Peritonitis reports spur changes at Fresenius.

Fresenius USA, Ogden, UT, Denver District.

Fresenius USA instituted changes in the way it processed Delflex peritoneal dialysis (PD) solutions after reports from the Centers for Disease Control and Prevention implicated its products "in a rash of cases of aseptic peritonitis" seen by dialysis clinics nationwide, according to recently released FDA inspection records.

The documents showed how a company can run into problems even when adhering to USP standards and its own approved procedures.

But this inspection also demonstrates how a firm can work closely with FDA to resolve issues without getting a warning letter. The company's response emphasized that a number of the 483 observations resulted from a "mutual effort" between Fresenius and the agency to track down the source of the problem.

The August-September 1996 audit, conducted by investigators Ted Steinke and Michael Kuchta along with microbiologist Diane Sprague, examined both PD solutions and related tube sets.

FDA's review covered tubing sterilization, batch records, complaints, betadyne used in connector sets, plus company testing for sterility, pyrogens, bioburden and bacterial endotoxin. After all that, the agency agreed with Fresenius' conclusion that the problem most likely originated not with the tubing sets, but with the solutions, the EIR stated.

In making the solutions, Fresenius used USP grade materials and performed USP sterility testing, the records stated. While USP has not issued a monograph on dialysates, the firm may have used a monograph covering sterility in general, according to a pharmacopeia spokesperson. Fresenius could not be reached for clarification.

Sterilization errors ruled out

However, sterilization did not appear to be the problem.

Fresenius had noticed high bioburden levels in mixing tanks and filled containers prior to sterilization. The firm suspected that this might have led to increased endotoxin. Although the endotoxin was within the firm's specifications, it may have been too high, according to the inspection report.

"There is not inspectional evidence that non-sterile lots of PD solutions were produced here, or that lots with levels of bacterial endotoxin exceeding the firm's specification were released and distributed...By [the] time the inspection concluded, solution bioburden counts had returned to normal levels, probably attributable to adjustments initiated in August," the EIR stated.

The firm recalled 53 lots produced during the months when bulk solution bioburden counts were high. Lots with out-of-specification endotox-in levels were destroyed, according to the records.

Despite these actions, the firm received a nine-item 483. Inadequacies cited included:

* Deficiencies in validating the sterilization process and in the "analytical consideration of bioburden."

* Product sampling and bioburden evaluation, and an increase in bioburden that seemed to contradict data in an NDA supplement.

* Identification of microorganisms before sterilization. Other 483 observations were:

* Reduced frequency for sanitizing equipment, a change FDA said was "not founded on adequate validation."

* A delay in increasing the frequency for chang-ing filters after the high bioburden counts were detected, an incorrect filter test pressure in the firm's SOP and failure of procedures to address the monitoring of filter clogging and replacement.

* Concerns about thermometer calibration and various aspects of finished product testing.

* No recorded justification or investigation after sterility testing was invalidated, among other laboratory-related concerns.

* Possible contamination sources, such as chipped paint and rust on the edges of charging hatches.

* Delays in closing complaints and filing Adverse Drug Reaction (ADRs) reports, along with failure to obtain complete information needed for complaint investigations.

Reply stresses 'mutual effort'

Fresenius' written response suggested that it had worked closely with FDA to identify any problems, stating that "many" of the observations were "the product of a mutual effort [with FDA investigators] to identify the source and practices/ procedures to eliminate a repeat of this experience."

The response defended many of the company's actions, arguing that FDA had approved its procedures and accepted them during "numerous ...inspections." Regarding the error in an SOP, Fresenius pointed out that it had discovered the problem in its own investigation and reported it to the agency.

As for sterility testing, Fresenius asserted that it had adhered to a USP monograph, the reply stated. Nevertheless, the company modified its SOP to require a documented investigation before repeat testing.

The company tightened several of its pro-cedures, including efforts to keep management aware of sampling frequency.

Addressing ADRs, Fresenius said that both peritonitis and abdominal pain - the only remaining "open" complaints - were listed on the drug label-ing and, therefore, did not qualify as "serious" and "unexpected." Consequently, the firm said, these would be covered in an annual report, not in ADRs.

The firm defended its complaint-handling procedures, while promising "increased emphasis" on documenting investigation activities and com-plaint status.

Records from the follow-up inspection in April and May 1997 show that Fresenius representatives met with FDA in November 1996 and that no warning letter was issued.

New cleaning procedures noted

The 1997 EIR noted the company's corrective actions, including new alert and action limits for bioburden and endotoxin, and, "perhaps most significantly," the establishment and validation of new cleaning procedures. "Bioburden both in bulk solutions and filled containers has returned to normal levels," the report stated.

Generally, FDA found all of the corrections adequate, while noting some delays in "bringing [complaints] to formal closure." The investigators acknowledged that the firm had been "in transition" due to its acquisition of National Medical Care. Hence, complaint handling was being assigned to different offices in the firm. Fresenius promised improvements in this area.

Not only did the firm avoid a 483 on the old observations during the return visit, it was cleared on new allegations as well.

The EIR said the investigators looked into reports that "Fresenius was collecting both un-used PD solutions and used PD cycling machines from patients' homes, then redistributing them to other patients without proper examination of the solutions or recertification of the machines."

However, according to the EIR, management denied that this was the case and explained the firm's re-examination and refurbishing procedures. The company did not return phone calls regarding an update.

Not all of Fresenius' interactions with FDA have had such a positive outcome. A device-related warning letter (Doc. 1650W) was issued to the Ogden plant in June 1994. It cited deficiencies in failure investigations, sterilization process validation and environmental controls. A warning letter issued to the company's Maumee, OH, plant in May 1995 (Doc. 3553W) cited GMP deficiencies involving liquid dialysis concentrates.

Fresenius, Ogden, UT, 8/14-21 & 9/4/96, Doc. 108494M, $27; 4/28-5/1/97, Doc. 108334M, $8. Retreival fees are additional.