On Sept. 27, 2011, FDA sent Genentech a Form 483 listing several violations at the company’s South San Francisco, California, plant. The violations included problems with investigations into batch failures, inappropriate equipment design, and insufficient protection against contamination. FDA visited the plant, which produces the cancer drug Avastin, 13 times in September 2011 and made four observations.
Written records of Genentech’s investigations into batch failures at the plant did not include conclusions or follow-up, according to the form. For example, an investigation into disintegrating gaskets on a vial washer did not include instructions to compare particulates isolated from culled finished-product vials of Avastin with the disintegrating gasket material recovered after the discrepancy was identified. The investigation could not rule out the potential contamination of the lot in question, which is in quarantine.
The form also notes that a deviation report opened when a capper lost power did not describe actions taken to address an oil leak that was discovered during the investigation. “There is no documentation to provide assurance that the capper oil leak was addressed/repaired prior to the resumption of manufacturing,” said FDA on the form. The report also did not describe the disposition of the in-process vials on the manufacturing line during the shutdown and repair period.
FDA also observed that equipment used to process Avastin was not designed appropriately. The current design of the plant’s capping area allows a gap between the end of the air-filter coverage and the semipermanent plastic barriers. The gap could allow air to pass over the vials during the conveying and capping process, according to FDA. The plant also based the settings for its displaced-stopper detectors on studies performed by one of its contractors, but does not have adequate evidence to support the integrity of these studies, according to the form.
Two of the form’s observations relate to failures to protect against contamination. For example, a contract facility provides the plant with closures in folded plastic bags inside cardboard boxes, but Genentech has no data or controls to ensure that this method of shipment does not affect cap integrity or bioburden.
In addition, the form notes that procedures designed to prevent microbiological contamination of sterile drug products are not followed. Inspectors observed an operator “resting his gloved hands on his midsection near the gown zipper.” After a supervisor spoke to the operator about proper aseptic technique, the operator continued to rest his gloved hand on his midsection. This operator performed several line interventions during the FDA inspection.