FDA Cites Boehringer Ingelheim Contract Manufacturing Subsidiary

December 28, 2007

A decision by Boehringer Ingelheim subsidiary Ben Venue Laboratories to release five finished lots of injectable anesthetic propofol that met product specifications yet significantly exceeded allowed levels of endotoxins during in-process testing has earned the company an FDA warning letter.

Ben Venue is a contract manufacturer that owns generic drug company Bedford Laboratories, which markets propofol, the active ingredient in AstraZeneca’s off-patent drug Diprivan that is used to induce and maintain general anesthesia.

The company wants to eliminate in-process testing for endotoxins altogether. During an inspection May 7 to June 15, FDA investigators noted the firm’s decision to stop taking in-process samples from bulk propofol for endotoxin testing, even after in-process bulk product failed such tests. Ben Venue’s quality control told investigators that since in-process testing for endotoxins was not a commitment in a drug application, the procedure could be eliminated.

The warning letter suggests that Ben Venue was relying on its sterilization process to reduce endotoxin levels in final lots of propofol. However, the company failed to demonstrate that the process was effective, the agency said.

The FDA also took issue with the company for relying on end-product testing alone to assure the drug meets endotoxin specifications as the product is a nonaqueous emulsion where test results for such toxins indicate a nonuniform distribution of the contaminant. 

Boehringer Ingelheim said it was working with the FDA and is confident the matter can be resolved. The warning letter can be accessed at www.fda.gov/foi/warning_letters/s6579c.pdf.