products from entering the United States. In addition, when FDA headquarters downgrades the severity of the inspection classifications recommended by field investigators, FDA is not verifying corrective actions that foreign manufacturers have promised to take to resolve serious manufacturing deficiencies. This impairs FDA’s ability to ensure that American consumers are protected from potentially serious health risks posed by adulterated drug products.

FDA’s risk-based inspection strategy recognizes that the agency does not have sufficient resources to routinely inspect all foreign manufacturers of pharmaceutical products imported into the United States. However, even though the strategy is intended to direct inspection resources according to risk, FDA’s foreign inspection program continues to be driven by new drug applications and the agency acknowledges that it may never inspect most foreign manufacturers exporting pharmaceutical products to the United States.

Recommendations to the Commissioner of the Food and Drug Administration

To improve the effectiveness of FDA’s foreign inspection program to ensure that only safe, pure, and high quality drugs are imported into the United States, we recommend that the Commissioner of FDA ensure that serious manufacturing deficiencies are promptly identified and enforcement actions are initiated by requiring investigators to prepare inspection reports and CDER to issue warning letters within established time periods and reexamine and revise FDA’s foreign inspection strategy to provide adequate assurance that all foreign manufacturers exporting approved pharmaceutical products to the United States comply with U.S. standards. At a minimum, the strategy should include (1) timely follow-up inspections of all foreign manufacturers that have been identified as having serious manufacturing deficiencies and that promised to take corrective action and (2) periodic surveillance inspections of all foreign pharmaceutical manufacturers, not just high-risk manufacturers.

Agency Comments and Our Response

In commenting on a draft of this report, FDA took issue with a number of our findings and recommendations. As discussed earlier, FDA believes it has made substantial improvement in the timeliness of inspection reports and enforcement actions. While we recognize FDA’s progress, we note that the agency is still falling short of its standards for timeliness. As a result, we believe that FDA needs to monitor its investigators and CDER to ensure that they comply with established time periods in preparing inspection reports and issuing warning letters.

FDA was critical of our draft on several counts. FDA said we had accepted the recommendations in the 1993 discussion paper without verifying their validity or feasibility. FDA claimed that the findings and recommendations in the 1993 discussion paper were flawed in significant ways that limited its usefulness to the agency. We note, however, that subsequent to the discussion paper, in a 1995 memorandum to the agency’s Assistant Inspector General, FDA officials reported that they had thoroughly reviewed the discussion paper, investigated the issues raised, verified program weaknesses, and had either begun or agreed to implement 10 of the 13 recommendations contained in the discussion paper.

FDA also took issue with how our report described the processes followed by its district and headquarters for classifying domestic and foreign inspection reports. Specifically, FDA stated that the review performed by the supervisor or team leader in the district office is not considered to be a district endorsement of the investigator’s recommendation. However, our review of FDA documents that describe the process for classifying domestic and foreign inspection reports supports our characterization. FDA issued guidance to its district offices in September 1996 indicating that beginning in fiscal year 1997, before inspection reports are forwarded to CDER, they “will be reviewed and endorsed by district management consistent with local procedures and timeframes for domestic reports.” Also, in its memorandum to the Assistant Inspector General, FDA officials reported that district offices had began endorsing foreign drug inspection reports before the 1993 discussion paper was issued.

FDA did not concur with our recommendation for conducting more frequent inspections of all foreign manufacturers that have been identified as having serious manufacturing deficiencies and have promised to take corrective action. FDA incorrectly suggests that our recommendation was based on the premise that a final classification that is lower than the recommended classification is always wrong if it results in a less-serious classification. Rather, our report questions FDA’s ability to verify the adequacy of some corrective actions that foreign manufacturers promised to take to resolve serious manufacturing deficiencies without reinspecting them.

FDA also did not concur with our recommendation regarding the implementation of its routine surveillance inspection strategy. Given further clarification of the strategy, we have modified our recommendation.

FDA’s written comments on a draft of this report are reproduced in appendix I. FDA also provided technical comments, which we considered and incorporated where appropriate.

As we arranged with your office, unless you publicly announce the report’s contents earlier, we plan no further distribution until 30 days after its issue date. We will then send copies of this report to the Secretary of Health and Human Services, the Commissioner of the Food and Drug Administration, the Director of the Office of Management and Budget, and others who are interested. We will also make the report available to others upon request.

Please contact me on (202) 512-7119 or John Hansen, Assistant Director, on (202) 512-7105, if you or your staff have any questions. Others who contributed to this report are Gloria E. Taylor, Brenda R. James, and David Bieritz.

Comments From the Food and Drug Administration

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