FDA, the European Medicines Agency and Australian Therapeutic Goods Administration intend to make permanent a pilot program allowing for joint facility inspections in what would be another step toward more U.S. reliance on foreign regulator and third-party data and a reduction in inspection burden.

Cooperation between FDA and EMA also is expanding with another pilot program for co-evaluation of Quality by Design (QbD) components in selected new drug applications.

The joint GMP inspection program began in December 2008 in part to address an industry complaint that the waiting periods between separate FDA and EMA inspections caused manufacturing delays.

It was intended to address Good Manufacturing Practices for active pharmaceutical ingredient manufacturers. Results were shared between the three agencies in the hopes of freeing resources for other needs.

Rick Friedman, director of the CDER Division of Manufacturing and Product Quality, said March 14 during a drug safety conference sponsored by The Pew Health Group that the partnership will move out of the pilot phase and become a permanent program.

Friedman said the agencies had been asking companies to volunteer for the joint inspections, with the possibility of turning two pre-approval inspections into one, for example.

“More and more we’re going to be doing interchangeable types of inspections where we leverage off of the information and make our own risk management decision as we’re asking industry to do,” he said. “We’re doing our own risk management … to leverage off of those inspections.”

It is a significant step for FDA as it grapples with its long-term vision for handling foreign facility inspections. The agency already has stated its existing model of inspecting all foreign facilities is not sustainable.

Over the next decade, the agency wants to set up agreements where it can rely on other mature market regulators or private third parties to handle some of the inspection load and share information.

Acting Principal Deputy Commissioner John Taylor said safety standards can be comparable, rather than equivalent, allowing FDA to use others’ data.

However, the fiscal year 2012 budget request from President Obama, while including funds for closer work with foreign governments, still is anticipating an increased FDA focus on foreign facility inspections (Also see "FDA Globalization Efforts Gain Traction Even As Budget Request Emphasizes Old Inspection Model" - Pink Sheet, 21 February, 2011.).

Surprisingly, Not A Lot Of Overlap

The FDA-EMA-Australian TGA partnership included disclosure of inspection locations, outcomes and other data for more than 1,000 sites.

The agencies had a significant portion of the identified sites in common, that is, those where more than one wanted to conduct an inspection. However, there were only 90 sites of interest shared by all three agencies, according to an interim report on the program issued by EMA in September.

Few joint inspections also were conducted. Seven had been done when the report was completed and FDA had participated in two: one with EMA at a Croatian facility and one with TGA at a Mexican facility.

EMA and TGA completed six joint inspections each, according to the report.

Two FDA-TGA joint inspections of Japanese facilities were cancelled. The report also identified 10 duplicate inspections by FDA and EMA that were completed in spite of the project. The agencies separately inspected one Chinese facility during the same month in 2009. Another duplicate was conducted at a different Chinese facility within two months the same year.

Reasons for the duplicate actions were not given in the report.

Friedman said during the Pew conference that the pilot revealed, surprisingly, that there was not a lot of overlap that could lead to duplicate inspections.

“We do have a good number of overlapping sites and those are the ones we want to leverage, but there are a surprising number of unique sites,” he said. “I think a lot of people want to get U.S. approval first at times because I think that that helps them with … shipping to the rest of the world.”

The partnership with the foreign regulators is an example of what FDA's ultimate goal may be: Inspectors from the agencies schedule a time to look through a facility and can talk to each other about negative findings to reach a common conclusion. Eventually, FDA would trust another regulator enough that it would not need its own staff to participate.

The FDA-EMA program as of last year had generated industry support, but not a lot of volunteers (Also see "EMA And FDA Co-Operate To Reduce GMP Inspections Burden" - Pink Sheet, 16 August, 2010.).

The new three-year QbD pilot program will allow FDA and EMA to review chemistry, manufacturing and control (CMC) and quality components of an application at the same time. The program stemmed from concerns that harmonized standards for QbD were being interpreted differently by the agencies, according to a written statement.

Participation in the pilot, which is scheduled to run from April 1 until March 31, 2014, will be voluntary. It only will be available for NDAs, some supplements and CMC meeting requests involving QbD elements submitted to FDA and EMA. FDA said in a written statement that biologics applications will not be included and statutory deadlines will not change.

FDA and EMA officials will be reviewing applications separately, but consulting throughout. EMA said in a written statement both sides want to develop “a common list of questions to the applicants and a harmonized evaluation of their responses.”

Private Inspector Training Available

While sharing responsibilities with European and other regulators has been encouraged and is expected, FDA still appears to be preparing to dramatically expand its internal, and potentially external, inspection force.

The agency’s inspection volume already is formidable between generic and branded drug and ingredient manufacturers.

FDA’s army of inspectors likely would increase if or when a generic drug user fee program is approved. The model that the agency and industry support includes fees that would pay for pre-approval and other inspections, allowing FDA to grow its internal staff (Also see "Generic User Fees Have Four-Month Negotiating Window As Differences Narrow" - Pink Sheet, 23 February, 2011.).

If the agency chooses to use private third-party firms to meet generic and other inspection responsibilities, it also will have to train or qualify them so the results will be reliable.

Friedman said an internal certification program for FDA inspectors could be adapted for outside use.

“If we were going to start to entertain ideas for third-party [inspectors], which we certainly are thinking about right now, that would be … a parallel type of program or similar program that we would use to certify contractors or others,” he said.

The Government Accountability Office is not optimistic third-party inspections could handle a significant inspection load. A review of a similar program implemented in FDA’s medical device divisions found little incentive for company use.

Submitting to the private inspection ensured the agency would get to the facility, while waiting for FDA inspectors could take years, GAO found. Companies also had to pay for the privilege, while agency inspections were free (“FDA Cloak And Dagger: GMP ‘Intelligence’ Sought As Part Of Globalization Plan,” “The Pink Sheet” DAILY, March 15, 2011).

By Derrick Gingery

FDA-EMA-TGA Joint Inspection Program To Be Permanent; Other Collaborations Expand

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