The European Medicines Agency and the U.S. FDA are once again calling for pharmaceutical manufacturers to apply to them for joint good manufacturing practices inspections for medicines. But while the initiative is aimed at reducing the burden of inspections for drug companies and the agencies, companies aren't queuing up for the service.

The agencies issued an initial announcement in March 2009 in order to address companies' concerns about waiting periods between inspections, which often led to delays in the manufacturing process. The first announcement focused on EU and U.S. manufacturing only. The latest reiteration expands the offer to manufacturing facilities in third countries.

The joint GMP inspections would rely on greater international collaboration to better distribute inspection capacity. As the pharmaceutical market becomes more global, companies rely less on the U.S. and EU as production sites and increasingly turn to countries outside the traditional pharma markets, in which they can manufacture products more cheaply. Inspection delays in these expanded territories, however, have become a problem for production schedules. According to industry sources, FDA and the EMA are the most active regulators inspecting outside their territories.

Eliminates Duplicate Efforts, Speeds Inspections

The new measure will allow the agencies to eliminate duplicate efforts and monitor more sites faster and at less cost to companies. The EMA points out that the majority of national regulatory authorities in the EU by law have systems in place to verify the GMP status of drug manufacturers that sell products locally. The same is true of most "developed" countries - Japan, South Korea, Australia and New Zealand included. But countries differ in their approaches to requiring inspections outside a national territory.

Companies' plans for new product approval submissions to both agencies trigger pre-authorization/pre-approval inspection in either the U.S. or European Economic Area. Manufacturers in the midst of this process may contact FDA and/or EMA to express an interest in a joint inspection. The agencies then decide whether a joint inspection is feasible. In turn, they guarantee confidentiality relating to the information provided. They will also consider requests from manufacturers who may be expecting to host routine surveillance inspections from both agencies in a similar time frame.

Industry trade associations have previously raised the issues of international duplication of inspection and associated resources. Industry, therefore, in theory, believes that a joint approach could make the inspections system more effective. The Association of the British Pharmaceutical Industry said that the development is "a positive step towards reducing the burden of increasing requests from a variety of sources to inspect manufacturing facilities."

Pfizer, the world's largest drug manufacturer, also voiced support for the renewed initiative. "From our perspective, it's more time efficient to conduct the GMP inspections jointly. We also have the opportunity to gain simultaneous feedback on our systems and processes from two regulatory agencies, which may provide additional insight beyond that provided during inspections by one agency alone. We also believe that collaboration between regulators is vital, given the global nature of our business. So it's a win-win, both for Pfizer and for the two agencies that are inspecting our plants," said a spokesperson for the company.

Still, the initiative has gotten off to a slow start - for reasons that no one seems to fully understand. "When we announced the initiative, the message did not really get through and so we are calling attention to this once again," said Monika Benstetter, spokesperson for the EMA.

Furthermore, a request for a joint inspection does not guarantee that such an inspection can go ahead. Scheduling conflicts and lack of available resources may lead one or both of the agencies to decline to participate. "Another reason for perhaps not agreeing to a joint inspection could be related to the product," suggested Benstetter, adding that joint inspections may not work for facilities that are producing complex molecules.

The agencies insist, however, that rejections will not affect the outcome of a submission which is ultimately processed separately by each agency. Where a major disagreement on the conclusion of the inspection arises between the agencies, they will proceed separately and conclude the inspection in accordance with their own national procedures.

If an inspection receives a negative result, the FDA and EMA will liaise with each other to ensure a common understanding and, if possible, an agreed conclusion before closing out the inspection process.

The EMA, backed by the European Commission, began cooperating with FDA in September 2003, when the agencies entered into confidentiality arrangements as a prerequisite for establishing a framework for exchanging information on advance drafts of legislation and regulatory guidance documents. In July 2009, the agencies launched a joint Good Clinical Practice (GCP) initiative. They began the program with an 18-month pilot phase looking at a subset of regulated products, specifically those regulated by the FDA Center for Drug Evaluation and Research and by the EMA for the centralized procedure in the European Economic Area.

In November 2008, a provisional date was announced for co-operation between the then EMA, the FDA and Australia's Therapeutic Goods Administration in the field of inspections for active pharmaceutical ingredients. An 18-month pilot project actually took off in December 2008. The agencies shared the 60 inspection results gathered to date during the course of 2009.

-Faraz Kermani (F.Kermani@elsevier.com)

EMA And FDA Co-Operate To Reduce GMP Inspections Burden

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