Ranbaxy may be subject to third-party supervision of its manufacturing of the antiviral ganciclovir, in return for gaining an exception for the product from FDA's Import Alert.

FDA issued the import alert Sept. 16, listing 33 finished products, including ganciclovir, and seven active pharmaceutical ingredients manufactured in the Ranbaxy's Dewas and Paonta Sahib facilities, after they failed to meet current good manufacturing practices requirements.

Most of the products identified on the alert are multiple source products, such as simvastatin and loratadine (see chart: " ¹ List Of Ranbaxy Drugs On 'Import Alert' Status "). However, Ranbaxy is the sole U.S. generic supplier of ganciclovir in capsule form; the product is used to treat cytomegalovirus, which often occurs in AIDS patients.

The drugs listed on the import alert are subject to refusal of admission into the U.S. but ganciclovir was an exception as FDA "considers it important to maintain a sufficient supply of this drug product."

District Inspectors Directed To Call FDA

The agency said it would work with Ranbaxy on "administrative controls" to ensure the antiviral product's safety. Each warning letter issued in tandem with the import alert spells out the expectations of Ranbaxy more directly: "Please contact the International Compliance Team immediately to discuss arrangements for your firm to continue importing ganciclovir oral capsules, which would likely include third-party supervision and verification of each batch prior to release."

According to the import alert, districts are encouraged to contact the Division of Import Operations and Policy if entries of ganciclovir API or finished dosage forms are offered for import. FDA will work with districts to review ganciclovir imports on a case-by-case basis.

The import alert could particularly affect the market for or access to one other product, isotretinoin (Roche's Accutane ). Ranbaxy has about 50 percent of the U.S. market for isotretinoin; Mylan has around 15 percent, according to Cowen & Co. analyst Ken Cacciatore. A holdup of Ranbaxy's product could mean a doubling of Mylan's isotretinoin revenue, which is currently about $25 million to $30 million annually, Cacciatore said in an investor's note after the alert.

In a Sept. 17 press statement, Ranbaxy said it is "very disappointed" by FDA's actions. "The company has responded to each concern FDA has raised during the past two years and had thought that progress was being made."

A History Of Violations

This is not the first time the facilities have come under FDA scrutiny.

The agency sent a warning letter to Ranbaxy in June 2006 citing GMP violations following a February 2006 inspection of the Paonta Sahib site (² Also see "Ranbaxy Stability Testing System Draws FDA GMP Warning Letter" - Pink Sheet, 26 June, 2006.). Violations cited in the letter affected a number of drugs including isotretinoin and the anti-retrovirals lamivudine and zidovudine - all three of which are on the current import alert list.

The new warning letters cite the Paonta Sahib site for maintaining inaccurate equipment cleaning records, incomplete batch production information and inadequate procedures to ensure packaging and labeling production.

The Dewas plant was cited for failing to establish defined areas for production of non-penicillin beta-lactam products to prevent contamination, failure to properly record batch information, failure to properly review batch discrepancies, and failure to ensure quality and purity specifications and design procedures to prevent microbiological contamination. The Dewas warning letter was issued following a January 2008 inspection and April response.

Products On Shelves Pose No Problem - FDA

While it may stop Ranbaxy products at the border, FDA is not asking for recall of products already in the drug stores.

Explaining that aspect of the alert, FDA said existing drugs made in the two plants met specifications and it found no evidence of harm to patients. The agency urged patients not to discontinue therapy.

"[We] have no reason to believe the drugs already in the U.S. from these plants pose a safety problem," Center for Drug Evaluation and Research Deputy Director Douglas Throckmorton said during a Sept. 16 press briefing on the FDA actions.

While leaders of the House Energy and Commerce Committee have repeatedly called for FDA to take action in such situations, they continue to be critical of whether the agency is doing enough.

The Ranbaxy case is "just more proof that the FDA and particularly [CDER ] have abandoned their mission," Commerce Subcommittee Chairman Bart Stupak, D-Mich., said in a release following the import alert.

"Apparently this FDA places administrative convenience over its mission to protect the public health," Committee Chairman John Dingell, D-Mich. added. "We can no longer leave methods of assuring drug safety up to discretion of this agency." Dingell could remove such discretion by adding more requirements for FDA foreign plant inspections to his global drug safety bill.

The panel has been investigating Ranbaxy's potential violations of good manufacturing practices and whether FDA "knowingly allowed" Ranbaxy to sell drugs even though the agency was "aware of this alleged pattern of systematic fraudulent conduct for at least 18 months" (³ Also see "Ranbaxy’s Ripples: Generic Drug Integrity Returns As Focus For Congress, FDA" - Pink Sheet, 21 July, 2008., p. 9).

During the Sept. 16 conference call, CDER Office of Compliance Director Deborah Autor said that the most recent inspections warranted an import alert, but "we did not believe in June 2006 that the deficiencies rose to the level that an import alert was justified."

Calling In Giuliani

And, Autor added, "until the company addresses these deficiencies, APIs and finished drug products from these plants will remain on the import alert, and will not approve any Abbreviated New Drug Applications or New Drug Applications that list either of the two facilities as the manufacturer of APIs or finished products."

Perhaps reflecting the challenge of dealing with these compliance issues on several fronts, Ranbaxy has hired former New York City Mayor Rudy Giuliani's consulting firm Giuliani Partners to provide advice and review compliance issues. The firm specializes in helping companies to resolve "critical strategic issues" and "enhance the reputation" of their businesses.

- Becky Jungbauer (r.jungbauer@elsevier.com)

Ranbaxy May Face Third-Party Oversight Of Ganciclovir Manufacturing

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