US Food and Drug Administration (FDA) is to expand worldwide

Over the horizon

26 September 2008 13:42  [Source: ICB]

A global inspection program is being developed to protect the world's supply of drugs

Cynthia Challener/Vermont

FINE CHEMICAL companies in the US and Europe have long complained that the ongoing shift of active pharmaceutical ingredient (API) manufacturing to lower-cost producers in emerging regions exposes the drug supply to growing risk. Their worries were dramatically substantiated this year, when adulterated heparin from China apparently killed scores of Americans in the US who suffered an allergic reaction to it. That the Chinese facility producing the material had never been inspected by the US Food and Drug Administration (FDA) - nor even China's State Food and Drug Administration - underlined the need for greater scrutiny.

Spurred by the incident, the US Congress has allocated additional money to the FDA for the establishment of overseas offices.

The agency is working to place one or two people in China, India, Europe and Latin America by the end of the year, and in the Middle East soon after, according to Murray Lumpkin, deputy commissioner of international and special programs.

A WORK IN PROGRESS

The Chinese government has, in principle, approved the creation of FDA offices, and the US State Department is meeting with China's foreign ministry to negotiate the final wording of an agreement.

The agency has hired a country director for the China office, and it is evaluating candidates for seven additional positions: three senior technical experts (for food, devices and medicines) and four inspectors (two each for food and medicines).

The new jobs will be filled with existing FDA employees, and new people will be hired to replace them.

"We opened the jobs to existing agency personnel to be certain of finding candidates with experience who are familiar with FDA policies and work independently," Lumpkin explains. "But we are creating new positions within the agency, and the overall result is the significant expansion of our resources."

The same process will be followed in the other regions. A country director for India was hired earlier this month, and candidates for the other positions are being reviewed. Advertisements have been or will soon be placed for the jobs in Europe, Latin America and the Middle East.

"We are very excited about the opportunity to establish a presence in key regions around the world," Lumpkin says. "It is a very good sign that the senior leadership in the country recognizes that the FDA must have both a global scope and presence to be truly effective."

He adds, though, that the process will be ongoing and iterative. The FDA has enjoyed positive collaborations with its counterparts in these regions for a long time, but having an official presence will take those relationships to a new level. India has been particularly receptive to the idea. Many leading API manufacturers there are open to additional attention from the agency.

Hyderabad, India-based Dr. Reddy's Laboratories, for example, welcomes any increase in inspections, according to a company spokeswoman. "We are confident that we comply with all requirements, and, in fact, have recently undertaken a voluntary accreditation exercise with the USP [United States Pharmacopeia] for several of our products, and have received certification for many," she says. "Any increase in FDA inspections can only serve to enhance our reputation and standing as a quality supplier."

SHARING RESOURCES

As well as creating overseas offices, the FDA has established a separate initiative to build on long-term collaborations with agencies in Europe and Australia. The FDA, the European Medicines Agency (EMEA) and Australia's Therapeutic Goods Administration have agreed to collaborate in planning and conducting inspections of API manufacturing facilities.

The pilot project, according to Emer Cooke, head of the EMEA's Inspection Sector, is designed to make better use of existing international inspection resources so that the agencies can increase their focus on areas of greater risk.

The EMEA is also working with the European Directorate for the Quality of Medicines (EDQM) and inspection agencies in France, Germany, the UK and Ireland as part of the program.

API manufacturers were chosen because of the concerns raised by the recent heparin problems, and because the International Conference on Harmonization (ICH) Q7 guidelines for inspection of good manufacturing practice (GMP) facilities provide an accepted international standard.

The agencies are developing a framework of operating procedures through which the program will be implemented. Cooke anticipates that the initiative will officially begin in early 2009, and run for 12-18 months. Inspection schedules will be shared to identify areas of potential overlap. For example, one agency may be able to conduct an inspection of a facility targeted by two or more of the collaborators, freeing the others to inspect sites that they were not previously able to do. Joint inspections are also an option. The results of all inspections will be shared, and the agencies will work together to identify the highest-risk facilities.

"The sharing of inspection reports is not new - we have been doing that on an ad hoc basis for years," emphasizes Lumpkin. "What is new in this collaboration is the prospective element."

MAKING A DECISION 

Lumpkin adds that it is important to recognize that each agency still has to make its own decisions using the shared information in the context of its own regulatory system. "There is no giving up or sharing of sovereignty."

The EMEA, for example, relies on individual EU member states to conduct inspections where there is a suspicion of noncompliance. "We stress the importance of manufacturer responsibility," says Cooke. Drug manufacturers must audit their suppliers and have knowledge of their full supply chain. "We have found, though, that they often do not have sufficient knowledge of their suppliers, and that those suppliers do not have adequate knowledge of the regulatory requirements in Europe."

The European Fine Chemicals Group (EFCG) counters that noncompliance is generally only discovered through audits and inspections, and that scheduling inspections only on the basis of suspicion of noncompliance means that many high-risk facilities are able to ship products into the EU.

The group would also like GMP certificates to be required for all APIs sold into the region. Manufacturers would cover the costs of being inspected through user fees.

"What we really need is a central agency in the EU that is responsible for all inspections and that is much tougher on quality of supply and will increase the transparency of the system," asserts Tony Scott, adviser to the EFCG.

The EMEA is developing guidance materials for the industry that address ways to properly manage the API supply. Cooke expects to have a draft prepared by the end of the year. The agency is also working with EU member states to gather data on GMP certificates, manufacturing authorizations and certificates of noncompliance, and hopes to make the information in the EudraGMP database available to the FDA and other agencies. An inspection-planning module will be added in the future.

With regard to the new collaborative effort between the EMEA and the FDA, the EFCG sees the program as an initial step in the right direction. "Only time will tell if the initiative will have an impact. We believe, though, that much more still needs to be done regarding inspections of foreign API manufacturers," Scott says.

The Bulk Pharmaceuticals Task Force (BPTF) in the US is eager to see the FDA take steps to improve its inspection program.

"We are very excited that the FDA has recognized that something must be done to improve the situation," remarks BPTF executive director Lynne Jones Batshon.

"The sharing of information between these three agencies has real potential to increase the effectiveness of the FDA. "We hope that it will be successful and that each agency will learn from the others involved."

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