Novartis Receives FDA Warning Letter for cGMP Violations at Austrian Plant

FDA has issued a Warning Letter to Novartis for cGMP violations at its manufacturing facility for finished pharmaceuticals in Unterach, Austria. The site became part of Sandoz and Novartis through the acquisition of EBEWE Pharma in 2009.

The Warning Letter was issued based on an inspection of the facility from Oct. 15–23, 2012 at which FDA noted several violations of cGMP in the company’s quality control unit. FDA cited the company for failing to obtain FDA’s approval of changes in the quality controls established in an approved application prior to distributing a product with those changes. The agency noted that the company manufactured and distributed finished parenteral drugs to the US market using unapproved procedures for visual inspection prior to obtaining approval of a supplement regarding these changes.

FDA said it informed Novartis several times, in writing and orally, not to distribute the implicated product until receiving approvals of the supplements and had informed the company in writing on March 14, 2012, that these supplements were not approvable. Although Novartis ceased using the unapproved method, FDA said that the company failed to provide a plan to address the products distributed in the US market that used the method.

FDA is asking Novartis to provide all the distribution information of the lots manufactured using these unapproved methods, including risk assessments if the drug were to remain on the market. The agency is also asking the company to provide a complete list of products it manufactures and a commitment to audit current production procedures against the standards established in approved applications (including approved supplements). It is also asking the company to provide an action plan to appropriately address each discrepancy identified by the audit and to describe the specific corrective actions the firm is implementing to ensure adherence to application commitments in the future as well as proper evaluation and handling of proposed changes to them.

FDA also cited Novartis for failing to establish a scientifically sound and appropriate test procedure to determine conformance of the finished drug product to an established specification. The agency said “the procedures established to perform the visual inspection of critical defects, such as particulate matter in finished parenteral drug vials, are inadequate in that operators following these procedures have repeatedly failed to detect visible particles.” The agency said that on at least 10 occasions, the company’s inspection of finished-product vials failed to detect visible particle material. “Although we recognize that in some instances your firm rejected batches with these defects, we are concerned that you did not detect visible particles until after release of other affected lots,” said FDA in its Warning Letter. “Because your lot inspection failed to detect visible particle matter in numerous instances, we are concerned that your inspection program is not robust enough to serve its intended purpose.”

FDA is asking Novartis to describe the actions taken to ensure that the finished parenteral drugs the company manufactures are essentially free of particle matter. The agency also is asking the company to describe its revised inspection program and enhanced acceptance-quality-limit program and to indicate the impact of the particle defects on product produced for the US market.

“We take seriously the warning letter observations cited by the FDA and will work closely and expeditiously to address these concerns to the agency’s full satisfaction,” said Ameet Mallik, Sandoz’ Head of Biopharmaceuticals & Oncology Injectables, in a June 4, 2013 Novartis press release. “Sandoz has made strong progress in strengthening operations in Unterach through significant investments in both resources and state-of-the-art technologies. We remain deeply committed to fully addressing all outstanding issues and meeting all quality standards.”

Sandoz said since 2011, it is not aware of any adverse events in products manufactured at the Unterach site associated with the observations in the letter. Also, the company does not anticipate any related product supply issues at this time.

In a separate matter, FDA announced on May 20, 2013, Sandoz was conducting a voluntary nationwide recall to the hospital/user level of two lots of its methotrexate sodium, USP, 25 mg/mL, 40 mL vial injectable product in the US due to the discovery of particulate matter in vials during routine quality examination of retention samples at the manufacturer. The lot numbers and expiration dates of the two recalled lots are: CL0996 (expiration date 12/2013) and CJ4948 (expiration date 05/2013). These lots were distributed nationally across the US and to a single foreign country (Poland).