Quick correction turnaround on loose vial seals doesn't crimp Ben Venue's style.

Ben Venue Laboratories, Bedford, OH, Team Biologics

Contract filler Ben Venue Labs dodged a warning letter despite the finding of repeat violations in its Bedford filling facility. Lead investigator Robert Jennings of "Team Biologics" and investigator Stephen Kilker of the Cincinnati district issued the seven-page, nine-item 483 to Ben Venue President and Chief Operating Officer Thomas Russillo Oct. 26, 2001.

A subsidiary of Boehringer Ingelheim and a contract manufacturer and filler of injectable drugs and medical devices, Ben Venue was cited for non-conforming product investigations, aseptic processing, process validation, quality control and process control.

According to the 33-page EIR, Ben Venue's previous audit in March 2000 resulted in FDA citations for process validation, failure investigations, aseptic facility deficiencies, cleaning validation, media fills and lyophilization.

The current Oct. 16-26, 2001, audit revealed "correction of some, but not all" violations from of the previous inspection. The current inspection covered the same three unnamed contract products under Center for Biologics purview as the last visit had.

Jennings observed the firm's investigations into sterility failures were incomplete and conclusions were not supported by data on five lots of product.

One of the lots cited failed a sterility test on May 11, 2001, testing positive for Enterobacter aerogenes, Enterobacter cloacae and Photobacterium logei. Jennings cited six instances where investigations into this matter were insufficient including an interview with an analyst revealing "that seals on some of the test vials were not tightly crimped." The FDAer continued that this information was not reported on the test record and no corrective actions were taken.

Jennings referred to another lot, "recalled by a contract firm due to concerns of sterility assurance on 7/26/01," as having an incomplete investigation "in that the information the incidence of seal problems in the subsequent...lot ... was not obtained until this inspection." The FDA called the rate of seal defects in this lot significant in that 341 units, or 1%, were found when the firm's investigation "showed normal incidence is lower."

Jennings also hit the firm for eight examples of aseptic processing including: a non-sterilized nitrogen supply hose breaching open the curtains of a Class 100 filling line; no requirements for active monitoring of aseptic conditions; smoke studies that did not fully demonstrate laminarity; and the lack of gowning instructions in gowning areas, in addition to various unsterilized pieces of equipment.

Four 483 items address process validation

Kilker noted that validation of a vial washer at the facility was done using pooled samples rather than using samples from individual samples. The FDAers explained this practice had "the potential to mask failures in individual channels by averaging."

Specifically, Kilker cited that in one run of vials through the washer, they "exceeded bioload limits" whereas in the next successful run, the vials were "found [with] similar bacteria, but results were averaged into acceptance specifications due to sample pooling."

The investigator also noted that process validation of biological products was incomplete in that bioburden evaluation during the manufacturing processes had not been performed.

The EIR noted this was a leftover issue from Ben Venue's previous audit and that corrective actions were incomplete. A review of the study protocols found the primary parameters addressed were chemical, protein and potency parameters rather than for bioburden.

Kilker continued noting that cleaning validation studies for compounding vessels "do not include data to show the cleaning methods that were used" and saw no assurance that required methods were performed.

Additionally, Kilker noted that validation of sanitizing agents on aseptic room surface materials did not include environmental isolates and that written procedures for monitoring cleaning of the freeze drier was not being followed.

Jennings added to the process validation citations noting the firm's review and approval of media batch fill records failed to identify missing records.

For example, the FDAer wrote that in eight media fills from July 2000 to March 2001, "six had missing records including media growth promotion (viability) and protocol deviations." Jennings also questioned why a fill was declared invalid due to missing growth promotion records while other similar studies with missing documentation were accepted.

In an interview, company spokesman Peter Hansbury said he was unable to comment on the specific inspection.

Hansbury noted that with the volume of contract work his firm handles, Ben Venue has a policy of correcting outstanding deficiencies within seven days of the inspection and that the firm did not have any currently outstanding violations with CBER.

Ben Venue Laboratories, Bedford, OH, 10/16-26/01, Doc. 109193M, $20.50 plus retrieval