Aloxi GMP Problems May Trigger Import Controls

France's Pierre Fabre Medicament Production could find the antiemetic it manufactures for Eisai is barred from the U.S. until it takes corrective action on manufacturing problems.

While FDA's power to control imports is often thought of as a way to bar substandard products from developing countries, the agency is threatening to use that same power against a French manufacturer of an oncology drug for Eisai over GMP violations.

Pierre Fabre Medicament Production did not adequately investigate particulate contamination and other problems with the manufacturing of Aloxi (palonosetron) at its plant in Idron, France, the agency said in a March 26 warning letter that was recently posted on FDA's website.

FDA first approved Aloxi in 2003 to prevent chemotherapy-associated nausea and vomiting. Eisai acquired the marketing rights for the drug in March 2008 when it bought MGI Pharma, which licenses it from the Swiss company Helsinn Healthcare. Over the following year, the drug's U.S. sales increased 37 percent (Also see "Eisai To Reinforce Oncology R&D, Sales To Achieve 17% Income Rise" - Scrip, 15 May, 2009.).

This may be attributable to expansions of its approved indications. Just before the Eisai acquisition, in February 2008, FDA approved expanding the indication to include prevention of postoperative nausea and vomiting (Also see "Eisai Wins U.S. FDA Post-Operative Indication For Antiemetic Aloxi" - Scrip, 4 Mar, 2008.). This was followed later that year by a further expansion of the chemotherapy-related nausea and vomiting indication (Also see "Eisai’s Oral Aloxi Approved For Chemo-related Nausea/Vomiting" - Pink Sheet, 25 Aug, 2008.).

Problems At A Backup Manufacturer

The product label lists three manufacturers: Catalent Pharma Solutions in Albuquerque, Helsinn Birex Pharmaceuticals in Dublin, Ireland, and Pierre Fabre. The additional locations may come in handy for Eisai, if the agency sticks to the policy outlined in the warning letter:

"Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm's compliance with cGMP, this office will recommend withholding approval of any new applications or supplements listing your firm as a drug product manufacturer. In addition, failure to correct these violations may result in FDA denying entry of articles manufactured at Pierre Fabre Medicament Production ... into the United States."

Helsinn said that even if that came to pass, it would not pose a problem for Aloxi supply in the U.S. "The warning letter refers to a new plant [going through] qualification and subject to pre-approval inspection," Paolo Ferrari, head of international marketing for the firm, said in an interview. "No commercial manufacturing is planned in this facility currently. Aloxi is manufactured in a separate facility [that is] fully GMP compliant." Therefore, he said, there is "absolutely no impact on the current manufacturing and supply chain."

The plant has undertaken corrective action, he added, and "qualification as a backup supplier is expected by year end. The supply chain of Aloxi is managed through two different suppliers in Europe and the U.S. Pierre Fabre's new facility will be qualified as a third, backup supplier."

Inadequate Investigations, Unacceptable Response

Based on the concerns described in the warning letter, the plant has a significant amount of work to do before it becomes qualified. Pierre Fabre's problems with FDA began when the agency inspected its plant from Sept. 1 to Sept. 8, 2009. The company explained the fixes it was making in a Sept. 29, 2009, letter, but FDA said the response "lacks sufficient corrective actions."

For example, one batch of drug had out-of-limit monitoring data for non-viable particles of up to 10,319 particles per cubic meter, almost three times the maximum permitted value. "You failed to investigate these NVP excursions and determine the impact on product quality or its possible relation to the higher particulate content observed in [the] batch," FDA said.

Other violations included not thoroughly investigating unexplained discrepancies, such as injection batches that "failed to meet the yield limits [but] no root cause was identified. ...Out-of-limit results obtained during the in-process fill weight examination for [certain] validation batches were not investigated. ...A self-check test of [two] validation batches reported 19 and 6 trays, respectively, with critical defects (particles) during your routine visual inspection evaluation. No investigation was conducted."

The agency also was critical of Pierre Fabre's visual inspection procedure. "Your procedure for the visual inspections of filled vials is inadequate in that it fails to demonstrate adequate control (detection) of critical defects (particles) in vials. We are concerned that you found vials with critical defects (particles) after two Brevetti automatic inspections and a 100 percent visual inspection conducted by your manufacturing operators. We are also concerned with your OOL yield, the number of particles per volume in your product, and the effectiveness of your visual inspections."

The French company also is cited for not establishing and following written procedures to describe in-process controls, tests, or examinations.

"For example ... your process validation, which consists of compounding, vial washing/depyrogenation, filling, capping, sterilization, and visual inspection for Aloxi injection resulted in a high vial rejection rate. Additionally, a lack of NVP monitoring with OOL results was reported, as well as fill weight discrepancies. This is all an indication of deficient process controls in a non-validated manufacturing process," FDA said.

The company proposed to release three batches onto the market after reviewing results from a "mock batch" of the antiemetic drug, which FDA said it was "concerned" about. "We recommend that you conduct a thorough evaluation of your initial Aloxi validation studies and execute a second process validation study to ensure validation of the manufacturing process."

An example of the company's failure to follow written production and process control procedures is the completion of visual inspections of a certain number of vials in 8 hours and 45 minutes that should have taken 12 hours to inspect in one case and 17 hours in another case. The company said it plans to train operators in the proper procedure, but FDA said, "Your response fails to indicate whether you conducted an investigation to address the discrepancies. Please provide evidence that you have addressed the visual inspection discrepancies in the elapsed time taken by the operator."

FDA also referred the company to its September 2004 guidance on "Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice."

It is not clear whether the warning letter has led or will lead to a recall, but the drug did undergo a recall starting in November 2008 for being out of conformance with cGMP, along with more than 100 other products distributed by Advantage Dose. The recall was ongoing as of June 2009 ('The Pink Sheet,' June 24, 2009).

-Martin Berman-Gorvine ([email protected])