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Executive Summary

SMITHKLINE BEECHAM TIMENTIN MANUFACTURING DRAWS FDA WARNING LETTER sent by the Newark, N.J. district office on July 7. During an April-May inspection of SmithKline Beecham's Piscataway, N.J. manufacturing facility, "our investigators documented deviations from the Good Manufacturing Practice regulations causing your Timentin product to be adulterated," Newark District Director Matthew Lewis wrote. The warning letter lists six deviations from GMPs pertaining to the production of the injectable antibiotic Timentin (ticarcillin/clavulanate). The first observation pertains to "inadequate" investigation "into 16 complaints of foaming on reconstitution of Timentin, lot RB 5210," FDA said. According to the agency, "no information was available to help determine the clinical significance of the foaming." SB did not have data on any possible correlation between polymer formulation and product degradation, FDA added, nor had the company validated its polymer determination test. "Field Alert Reports were not submitted to the FDA regarding this significant product problem," the warning letter adds. The warning letter also charges that SB removed an inspection station from its aseptic filling room "without adequate documentation that a comparable inspection procedure was in place." Moreover, the letter declares, SB made the change "without filing a supplement...and receiving approval for the filing." The four remaining items cited by FDA relate to the sterility testing for Timentin and the filling process for its Add-Vantage injectable system. FDA specifically cited a lack of records for some sterility tests and a lack of "100% inspections for particulates or defects." SmithKline Beecham said that it has reached agreement with FDA on necessary steps to be taken to satisfy the agency. The company did not elaborate on specific changes. FDA issued an FD-483 inspectional observation form on May 26, the warning letter notes. SB responded to the 483 by the end of June. The warning letter includes comments on SB's response and adds that "the appropriateness and implementation of the corrective actions that your firm committed to...will be checked at the time of the FDA's next inspection of your facility." FDA's comments indicate that SmithKline Beecham agreed to develop a polymer test method to investigate the foaming incidents. SB also apparently argued that the complaints did not merit a Field Alert Report. SB also has agreed to certain manufacturing changes in its aseptic filling lines and its particulate inspection processes, the letter indicates. SmithKline Beecham has conducted three recalls of Timentin, most recently in October 1990. That Class II recall involved approximately 30,000 vials which were recalled "due to lack of assurance of sterility" ("The Pink Sheet" Jan. 28, 1991, T&G-11). A November 1988 Class III recall of nearly 300,000 vials manufactured at the Piscataway plant (then a Beecham facility) involved an "increased rate of polymerization with a potential to clog in-line filters." SB said no recalls have resulted from the April-May inspection.

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