FDA has issued a Warning Letter to the Pfizer subsidiary Wyeth Lederle SpA for GMP violations of finished pharmaceuticals at the company’s facility in Catania, Italy. The Warning Letter, dated March 27, 2013, cites violations regarding endotoxin testing for the diluting agent for the company’s anticancer drug Torisel (temsirolimus).
The Warning Letter cites violations based on an inspection of the facility made July 9 to July 20, 2012, which showed that a batch of the diluent was released without finding the cause of out-of-specification (00S) endotoxin results. The failures began on April 17, 2012, and the plant continued to test and retest samples from this lot through August 14, 2012, which resulted in inconsistent results. In an attempt to find the root cause of the OOS results, FDA said the company used different endotoxin testing platforms, tested at three different laboratories, and wiped external vials with sanitizer to try to mitigate endotoxin failed results, but that at no point did the company conduct quantitative endotoxin testing to determine the extent of the endotoxin specification failure. It also said that the company’s explanation that secondary packaging components (i.e., cardboard) were the interfering components, which resulted in the OOS results, was “inadequate” because the company did not substantiate that the interference was the source of the endotoxin OOS results and if it were the source, how the cardboard entered the samples.
The agency concluded that the company did not have “justifiable route cause” for the inconsistent results. Moreover, the agency said that it was also concerned that the company did not extend its initial investigation on the reported endotoxin failures to include a portion of the batch that had been earlier released to the US market in January 2012. FDA, however, said the company later decided to recall this portion of the batch after discussions with FDA. FDA, however, said the company failed to submit a Field Alert Report (FAR) within the required three days of receipt of knowledge of the contamination. FDA did not receive the initial FAR concerning the OOS endotoxin results until Aug. 9, 2012
FDA is requesting that the company provide additional evidence to support repeated endotoxin failures were the result of secondary packaging. If not the case, the agency is requesting that the company provide an updated manufacturing investigation outlining potential sources for endotoxin contamination in the lot and proposed preventive actions.