FDA issues 6-item 483 to Ben Venue for testing, cleaning flaws.

Ben Venue Laboratories, Bedford, OH Cincinnati District

FDA investigators Mark Parmon and Stephen Kilker inspected Ben Venue Laboratories May 7-June 15, 2007, observing GMP violations in several areas of the drug manufacturer's operation.

The inspectors found that several lots of product were found to not have met endotoxin specifications; however, they were released on the basis of endotoxin tests for the final product, which found no detectable amounts of endotoxin present. The investigations for the high in-process endotoxin results were not definitively invalidated before the products were released, the FDAers wrote.

In discussions with the inspectors at the close-out meeting, Quality Assurance Manager Deborah Rogers stated that the in-process result was used for information only. Because the original submission did not require the in-process testing the firm decided to remove this test from the Propofol product.

The inspection also found that Ben Venue used test methods whose accuracy, specificity and reproducibility had not been established. The validation for an endotoxin test method "does not include a fortification of the undiluted sample to demonstrate to what extent inhibition or enhancement was present in order to justify use of a dilution fortification for positive control," the investigators wrote. Further, "validation does not address the measurement of pH of final sample dilutions for endotoxin analysis to determine if a pH adjustment is necessary."

Ben Venue's quality control unit was found to lack authority to review production records to assure that no errors had occurred. Specifically, the 483 noted, review of endotoxin test results for some products failed to catch errors in endotoxin testing in the microbiology department. In one incident, review of calibration records failed to detect that the calibration plates were beyond their due dates.

The FDAers also observed that some procedures for appropriate laboratory testing for pyrogens were not written and followed. A company procedure requires, in the event of out-of-specification results, that the original pooled sample be retested in duplicate and a new dilution be made and run with four replicates. In two cases, only two replicates were used in retesting new preparations.

In addition, Ben Venue's procedure for endotoxin retesting does not include directions for retesting in-process samples for endotoxin, although the firm routinely retests bulk pre-filtered samples according to the procedure's retest scheme.

The company had not established written procedures for cleaning and maintenance, specifically for equipment used for an emulsion product to ensure uniform particle size. The need for this procedure was documented in a CAPA opened Sept. 5, 2006, but was not available until May 23, 2007. Ben Venue Laboratories, Bedford, OH, 05/07-06/15/2007, Doc. 110114M, $78 plus retrieval