Baxter handles plane crash, but finds FDA validation wish list harder to manage.

Baxter Healthcare, Irvine, CA, Los Angeles District.

FDA's January inspection of Baxter Healthcare's Irvine, CA, plant led to a warning letter when investigator Omotunde Osunsanmi cited deficiencies in validation, qualification and quality audits during a combination Quality Systems/Medical Device Reporting (MDR) audit.

The 483 represented a shift from the pre-vious inspection, in December 1996, to assess corrective action after a plane crashed into one of the manufacturing plants about 18 days earlier. That audit was classified "no action indicated," according to the most recent EIR.

In contrast, the January inspection records showed that Baxter and the investigator held different views on validation. Discussing a 483 citation regarding unvalidated corrective actions, QA Vice President Judith Scott told Osunsanmi that FDA was constantly raising the bar of expectations and the firm continues to meet the new standards/expectations," the records stated.

Although the plant makes a product subject to medical device tracking - replacement heart valves - the audit focused on Swan-Ganz pulmonary artery catheters (PACs), which are untracked.

Changes to PACs were tracked via changes to components, making it impossible to cover PAC design control, Osunsanmi wrote in the EIR. Instead, the FDAer covered changes to the components, which were produced in Irvine and shipped to Baxter's Puerto Rico facility for the PACs' final assembly.

Complaints direct FDAer to validation

It appeared from the EIR that Osunsanmi's review of complaints and MDRs alerted her to recurrent problems with catheter balloons that had holes, ruptured or failed to inflate, as well as thermistors found out-of-specification or failing after 12 hours.

The inspection revealed that the number of MDRs - which included several deaths - did not match the number of MedWatch reports for PACs on file at the Center for Devices. The plant's regulatory affairs manager, Allison Mezzanatto, explained that complaints were treated as MDR-reportable only if connected with injuries during the past two years.

However, this policy did not appear in the firm's written procedures, according to the EIR. MedWatch reports not submitted as MDRs were forwarded to CDRH for review, the report said.

Despite questions raised about complaint handling, the 483 listed no observations regarding Baxter's handling of complaints or MDRs.

Instead, Osunsanmi focused on validation, writing in the EIR that Baxter did take corrective action in response to the complaints, modified its production process for the balloon and thermistor components, but did not validate the changes.

Consequently, the investigator wrote a 483 citation for not validating the balloon-forming process, the computerized extrusion process and the polyvinyl chloride compounding process used in the tubing extrusion.

When the firm could not provide PAC functionality validation data, Osunsanmi advised management to send the data - if it turned up - along with the response to the 483.

According to the EIR, Baxter VP Scott countered that her firm conducted validation with every change to the PAC, such as qualifying the curing oven, a new thermistor position and a new pre-cure compounding vessel, as well as validating a new adhesive.

Management defends validation efforts

Although these activities may not have met the investigator's expectations, finished prod-uct testing indicated to the firm that the processes were validated, Scott said.

Osunsanmi listed in the EIR the validation documentation FDA wanted: latex and coagulant compounding, balloon dipping, leaching, stripping processes and inspection testing, as well as the extrusion concerns mentioned in the 483.

A second 483 item faulted qualification of the balloon-curing ovens for not including tem-perature distribution and monitoring of air flow velocity and direction.

According to the EIR, management replied that "oven temperatures were not an important part of the validation" and that the success of the qualification rested on the measurement of the balloons cured at different locations in the ovens.

The third and final 483 item hit the firm's quality audits for not verifying the quality system's effectiveness, since the audits neither identified nor corrected validation deficiencies.

Osunsanmi wrote in the EIR that Baxter could not provide a periodic audit certification.

However, before the end of the inspection, Scott provided, as a corrective action, a schedule that addressed "audit areas, responsible person, date of final report, original due date and current due date." Reviewer signatures and provision for certification of review by Scott would be added to the forms, the EIR stated.

Some records lost in plane crash

Baxter's response indicated that at least some of the validation records were lost during the plane crash.

However, after the inspection the company retrieved validation data and promised to pursue "a systematic approach to formalizing relevant historical data" along with "processes...to facilitate retrieval and use of the data."

The company attached a report to demon-strate that the balloon manufacturing process was validated. The firm was reviewing data on the computerized extrusion process. A 1988 PVC compounding validation report also was under review, with a summary promised within a month, according to Baxter's response letter.

Baxter prepared a temperature map and verification of air flow for the curing ovens, sub-mitting the results as a second attachment, the response stated.

The firm also upgraded its quality system audit procedure to include a checklist that required verifying validation documentation in each audit. In addition, Baxter added a column to the audit schedule to indicate completion dates.

The company submitted the validation information March 15, as promised, asserting that its processes were operating in a state of control.

In this follow-up response, Baxter also expressed surprise at learning during a meeting with FDA that complaints about the product had raised concerns about safety.

To allay these concerns, the company supplied data that showed a downward trend in complaints since 1995.

Nevertheless, the agency already had issued a warning letter March 12 (Doc. 7452W). The letter criticized the firm's response for not providing "documented evidence which provide a high degree of assurances that your...processes have been validated."

The letter said FDA would reinspect, but would not okay any product submissions or export certificates until violations were corrected.

The company could not be reached for a comment on the inspection or report on the status of corrective actions.

Baxter Healthcare, Irvine, CA, 1/27-2/5/99, Doc. 108657M, $13.50 plus retrieval.