Biennial, prelicense audits net two 483s to Ben Venue.

Ben Venue Labs, Bedford, OH, Cincinnati District.

Two consecutive inspections of Ben Venue Labs show how audits that differ in focus can un-cover completely different sets of violations, and how addressing one round of observations is no guarantee of clear sailing the next time FDA comes calling.

Ben Venue underwent a regular biennial in-spection in August 1996, when investigator Frederick Lochner and microbiologists Daniel Kearns and Dr. Kirsten Vadheim, Ph.D. left a four-item 483.

According to the EIR, a February-March 1996 inspection covering a CBER-regulated product and a CDER preapproval check found no problems, al- although a 1993 CBER audit netted a "lengthy" 483.

Ben Venue subsequently introduced steam sterilization in place of ethylene oxide and modified its water systems, lyophilizer equipment, and proce-dures for lyophilization and quality control review, the EIR stated.

The deficiencies identified during the August 1996 audit leaned mainly towards documentation and record-keeping issues. FDA cited:

* Out-of-limits results for testing of a water-for-injec-tion loop in November 1995, without any deviation report generated until the inspection.

The EIR acknowledged that this was the only in-stance where a deviation lacked proper follow-up.

* Batch records that did not always contain ultra-violet scans used for in-process testing. While management countered that the records satisfied requirements by listing the numerical values of the scans, Vadheim said they had some difficulty tracking down the necessary notebook when she asked to look at spe-cific scans. The 1993 plant visit yielded a similar observation, the EIR said.

* A "Detailed Summary Report" regarding hose and valve leaks in a sterile filling room, with no record of when the leak began or ended, how much of the product was lost, and no indication of hose and valve integrity.

* Lack of documentation showing that the quality affairs unit was aware of trends involving leaks.

Upgrades noted

Vadheim acknowledged "significant upgrades" to the water-for-injection (WFI) system and considered it in "reasonable control," but suggested improvements.

For example, Vadheim questioned Ben Venue's triage of various water system points for testing on a daily, weekly and monthly basis. She doubted the adequacy of monthly testing and the company's basis for deeming some points more critical than others, according to the EIR.

Vadheim also found that the firm's deviation reports lacked adequate detail, relying on a sparse boiler-plate format, the records indicated.

The investigators expressed further concern about labeling security, noting that labels and filled, unlabeled products were left unattended while the area was shut down but not secured. The company insisted this was not a problem, but FDA countered with a complaint about a label that lacked a drug name. This item appeared in the EIR but not the 483.

When FDA returned a year later, a combined prelicensing/GMP inspection focused primarily on the heating and ventilation system, water, processes and equipment. A 10-item 483 resulted, zeroing in on aseptic areas and fill procedures. This time, the audit was conducted by CBER investigators Walter Lange and Dr. John Levchuk, Ph.D., along with Stephen Kilker of the Cincinnati District Office.

An aseptic storage room was cited for chipped and rusted equipment that could not be sterilized or sanitized, no validated minimum cooling time for oven-sterilized components, no validation or procedural controls to assure that particles or chemicals did not contaminate racks and components during sanitization, and carts that passed under air-return vents when leav-ing hot-air ovens.

Ironically, one equipment item, a nonsaniti-zable step ladder, was in the storage area because of maintenance work initiated in response to an investi-gator's query, the EIR stated.

Further concerns covered by the 483 included:

* Inadequate product-thawing procedures, no record that the thawing method had been validated and no documentation of training in these procedures.

* "Direct connection of WFI, city water and used water in the sanimatic parts washer," allowing for possible contamination of the city water and WFI system.

* Deficiencies in personnel access to a compounding room, including failure of staff to follow the procedure for shoe covers and gloves.

* A procedure for personnel access into an aseptic filling suite that could not be followed and no alarm system for the doors.

* Failure to perform scheduled preventive main-tenance on freeze driers and fillers.

* Inadequate investigation following exposure of media plates containing growth matter.

* Media fill procedures that failed to address all worst-case test conditions, particularly those associated with lyophilization and manual filling. FDA also complained about overlap in parameters among filling configurations, uninvestigated sterility test failures and lack of data to support an incubation temperature.

* An SOP for inspecting media fill containers that did not address the accountability of units with seal or glass defects, such that they might be discarded and not included in calculating a contamination rate.

* A check for visible foreign materials that was performed after labeling.

According to the EIR, management promised corrective actions on all the deviations.

Ben Venue Labs, Bedford, OH, 8/12-16/96, Doc. 108067M, $6; 8/18-22/97, Doc. 108311M, $11.50. Retrieval fees not included.