FDA tells Gist-Brocades it needs 'global approach'.

Gist-Brocades, Delft, The Netherlands

Gist-Brocades, which had its bulk antibiotics barred for U.S. import and approval after a May 1996 inspection and subsequent warning letter, will take a "more integral approach to GMPs" and communicate better to FDA in the future, but does not plan to recall any of the drugs subject to agency concerns, a company executive said in a recent interview.

Chris Oldenhof, director of quality assurance for the Dutch company, which also is the subject of a congressional investigation, said: "We may need to be more focused on the whole system rather than specifics. We didn't communicate clearly to FDA what we did in connection with correcting items on the 483."

Two 483s from the 1996 audit, just released, show that FDA was worried about whether Gist-Brocades' products contained microbial contamination due to poor validation, stability and in-process quality control. The audit focused on the firm's bulk sterile and non-sterile penicillin, sterile ampicillin and other non-sterile drugs.

The Jan. 27 warning letter (Doc. 5050W), its second in less than two years, repeated the agency's request, made at a December 1996 meeting, for an update on validation efforts and information on media fill studies as well as studies that were subject to retrospective validation.

The inspection findings not only barred Gist-Brocades' products for import, but delayed the applications of any finished dosage forms using the firm's ingredients, the letter added.

In the letter, FDA acknowledged the company's "considerable effort and expense" in attempting to meet the agency's requirements. Nevertheless, the agency said: "Individual [Current Good Manufacturing Practice] CGMP deficiencies are often corrected without a more global approach to achieving comprehensive CGMP compliance."

No recall planned

Oldenhof said the firm does not plan to do a recall of its drugs as did Italian bulk maker Biochimica Opos. The House Commerce Oversight Subcommittee cited both companies as examples of possible FDA laxity in foreign inspections, and requested documents regarding the agency's audits. This probe had led the agency to target 60% of all inspections to be overseas from the current 40% (See related article on ACS Dobfar, May issue, page 2). FDA also was concerned about microbial contamination in the case of the two Italian firms.

In the Gist-Brocades 483s, FDA Investigator David Pulham and Microbiologist Raymond Oji cited the following problems:

* Failure to classify and monitor clean rooms under dynamic conditions.

* Airborne particulate sampling probes placed upside down, sideways and lying on a table.

* Out-of-specification pressure differentials involving an aseptic fill room.

* Unvalidated sterile filtrations.

* Lack of sterility data to support expiration dates.

* Deficiencies in storage conditions for stability samples used in sterility testing.

* Uncalibrated pressure gauges used to perform testing described in the 483 as "critical."

* No established maximum times for manufacturing processes.

* Checking of raw material bioburden only upon receipt, although the materials could be held for as long as one year.

The warning letter listed a history of violations dating back to 1988, including problems with water-for-injection sampling, failure investigations, environmental monitoring, complaint investigations regarding non-sterility, documentation of sterile processing, sanitization and training, calibration and quality control testing.

The letter also gave advice on how to monitor sterile processing areas, what constitutes a thorough investigation and the need for notifying company officials of investigations.

Gist-Brocades, Delft, Netherlands, 5/6-13/96, Doc. 107974M, $6 plus handling.