Drug Safety: Preliminary Findings Suggest Weaknesses in FDA's Program for Inspecting Foreign Drug Manufacturers
Released: 2007-11-01T00:00:00

Letter

Background

FDA is responsible for overseeing the safety and effectiveness of human drugs that are marketed in the United States, whether they are manufactured in foreign or domestic establishments. Foreign establishments that market their drugs in the United States must register with FDA. As part of its efforts to ensure the safety and quality of imported drugs, FDA is responsible for inspecting foreign establishments whose products are imported into the United States. The purpose of these inspections is to ensure that foreign establishments meet the same manufacturing standards for quality, purity, potency, safety, and efficacy as required of domestic establishments.

Requirements governing foreign and domestic inspections differ. Specifically, FDA is required to inspect registered domestic establishments that have been previously approved to market their drugs in the United States every 2 years, but there is no comparable requirement for inspecting foreign establishments. FDA does not have authority to require foreign establishments to allow the agency to inspect their facilities. However, FDA has the authority to conduct physical inspections of the imported product or prevent its entry at the border.

Within FDA, CDER sets standards for and evaluates the safety and effectiveness of prescription drugs and over-the-counter drugs. Among other things, CDER requests that ORA inspect both foreign and domestic establishments to ensure that drugs are produced in conformance with federal statutes and regulations, including current GMPs. CDER requests that ORA conduct inspections of establishments that produce finished drug products. CDER also requests inspections of those that produce bulk drug substances, including the active pharmaceutical ingredients (API) used in finished drug products. These inspections are performed by investigators and laboratory analysts. ORA conducts two primary types of inspections: Preapproval inspections of domestic and foreign establishments are conducted before FDA will approve a new drug to be marketed in the United States. These inspections occur following FDA’s receipt of an NDA or ANDA and focus on the manufacture of a specific drug product. Preapproval inspections are designed to verify the accuracy and authenticity of the data contained in these applications and ensures that the manufacturer of the finished drug product, as well as each manufacturer supplying a bulk drug substance used in the finished product, manufactures, processes, and packs the drug adequately to preserve its identity, strength, quality, and purity.

Postapproval GMP surveillance inspections are conducted to ensure compliance with applicable laws and regulations pertaining to the manufacturing processes used by domestic and foreign establishments in the manufacture of finished drug products marketed in the United States and bulk drug substances used in the manufacture of those products. These inspections focus on a manufacturer’s systemwide controls for ensuring that drug products are high in quality. Systems examined during these inspections include those related to quality control, production, and packaging and labeling. These systems may be involved in the manufacture of multiple drug products.

FDA allocates funds to ORA to carry out preapproval and postapproval inspections of foreign and domestic establishments. ORA develops an annual work plan and a budget that estimates human resources available to conduct activities related to foreign inspections. ORA also develops estimates for inspections of domestic establishments. Typically, ORA investigators and laboratory analysts travel abroad for about 3 weeks at a time, during which they inspect approximately three establishments. Each establishment inspection typically lasts a week, with 1 day of each week set aside for documenting the inspection or for extending the inspection, if necessary.

CDER uses a risk-based process to select some domestic and foreign establishments for postapproval GMP surveillance inspections. According to an FDA report, the agency developed the process after recognizing that it did not have the resources to meet the requirement for inspecting domestic establishments every 2 years. The process uses a risk model to identify those establishments that, based on characteristics of the establishment and of the product being manufactured, have the greatest public health risk potential should they experience a manufacturing defect. (See table 1 for a description of the risk-based site selection model used by FDA in fiscal year 2007.) For example, FDA considers the risk to public health from poor quality over-the-counter drugs to be lower than for prescription drugs, and consequently establishments manufacturing only over-the-counter drugs receive a lower score on this factor than other manufacturers. Through this process, CDER annually prepares a prioritized list of domestic establishments and a separate, prioritized list of foreign establishments. CDER began applying this risk-based process to domestic establishments in fiscal year 2006 and expanded it to foreign establishments in fiscal year 2007.

FDA relies on multiple databases to manage the foreign drug inspection program. FDA assigns unique numeric identifiers to establishments, known as the FDA establishment identifier (FEI) number. An FEI number could be assigned at the time of registration, importation, or inspection.

DRLS contains information on foreign and domestic drug establishments that have registered with FDA. Establishments that market their drugs in the United States must register with FDA. These establishments provide information, such as company name and address and the drug products they manufacture for commercial distribution in the United States, on paper forms that are entered into DRLS by FDA.

OASIS contains information on drugs and other FDA-regulated products imported into the United States, including information on the establishment that manufactured the drug. The information in OASIS is automatically generated from data managed by U.S. Customs and Border Protection, which are originally entered by customs brokers based on the information available from the importer. Each establishment is assigned a manufacturer identification number that is generated from key information entered about an establishment’s name, address, and location.

FACTS contains information on FDA’s inspections of domestic and foreign drug establishments. FDA investigators and laboratory analysts enter information into FACTS, following completion of an inspection.

According to DRLS, in fiscal year 2007, China and India had more establishments registered to manufacture drugs for the U.S. market than any other country. Other countries that had a large number of establishments registered to manufacture drugs for the U.S. market in this year were Canada, France, Germany, Italy, Japan, and the United Kingdom. (See fig. 1.) These countries are also listed in OASIS as having the largest number of manufacturers importing drugs into the United States.

FDA Lacks Accurate Information to Effectively Manage the Foreign Drug Inspection Program

FDA does not know how many foreign establishments are subject to inspection; including the number of establishments that are registered and whose products are currently imported into the United States and establishments that are not required to register but whose products are ultimately used in drugs that are marketed here. Instead of maintaining a list of such establishments, FDA relies on information from several databases that were not designed for this purpose.

DRLS, established in 1991, is intended to list the establishments registered that manufacture drugs for the U.S. market. However, requirements for the registration of foreign establishments were not implemented until 2002. FDA expected that requiring foreign establishments to register would provide it with a comprehensive list of such establishments. In fiscal year 2007, approximately 3,000 foreign establishments were registered with FDA that manufactured human drugs, biologics, or veterinary drugs; FDA was unable to determine from this database the number of registered establishments specifically manufacturing human drugs.

DRLS provides FDA with some information about establishments subject to inspection, but contains inaccuracies and does not provide a complete count. FDA officials told us that the count of registered foreign establishments in DRLS does not reflect the actual number whose products are being imported into the United States for several reasons. First, foreign establishments may register with FDA, whether or not they actually manufacture drugs for the U.S. market. FDA officials told us that this is made more likely by the fact that FDA does not charge foreign establishments a fee to register. FDA officials pointed out that some foreign establishments register because, in foreign markets, registration may erroneously convey an “approval” or endorsement by FDA. Second, foreign establishments may not renew their registration information, although they are required by FDA to do so annually. Agency officials told us that if foreign establishments stop manufacturing drugs for the U.S. market or go out of business they may not report the change to FDA, even though it is required. FDA officials told us that the agency does not routinely verify the information provided by the establishment to ensure that it is accurate or confirm that the establishment actually manufactures drugs for the U.S. market. FDA does not know how many foreign establishments are erroneously registered. Third, foreign establishments that manufacture APIs are not required to register if their products are not directly imported into the United States.

OASIS also provides FDA with some information about establishments subject to inspection, but this database contains inaccurate data on the count of foreign establishments manufacturing drugs imported into the United States. According to OASIS, 6,760 foreign establishments manufactured drugs that were imported into the United States in fiscal year 2007. However, FDA officials told us that errors in data entry result in inaccurate counts of establishments whose drugs are imported into the United States. FDA officials told us that if information about an establishment—such as its name—was entered by customs brokers incorrectly, a new manufacturer identification number, and thus a new FEI number, could be assigned to an establishment that already has an FEI number. For example, a customs broker may enter an establishment’s name slightly differently from the way it is displayed in OASIS, such as using “Inc.” instead of “Incorporated,” which would lead to the creation of a second FEI number for the establishment. Therefore, a single establishment may be counted more than once in OASIS, which would result in an artificially high count of foreign establishments importing drugs into the United States. FDA officials acknowledge this problem but were unable to provide us with an estimate of the extent of that error. In addition, the agency does not have a process for systematically identifying and correcting these errors. To mitigate this problem, the officials told us that FDA has provided regional training to brokers as a way to improve accuracy. FDA officials also told us that the agency is pursuing a new government-wide initiative that would address this problem by providing a unique identifier for each foreign establishment involved in the import supply chain.

FDA’s data suggest that between 3,000 and 6,760 establishments could be subject to FDA inspection. However, FDA officials told us that the two databases—DRLS and OASIS—cannot be electronically integrated or interact with one another, so any comparisons are done manually for each individual establishment. Because comparisons of the data and error identification are done manually, the databases are not conducive to routine data analysis. FDA officials told us that they have not generated an accurate count of the establishments whose drugs are imported into the United States.

Because FDA does not have a list of all foreign establishments subject to inspection, in fiscal year 2007 it created a list of such establishments for the purpose of applying its risk-based process. In preparing this list, FDA draws on information from DRLS. It also obtains information from previous inspections to help it identify establishments that are subject to inspections but are not required to register—such as the manufacturer of an API whose product is not directly imported into the United States. For fiscal year 2007, this list consisted of 3,249 foreign establishments. However, as a result of the inaccuracies in DRLS, FDA recognizes that this list does not provide an accurate count of establishments subject to inspection.

FDA Conducts Relatively Few Foreign Establishment Inspections and Relies on the NDA and ANDA Review Process as the Primary Selection Factor

FDA conducts relatively few inspections of foreign drug establishments. However, because FDA is not certain how many foreign establishments are actually subject to inspection, the percentage of foreign establishments that have been inspected cannot be calculated with certainty. Most foreign establishments are selected for inspection as part of the agency’s review process associated with an NDA or ANDA. Therefore, the vast majority of foreign inspections include a preapproval inspection. In addition, although FDA has implemented a risk-based process in selecting foreign establishments for GMP surveillance inspections, relatively few such inspections are conducted. FDA tries to make efficient use of its resources by selecting establishments for these inspections that allow it to coordinate travel with preapproval inspections.

Relatively Few Foreign Establishments Are Inspected by FDA Each Year

In each year we examined, FDA inspected a small portion of foreign establishments through either preapproval or GMP surveillance inspections. However, its lack of a list of foreign establishments subject to inspection makes it difficult to determine an exact percentage. Based on our review of data on inspections, FDA conducted an average of 241 foreign establishment inspections per year from fiscal year 2002 through fiscal year 2007. Comparing this average number of inspections with FDA’s count of 3,249 foreign establishments it used to plan its fiscal year 2007 prioritized GMP surveillance inspections suggests that the agency inspects about 7 percent of foreign establishments in a given year. At this rate it would take FDA more than 13 years to inspect this group of establishments once, assuming that no additional establishments are subject to inspection.

FDA’s data indicate that some foreign drug manufacturers have not received an inspection, but the exact number of establishments not inspected was unclear. Of the list of 3,249 foreign establishments, there were 2,133 foreign establishments for which the agency could not identify a previous inspection. Agency officials told us that this count included registered establishments whose drugs are being imported into the United States that have never been inspected but also included other types of establishments, such as those whose products were never imported into the United States or those who have stopped importing drugs into the United States without notifying FDA. FDA was unable to provide us with counts of how many establishments fall into each of these subcategories. Of the remaining 1,116 establishments on FDA’s list, 242 had received at least one inspection, but had not received a GMP surveillance inspection since fiscal year 2000, and the remaining 874 establishments had received at least one GMP inspection since fiscal year 2000. Of these 874 establishments, 326 had last been inspected in fiscal years 2005 or 2006, 292 were last inspected in fiscal years 2003 or 2004, and the remaining 256 received their last inspection from fiscal year 2000 through fiscal year 2002.

FDA has increased the number of foreign establishments it inspects, most of which are concentrated in a small number of countries. From fiscal year 2002 through fiscal year 2007, the number of foreign establishment inspections FDA conducted annually varied from year to year, but increased overall from 222 in fiscal year 2002 to 295 in fiscal year 2007. During this period, FDA inspected establishments in a total of 51 countries. More than three quarters of the 1,445 foreign inspections the agency conducted during this period were of establishments in ten countries, as shown in table 2. The country with the most inspections during this period was India, which had 200 inspections. Inspections of establishments located in India increased from 11 in fiscal year 2002 to 65 in fiscal year 2007.

The Need to Conduct Preapproval Inspections Associated with NDAs and ANDAs Drives FDA’s Selection of Foreign Establishments

While enforcing GMP compliance through surveillance inspections is FDA’s most comprehensive program for monitoring the quality of marketed drugs, FDA’s inspections of most foreign establishments occur as part of the agency’s review of an NDA or ANDA. Agency officials said that FDA may need to inspect establishments involved in the manufacture of the drug referenced in an NDA or ANDA in order to meet specific goals for the timely review of these applications. As we reported in 1998 and we still found in 2007, most inspections of foreign manufacturers occur only when they are listed in an NDA or ANDA. For fiscal years 2002 through 2007, 88 percent of FDA’s inspections of foreign establishments were conducted as part of the preapproval process. When FDA receives an NDA or ANDA, CDER officials review the inspection history of each establishment listed on the application. According to FDA officials, if an establishment listed on the NDA or ANDA has received a satisfactory GMP inspection in the previous 2 years and the agency has no new concerns, FDA will consider this inspection sufficient and will not perform a preapproval inspection of this establishment.

FDA often includes a GMP inspection when it visits an establishment for a preapproval inspection. As presented in figure 2, from fiscal year 2002 through fiscal year 2007, the majority of FDA’s foreign inspections combined a preapproval inspection with a GMP inspection. According to FDA officials, because foreign establishments are inspected infrequently, it is expedient for investigators and laboratory analysts to conduct preapproval inspections and GMP inspections during the same visit to a foreign establishment. During one establishment visit, FDA investigators can conduct inspections related to multiple compliance programs. Because a GMP surveillance inspection examines the major manufacturing systems at an establishment, the results of such an inspection can be generalized to all products manufactured at a particular establishment. FDA can thus use the results of the combined inspection to make decisions in the future if that establishment is listed again in another NDA or ANDA.

FDA conducts fewer GMP surveillance inspections of foreign establishments than it does of domestic ones. Of the 1,445 foreign establishment inspections conducted from fiscal year 2002 through fiscal year 2007, 1,177 inspections included a GMP component, of which 998 were conducted in conjunction with a preapproval inspection. In contrast, FDA conducted 9,694 domestic establishment inspections that included a GMP component, of which 7,742 were not conducted in conjunction with a preapproval inspection. Figure 3 shows a comparison of foreign and domestic inspections, by type of inspection.

FDA’s funding for its domestic and foreign inspection programs is consistent with this approach. From fiscal year 2002 through fiscal year 2007, FDA dedicated more funding to domestic establishment inspections than foreign establishment inspections. The agency dedicated more funding to conduct foreign preapproval inspections than foreign GMP surveillance inspections, as shown in table 3.

FDA’s Risk-Based Process Is Used to Select Relatively Few Foreign Establishments for GMP Surveillance Inspections

Relatively few foreign establishments identified through CDER’s risk- based site selection process are selected for GMP surveillance inspections. In fiscal year 2007, after using this process to rank the 3,249 establishments by their potential risk level, CDER forwarded to ORA a list of 104 foreign establishments that it considered to be a high priority for inspection. Of these, CDER requested that ORA complete GMP surveillance inspections of 25 establishments and FDA officials estimated that about 30 such inspections were actually completed in fiscal year 2007. In fiscal year 2008, CDER submitted a list of 110 foreign establishments to ORA, with a negotiated target of at least 50 inspections.

The application of the risk-based site selection process does not ensure that the foreign establishments posing the greatest potential risk are selected for GMP surveillance inspections. First, FDA officials acknowledge that they do not have an accurate list of foreign establishments manufacturing drugs for the U.S. market to use in the application of the risk-based process. Second, the usefulness of the risk- based process is weakened by the incomplete and possibly inaccurate information on those foreign establishments that FDA has not inspected recently, as well as those that have never been the subject of a GMP surveillance inspection. As a consequence, FDA lacks sufficient data to make an accurate assessment of the potential risk of such establishments. FDA recognized the effect of such data limitations on the domestic application of the risk-based process and undertook a data quality improvement initiative in fiscal year 2005, but it has yet to make a comparable effort to improve its data on foreign establishments.

To help account for the differences in information available to FDA between foreign establishments that have and have not been inspected, the agency categorizes establishments into one of three groups for the purposes of examining risk scores: (1) those that have received a GMP surveillance inspection since fiscal year 2000; (2) those that have not received a GMP surveillance inspection since fiscal year 2000, but have received another type of inspection in that time (for example, a preapproval inspection or a veterinary drugs inspection); and (3) those that may never have received an inspection. These groups were created to account for limitations in the data and are not designed to indicate relative risk among groups. FDA officials told us that risk scores can be more readily compared within a group, than among groups. In 2007, FDA selected 33 establishments from the first group, 31 from the second group, and 40 from the third group to create the list of 104 establishments it submitted to ORA.

FDA officials indicated that they do not know if the establishments on the prioritized list forwarded to ORA differ significantly from each other in risk level. Consequently, they do not necessarily select the highest ranked establishments and therefore consider the locations of other planned inspections in making a final determination of foreign establishments from the prioritized list for GMP surveillance inspections. According to FDA officials, this gives them needed flexibility to make selections that will make efficient use of available resources. For example, if ORA is sending an investigator and laboratory analyst to a particular region in China for a preapproval inspection and an establishment in the same region appears on the prioritized list for GMP surveillance inspections, ORA might add this establishment to the inspection itinerary.

Challenges Unique to Foreign Inspections Influence the Manner in Which FDA Conducts Such Inspections

Inspections of foreign drug establishments pose unique challenges to FDA—in both human resources and logistics. For example, unlike domestic inspections, FDA does not have a dedicated staff devoted to conducting foreign inspections and relies on volunteers. In addition, unlike domestic GMP surveillance inspections, foreign establishment GMP surveillance inspections are announced in advance and inspections cannot be easily extended due to travel itineraries that involve more than one establishment. Other factors, such as language barriers, can also add complexity to the challenge of completing foreign establishment inspections.

According to FDA officials, the agency does not have a dedicated staff to conduct foreign inspections. They explained that the same investigators and laboratory analysts are responsible for conducting both foreign and domestic inspections. These staff members must meet certain criteria in terms of their experience and training to conduct inspections of foreign establishments. For example, they are required to take certain training courses and have at least 3 years of experience conducting domestic inspections before they can be considered to conduct a foreign inspection. FDA reported that it currently has approximately 335 employees who are qualified to conduct foreign inspections of drug manufacturers. Approximately 250 of these employees are investigators and 85 are laboratory analysts. These counts do not represent the number of individuals that actually conduct foreign inspections in a given year. Not all investigators and laboratory analysts who are qualified to conduct a foreign inspection do so in a given year, while others may perform multiple inspections during the same period. Using data from FACTS, we found that the total number of employees conducting pre-approval and GMP surveillance inspections of drug manufacturing establishments, either foreign or domestic, decreased from 587 in fiscal year 2002 to 446 in fiscal year 2007, as shown in table 4. However, of these, the number of employees who conducted foreign inspections of drug manufacturers increased from 100 to 141 during that same period. While an investigator and analyst team may participate in foreign inspections, FDA officials stated that in certain circumstances, such as inspections that do not involve the review of laboratory facilities, only an investigator is sent.

FDA relies on investigators and laboratory analysts to volunteer to conduct foreign inspections. FDA officials told us that it is difficult to recruit investigators and laboratory analysts to voluntarily travel to certain countries. However, officials noted that the agency provides various incentives to recruit employees for foreign inspection assignments. For example, employees receive a $300 bonus for each three week trip completed. FDA indicated that if the agency could not find an individual to volunteer for a foreign inspection trip, it would mandate the travel. However, FDA does not typically send investigators and laboratory analysts to countries for which the U.S. Department of State has issued a travel warning nor would it mandate travel to such a country. We found that 49 foreign establishments registered as manufacturers of drugs for the U.S. market were located in 10 countries that had travel warnings posted as of October 2007. However, FDA officials told us that in the past they have conducted inspections in countries with travel warnings. They also provided us with one example in which an establishment in a country with a travel warning hired security through the U.S. Department of State to protect the inspection team.

FDA also faces several logistical challenges in conducting inspections of foreign drug manufacturing establishments. FDA guidance states that inspections at foreign facilities are to be approached in the same manner as domestic inspections. However, the guidance notes that one main difference posing a significant challenge to the inspection team abroad is the logistics borne by the program itself. For example, FDA is unable to conduct unannounced inspections of foreign drug manufacturers, as it sometimes does with domestic manufacturers. FDA policy states that the agency, with few exceptions, initiates inspections of establishments without prior notification to the specific establishment or its management so that the inspection team can observe the establishment under conditions that represent normal day-to-day activities. However, prior notification is routinely provided to foreign establishments. FDA recognizes that the time and expense associated with foreign travel requires them to ensure that the foreign establishment’s managers are available and that the production line being inspected is operational during the inspection. In addition, FDA does not have explicit authority to inspect establishments in foreign countries, and it therefore may have to obtain permission from the government and company prior to the inspection. FDA officials explained that, in some cases, investigators and laboratory analysts may need to obtain a visa or letters of invitation to enter the country in which the establishment is located. In addition, FDA does not have the same flexibility to extend the length of foreign inspection trips if problems are encountered as it does with domestic inspections because of the need to maintain the inspection schedule, which FDA officials told us typically involves inspections of multiple establishments in the same country.

FDA officials also told us that language barriers can make foreign inspections more difficult to conduct than domestic inspections. The agency does not generally provide translators in foreign countries, nor does it require that foreign establishments provide independent interpreters. Instead, they may have to rely on an English-speaking representative of the foreign establishment being inspected, who may not be a translator by training, rather than rely on an independent translator.

Concluding Observations

Millions of Americans depend on the safety and effectiveness of the drugs they take. More than nine years ago we reported that FDA needed to make improvements in its foreign drug inspection program. Yet, our preliminary work indicates that fundamental flaws that we identified in the management of this program in 1998, continue to persist. FDA still does not have a reliable list of foreign establishments that are subject to inspection. As more imported drugs enter the United States, it becomes increasingly important that foreign establishments receive appropriate scrutiny. We understand that FDA currently cannot inspect all foreign establishments every few years. We also recognize that FDA has taken steps to improve its management of the foreign drug inspection program by enhancing the risk-based process it uses to select establishments for GMP surveillance inspections. In addition, FDA is pursuing an initiative that is intended to improve its identification of foreign drug establishments. However, until FDA responds to systemic weaknesses in the management of this important program, it cannot provide the needed assurance that the drug supply reaching our citizens is appropriately scrutinized, and safe.

Mr. Chairman, this completes my prepared statement, I would be happy to respond to any questions you or the other Members of the subcommittee may have at this time.

Contacts and Acknowledgments

For further information about this testimony, please contact Marcia Crosse at (202) 512-7114 or crossem@gao.gov. Contact points for our Offices of Congressional Relations and Public Affairs may be found on the last page of this testimony. Geraldine Redican-Bigott, Assistant Director; Katherine Clark; Robert Copeland; William Hadley; Cathleen Hamann; Julian Klazkin; Romonda McKinney; Lisa Motley; and Suzanne Worth made key contributions to this testimony.

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