Global Manufacturing Challenges Industry Regulators

Published on: 
BioPharm International, BioPharm International-09-01-2008, Volume 21, Issue 9
Pages: 40–45

The heparin debacle and other crises involving imported drugs and biologics has put pressure on the US FDA to step up its oversight of foreign drug manufacturing.

The heparin debacle and other crises involving imported drugs and biologics has put pressure on the US Food and Drug Administration to step up its oversight of foreign drug manufacturing. Congress is giving the FDA additional funds to expand foreign inspections and overseas operations. Legislative leaders also are developing new bills to strengthen FDA authority to block suspect imports and to crack down on fraudulent foreign operators.

Jill Wechsler

At the same time, there is broad agreement that the current approach for monitoring drug quality is obsolete as more active pharmaceutical ingredients (APIs) and drug products are produced and imported from overseas (see sidebar: Global Enterprise). Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, told the House Energy and Commerce Committee in May that inspections alone cannot fully evaluate the capability of manufacturing facilities to generate safe and high-quality products. FDA Commissioner Andrew von Eschenbach similarly acknowledges that the FDA will never have enough resources to inspect all facilities frequently enough to catch all safety and quality problems.

Global Enterprise



To better assess the quality of foreign products, the FDA is establishing on-the-ground regulatory offices in critical parts of the world as part of the FDA's "Beyond our Borders Initiative." The first in-country operation will be in China, followed by similar programs in India, Europe, Latin America, and the Middle East (most likely in Amman, Jordan). An additional $20 million from a supplemental budget appropriation approved in June will enable the FDA to staff the first four operations by the end of next year with 35 US employees and 13 foreign nationals.

The FDA plans to open offices in Beijing, Shanghai, and Guangzhou, China by year-end. A staff of 13 will conduct some site inspections, but primarily work with Chinese regulatory authorities to better track local enforcement activities, become more informed of legal and political issues affecting drug regulation, and further acquaint Chinese officials and manufacturers with US drug quality standards and enforcement policies.

India is next in line, and the FDA is negotiating to establish offices in New Delhi and Mumbai to oversee the vast volume of drugs and APIs exported to the US. FDA facilities in Europe will monitor sites that produce drugs and medical products for export, while a Central American operation will focus on the large amounts of fruits and vegetables shipped to the US.

In addition, the FDA is expanding overseas inspections of drug and biotech manufacturing facilities. The agency conducted 322 foreign inspections in FY 2007—a big jump from 212 in 2006, 266 in 2005, and 260 in 2004. The plan is to carry out 500 foreign inspections in 2009, which will be supported by increased appropriations. Most of these visits involve pre-approval inspections (PAIs), which are required for every facility listed on a new drug application, biologics license application, or supplement before the product can be distributed in the US.

In addition to more PAIs, the FDA plans to boost routine surveillance of overseas manufacturers. Similar to its risk-based approach for targeting US good manufacturing practices (GMP) inspections, the agency will set priorities for inspecting foreign plants based on dosage form, date of last inspection, shipping volume, and the firm's compliance history with both the FDA and local regulatory authorities. The 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 the FDA receives information that raises doubts about the safety of a regulated product, it will rapidly conduct a for-cause inspection, whether foreign or domestic.

The 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 would more accurately identify who is manufacturing which medical products and what is being distributed in the US. The FDA has 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 draft guidance explains the registration and listing information manufacturers should submit and provides technical information on the e-filing process.


Because US officials cannot inspect every plant or check the high volume of drugs coming across US borders, the FDA seeks to collaborate more with regulatory counterparts to better use its resources and to avoid redundant oversight activities. A 2007 survey of 22 companies by the European Federation of Pharmaceutical Industries and Associations shows that regulators spent 3,000 man days and the industry more than 100,000 man days on foreign inspections, reported Genentech Senior Director John O'Connor at the DIA annual meeting in June. While most manufacturing sites experienced three or four inspections a year, a few companies reported requests for more than 25 site visits.

To reduce such duplicative efforts, the FDA 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 three agencies will review manufacturing facilities on each other's lists and agree on which agency should go in first, explained FDA Deputy Commissioner Murray Lumpkin. In certain cases, all three regulators may visit a certain plant together. If successful, the program could expand from APIs to drug products.

Sharing information on inspection findings also can help regulatory authorities avoid unnecessary inspections. The FDA has more than 70 cooperative arrangements with foreign counterparts that permit mutual access to inspection information. Some 30 confidentiality arrangements, moreover, permit the FDA to share actual inspection reports with certain regulators. Such information can support regulatory decisions on where best to target foreign inspection resources.

Third-party accreditation also can help agencies use limited resources more efficiently. The FDA seeks to accredit more government and independent entities as capable of verifying that certain operations or products comply with US safety and security standards.

Information sharing and joint inspection activities can make the foreign-inspection process more efficient and productive. But neither the FDA, the 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 that joint inspection activities will breed confidence in the approaches and decisions of colleagues, explained EMEA Head of Inspections Emer Cooke at the DIA meeting in June. These collaborative activities could eventually lead to increased reliance on each other's inspections, Cooke suggested that "cooperation, not competition" is the key to success.

Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634,