Foreign drug manufacturers may face refusal of their products at the U.S. border if they do not submit to an FDA inspection, another part of the agency’s growing effort to increase oversight of the global marketplace.

Agency officials are working on a policy to place import alerts on companies that refuse or attempt to stonewall or avoid FDA inspectors that want to check their plants, meaning the products could not be allowed in the U.S.

“One of the things we’re actually discussing right now is seeking ways of placing a firm that refuses an inspection or does not respond to us … on the import alert and just block the border and not allow that product to come in,” said Carmelo Rosa, acting branch chief of the CDER Division of Manufacturing and Product Quality Office of Compliance.

FDA uses import alerts to flag problems with companies attempting to export drugs or other products to the U.S. that are not approved for sale, misbranded, or have other problems associated with them.

Products or shippers mentioned in import alerts have met agency criteria for automatic detention.

Rosa made the announcement Oct. 20 during the Generic Pharmaceutical Association’s Fall Technical Conference in the context of FDA’s effort to fight counterfeiting, especially with generic drugs.

The idea stemmed from problems with foreign firms avoiding or attempting to stall agency attempts to inspect them. Rosa said one firm said it was undergoing renovations several times to get out of an FDA visit.

Rosa said the FDA Office of Chief Counsel and others already like the import alert idea. “We have as an agency … a responsibility to protect our borders from products that are coming from unknown sources,” he said.

Tracking, Tracing, Quality Upgrades Needed

Ilisa Bernstein, acting deputy director of the CDER Office of Compliance, said at the conference FDA is working on a track-and-trace system for domestic and foreign products to improve drug security efforts. It would employ the standardized numerical identifier policy for drug packages that was released earlier this year.

Rosa also said the agency is considering establishing a universal and uniform product pedigree information standard that would document who had a product and when, how long they had it and who they bought it from and sold it to.

Ideally the standard would be electronic and used throughout the country and promoted by all stakeholders in the drug supply chain.

Rosa said the lack of traceability of products while in the supply chain is a big problem. Supplier qualification programs, quality agreements and lifecycle monitoring also usually are lacking.

Manufacturers are not adequately auditing their suppliers for product and ingredient quality and there is an over-reliance on regulatory agency inspections to fill the gaps, Rosa said.

The European Medicines Agency and FDA are working on updates to their Good Manufacturing Practices to better ensure supply chain quality, which will include requirements for supplier audits. Manufacturer audits likely will be accepted, but an FDA official said third-party audits may be better and more efficient (Also see "FDA And EMA Revising GMP Rules To Address Supply Chain Deficiencies" - Pink Sheet, 2 August, 2010.).

Don’t Rely on Agency Inspections

Regulatory inspections can be spotty as well and may not cover the relevant quality systems or may not be subject to an inspection, Rosa said.

Foreign inspection efforts are increasing as more attention is paid to the growing drug importation market. The agency now performs about 1,000 routine domestic site inspections per year. The agency performed 825 foreign site inspections in fiscal year 2009, Rosa said.

The agency also is increasing its overseas bioequivalence inspections. Rosa said the number has doubled from 22 to 44 between fiscal years 2005 and 2009. In FY 09, more than half of all BE inspections were foreign sites, he said.

Manufacturers still have to carry some of the burden in terms of ensuring quality, Rosa said. That includes establishing better quality control systems for suppliers and product ingredients.

“We have to elevate the discussion and the approach towards quality of our vendors or suppliers to another level,” he said. “It should not be left to the individual site, to the individual facility. It has to be taken to another level where we think globally of this problem.”

CDER Director Janet Woodcock made similar comments in April to the Food and Drug Law Institute, saying firms operating outside the U.S. may have to work harder to ensure their products meet FDA standards.

Woodcock said the goods may be cheaper to make, but the regulatory work is going to be more expensive (“Foreign Manufacturing Cost-Savings Might Be Offset By Regulatory Due Dilligence, FDA’s Woodcock Cautions,” “The Pink Sheet,” April 26, 2010).

Firms Have Strong Legal Options To Get Imports In

As FDA mulls its options on issuing import alerts, the agency must consider the legal remedies that firms have to fight the actions.

Most prominently, Amphastar Pharmaceuticals sued FDA on Nov. 5 after the agency detained shipments of heparin raw ingredient for its ANDA of enoxaparin, the generic of Sanofi-Aventis’ low-molecular weight heparin Lovenox (Also see "Amphastar Lawsuit Over Heparin Shipments Suggests Lovenox ANDA Approval May Be Far Off" - Pink Sheet, 1 November, 2010.).

While the lawsuit may not have resolved any concerns FDA has about the product, the court action was able to remove one impediment to approval – getting the materials into the country.

Hyman, Phelps & McNamara attorney Dara Katcher Levy noted in a blog post that "a week later, on Nov. 12, Amphastar filed a Notice of Withdrawal without prejudice of its prior Motion for Preliminary Injunction on the basis that FDA had released the materials shortly after" the suit had been filed.

"It is becoming increasingly common for import issues to be resolved through utilization of the courts (often, limited to initial pleadings) in order to compel cooperation from FDA," Levy noted.

As the episode illustrates, if firms are consistently successful in challenging FDA's holds on products regardless of whether they are related to inspections or not, the agency may decide the policy is not worth the effort.

Drug Security Legislation Also Pending

Congress could end up making import regulations for the FDA, if some pending legislation is acted upon, although the advent of Republican control in the House following the most recent election means that any current proposals will likely need to be significantly reworked in order to be enacted.

Sen. Michael Bennett, D-Colo., has sponsored a bill that would require all registered drug manufacturers to implement quality management systems and ensure the safety of all drugs, ingredients and materials used in manufacturing.

It also requires drug producers to document all parties involved in the production of their product and its ingredients. The bill, which remains in committee, did not include provisions for inspection fees or criminal liability for company executives, which had been in earlier versions (Also see "Rx Manufacturing Safety Bill Resurfaces Without Inspection Fees" - Pink Sheet, 3 August, 2010.).

Rep. Betty Sutton, D-Ohio, also introduced a bill that would require foreign manufacturers to have a registered agent in the U.S. that can accept process services for civil and regulatory actions in state and federal courts. Those companies without an agent could not import drugs to the U.S.

That bill was approved by the House Energy and Commerce Committee in July, but has not received floor action. It is doubtful it will pass in the current lame-duck session and the bill will have to be reintroduced in the next Congress.

By Derrick Gingery

Drug Shipments Into U.S. Could Depend On Facility Inspection; FDA Mulls Import Alerts

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