A warning letter sent to an Italian subsidiary of Pfizer, Wyeth Lederle S.p.A., by the US Food and Drug Administration (FDA) claims that the company's Catania, Italy manufacturing facility has significant manufacturing and reporting deficiencies which may prevent the company's products from entering into the US.
The letter references a July 2012 inspection of the Catania plant where FDA inspectors say they found unexplained discrepancies that went uninvestigated by the company. In one instance, a diluent of the Pfizer drug Torisel was found to have failed endotoxin limit testing, but was nevertheless shipped to a contractor for later distribution to the US in January 2012.
A formal investigation into similar failures was not initiated until April 2012, FDA said, and testing continued through August 2012 in an attempt to determine the root cause of the out-of-specification results. Despite extensive testing, "At no point did you conduct quantitative endotoxin testing to determine the extent of the endotoxin specification failure," FDA observed.
And while FDA noted that Wyeth had attempted to justify some of the OOS results as the effects of interference, regulators said this explanation was not credible.
"Your response is inadequate because it does not provide scientific justification that [redacted] interference was the source of the endotoxin OOS results," FDA wrote. "Based on the testing data we believe your root cause hypothesis is not probable due to continued inconsistent results, and we do not find that you have established a justifiable root cause."
Further, the company's initial response to FDA did not address the release of the contaminated Torisel to the US. The company had later recalled that product, FDA observed, but inspectors said they were "concerned that you did not originally extend your investigation to include the US-marketed portion of the batch when you initiated your investigation into the reported endotoxin failures."
Other alleged deficiencies noted by FDA included ones familiar to any regulatory professional engaged in post-marketing functions: field alert reports (FAR). The forms are used to report (within three working days) any information indicating that a product is contaminated with bacteriological substances, or otherwise adulterated, deteriorated or physically degraded such that it fails to meet specifications.
FDA claimed that the company did not submit any FAR for the shipped batch of Torisel Diluent for approximately nine months. FDA dryly noted that these requirements have been in place since 23 May 1985.
Regulators said that the company's products may be subject to refusal of admission into the US, and might also not approve any product using Wyeth's ingredients until the alleged deficiencies are corrected.
Torisel (temsirolimus) is an IV drug used to treat renal cell carcinoma. It is approved by both FDA and the European Medicines Agency (EMA).