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FDA is taking several measures to ensure that imported drugs meet manufacturing standards.
The global expansion of pharmaceutical manufacturing and recent crises involving unsafe drug imports has put pressure on the US Food and Drug Administration to step up its oversight of foreign drug manufacturing. Congress is giving FDA additional funds to expand overseas inspections and operations, and legislative proposals aim to strengthen the agency's authority to block suspect imports and to crack down on fraudulent foreign operators.
At the same time, the current approach for monitoring drug quality is generally considered to be obsolete because more active pharmaceutical ingredients (APIs) and drug products are produced and imported from overseas (see sidebar, "Global enterprise"). Janet Woodcock, director of FDA's Center for Drug Evaluation and Research (CDER), told the US House of Representatives' Energy and Commerce Committee (E&C) in May 2008 that inspections alone cannot fully evaluate the capability of manufacturing facilities to generate safe, high-quality products. And "borders can no longer be the first line of defense," said Murray Lumpkin, FDA deputy commissioner for international and special programs, at the Drug Information Association (DIA) annual meeting in June 2008. He explained that US authorities can't "inspect out" bad products at the border, they can only check that quality has been built in to a product during manufacturing.
FDA Commissioner Andrew von Eschenbach acknowledges that the agency will never have enough resources to inspect all facilities frequently enough to catch all safety and quality problems. The commissioner is traveling around the world to promote regulatory cooperation and capacity building and to establish FDA foreign offices better able to monitor local drug production and export activities.
These developments are spurring more collaborative inspection initiatives by regulatory authorities and broader support for systems to ensure the quality and safety of medical products. International standards for good manufacturing practices (GMPs) are in the works, along with risk-based approaches that focus resources on monitoring products that are more likely to harm patients if they are contaminated or compromised. Regulatory authorities are collaborating and sharing information about domestic manufacturers and inspection findings to better target resources at high-risk areas and reduce redundant oversight activities that waste resources. The regulators also want drugmakers to take full responsibility for component and product failures and to increase investments in controls and oversight of foreign suppliers.
The heparin debacle of the past year demonstrates many of the challenges and opportunities created by the globalization of pharmaceutical manufacturing. FDA's failure to conduct the required preapproval inspection of the Chinese API producer allegedly involved in the contamination was a major embarrassment for the agency. But the incident highlighted how inadequate funding has undermined FDA enforcement capability. And the problem demonstrated the need for better information systems to track manufacturers, imports, inspection activity, and companies' compliance status. Difficulties in identifying the source of product contamination, moreover, illustrate the need for broader approaches to ensure drug quality and for cooperation from Chinese and other regulatory authorities to detect and prevent similar problems.
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The heparin case also has put drug-importation issues high on FDA's priority list. Ranbaxy (Gurgaon, India) recently was hit with charges of fraudulent conduct, fabrication of stability and bioequivalence information, and attempts to conceal GMP violations, stemming from a 2006 inspection of the firm's Paonta Sahib, India, plant. FDA sent the company a Warning Letter, and the US government is suing Ranbaxy to gain access to a full audit report by consultant Parexel. Officials believe the report will document the distribution of adulterated and misbranded products, including antiretrovirals for US international AIDS-treatment programs.
Authority and responsibility
FDA oversight of foreign facilities and food and drug imports is a hot topic on Capitol Hill. The E&C has been investigating the heparin incident and FDA's foreign-inspection failures. Now the committee seeks to discover whether FDA took appropriate action to keep adulterated Ranbaxy products out of the US. Observers hear murmurs about the beginning of another generic-drug scandal—20 years after fraudulent activity rocked FDA and the then-nascent generic-drug industry.
E&C Chairman John Dingell (D-MI) and Senator Edward Kennedy (D-MA), chairman of the Senate Health, Education, Labor, and Pensions (HELP) Committee, have been developing legislation, referred to as the FDA Globalization Act, to enhance FDA's authority and to increase funds for its inspections and compliance programs. Government officials agree on the need for authority to investigate overseas violations of the Food, Drug, and Cosmetic Act and to challenge criminal conduct occurring outside the US that threatens the health and safety of US consumers. The agency also wants to be able to destroy unsafe products at the border, to impose stiffer penalties for criminal offenses involving fraudulent or counterfeit products, and to block imported products when agency officials encounter "undue delay, limits, or denials of access to foreign manufacturing sites," Woodcock testified in May.
But she voiced concern about imposing broad new user fees on importers and manufacturers, except those fees levied on entities that receive special benefits from government programs. Instead, FDA and other regulatory authorities emphasize that manufacturers must do more to ensure the safety and quality of imported APIs and products. If pharmaceutical companies in the US and Europe want to outsource manufacturing, they can expect closer scrutiny of how well they check suppliers' operations and component specifications, especially for products from abroad.
Sen. Sherrod Brown (D-OH), for example, is investigating whether foreign drug outsourcing aims to obtain cheaper and less stringently regulated imports at the expense of lost jobs and health threats for Americans. Brown asked Woodcock to explain comments at an April 2008 Senate HELP Committee hearing that drug companies outsource to obtain products from parts of the world with "lower, less stringent standards" and reduced labor costs. Brown also has queried Pfizer (New York) and Merck (Whitehouse Station, NJ) officials about whether plans to increase outsourcing raise risks. The senator wants to know which countries Merck plans to outsource to, local wages in those regions, and how Merck will track the chain of custody for each ingredient and ensure that all facilities meet quality and safety standards. If pharmaceutical companies outsource to save money, Brown says, those reduced costs should translate into savings for US consumers.
To prevent future heparin crises, FDA is expanding on-site visits to foreign facilities that produce drugs and APIs for the US market. Discussing the heparin incident, von Eschenbach explained that a timely FDA inspection of the Chinese API producer probably would not have detected the dangerous contaminant or blocked similar activity by other suppliers. But an FDA inspection might have exposed flaws in the production system that could have shut down that plant.
FDA conducted 322 foreign inspections in fiscal year (FY) 2007—a big jump up from 212 in FY 2006, 266 in FY 2005, and 260 in FY 2004. The plan is to carry out 500 foreign inspections in 2009, which will be supported in part by $150 million in supplemental appropriations for FDA approved by Congress in June 2008. Most of these visits involve preapproval inspections (PAIs), which are required for every plant listed on a new drug application or supplement before the product can be distributed in the US.
In addition to more PAIs, FDA plans to boost routine surveillance of overseas manufacturers. Similar to its risk-based approach for targeting US GMP inspections, the agency will identify foreign plants that warrant inspection based on dosage form, date of last inspection, shipping volume, and the firm's compliance history with both FDA and local regulatory authorities.
FDA's Office of Regulatory Affairs, which operates the agency's field inspection force in the US and abroad, is establishing an international cadre of inspectors to conduct site visits around the world. And whenever FDA obtains information that raises doubts about the safety of a regulated product, it will rapidly conduct a "for cause" inspection, whether foreign or domestic.
The plant-inspection burden
FDA also is making internal changes to better cope with the globalization of the pharmaceutical supply chain and the need to deal with an ever-growing number of brokers, traders, distributors, repackagers, and manufacturers. A top priority is to build an interoperable data system for facility registration and product listing. This system would accurately identify who is manufacturing which medical products and what is being distributed in the US. FDA launched a pilot to encourage manufacturers to shift from paper registration to electronic filing of establishment-registration and drug-listing information in advance of required e-filing by June 2009. A July 2008 draft guidance explains which registration and listing information manufacturers should submit and provides technical information about the e-filing process.
Beyond FDA's borders
FDA also is establishing on-the-ground regulatory offices in critical parts of the world as part of its "Beyond our Borders Initiative." The first in-country operation will be in China, followed by similar initiatives in India, Europe, Latin America, and the Middle East (most likely in Amman, Jordan). An additional $20 million from the June 2008 supplemental appropriation will enable FDA to staff the first four operations by the end of next year with 35 US employees and 13 foreign nationals.
FDA hopes to open offices in Beijing, Shanghai, and Guangzhou, China, by year's end. A relatively small staff of 13 will conduct site inspections. It also will work with Chinese regulatory authorities to better track local enforcement activities, learn about legal and political issues affecting drug regulation, and further acquaint Chinese regulators and manufacturers with US drug-quality standards and enforcement policies.
Establishing official foreign operations involves extensive negotiations. In December 2007, FDA signed a Memorandum of Agreement (MOA) with Chinese officials to improve the safety of drugs and medical devices. The MOA calls for the registration of Chinese firms that export to the US, enhanced quality tracking of drugs by Chinese authorities, and notification to FDA of inspectional failures involving plants that export to the US. The US State Department approved the assignment of FDA staffers to Chinese offices in March 2008, but a final agreement was delayed by a request from the Chinese for a similar presence in the US, which the State Department must approve.
India is next in line, and FDA is negotiating to establish offices in New Delhi and Mumbai to oversee the vast volume of drugs and APIs exported to the US. Offices in Europe will monitor sites producing drugs and medical products for export, while a Central American operation will focus on the large amounts of fruits and vegetables shipped from that region to the US.
Because US officials cannot inspect every plant or check the high volume of drugs that cross US borders, FDA seeks to collaborate more with regulatory counterparts to optimize resources and avoid redundant oversight activities (see sidebar, "The plant-inspection burden"). "Regulatory cooperation no longer is discretionary," said Lumpkin at the DIA meeting. He noted growing interest in engagement with trusted regulatory agencies to leverage scientific and regulatory resources by the following means:
Sharing foreign-inspection reports. FDA has more than 70 cooperative arrangements with foreign counterparts, including the Chinese MOA, that permit access to manufacturing information. Roughly 30 confidentiality arrangements with foreign counterparts, moreover, permit FDA to share actual inspection reports. Such information can help regulators learn more about foreign facilities in making decisions about where to target foreign inspection activities.
Joint-inspection pilot. FDA also is teaming up with the European Medicines Agency (EMEA) and Australia's Therapeutic Goods Administration to better coordinate foreign drug inspections. The three agencies will consult each other on inspection schedules and reports, initially for API manufacturers in China and India. The aim is to avoid redundant site visits and to cover more facilities. The three agencies will review manufacturing sites on each other's lists and agree on which agency should visit them first, Lumpkin explained. In certain cases, all three regulators may visit a plant together. If successful, the program could expand from APIs to drug products.
Third-party certification. FDA wants to accredit government and independent entities that can verify that certain operations or products comply with US safety and security standards. FDA has launched a third-party inspection pilot for aquacultured shrimp and is working with foreign authorities on similar programs for medical products. Agency officials would like drug-import legislation to specifically authorize its use of third-party accreditation, but skeptics on Capitol Hill note that this approach has not worked well for medical devices.
Information sharing and joint-inspection activities can make the foreign-inspection process more efficient and productive. But neither FDA, EMEA, nor other regulatory authorities are ceding the right to evaluate and make independent enforcement decisions regarding any drug product or facility. The hope is, though, that joint inspection activities will breed confidence in colleagues' approaches and decisions, said Emer Cooke, EMEA's head of inspections, at the DIA meeting. These collaborative activities could eventually lead to increased reliance on each other's inspections, Cooke suggested, adding that "cooperation, not competition" is the key to success.
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, firstname.lastname@example.org