Pharmaceutics receives 5-item 483 for laboratory testing, control flaws.(HUMAN DRUGS)

Pharmaceutics International, Hunt Valley, MD Baltimore District

FDA investigators Kenneth Nieves and Tara Gooen found several lapses in laboratory procedures during their inspection of contract drug manufacturer Pharmaceutics International June 4-26, 2007.

Specificity of test methods had not been established, the inspectors wrote. The methods for testing for impurities and degradation products for Soft Gelatin Capsules, USP, 100mg and 200mg, had not been demonstrated to be stability-indicating. The validation study did not meet the resolution requirement during the forced degradation study; the active peak was not resolved when in the presence of acid and peroxide.

Laboratory OOS investigations and subsequent QA investigations were not always complete. An OOS result for one of 36 estradiol acetate 0.45mg tablets during content uniformity testing was followed by three reinjections, which confirmed the results. On re-test, 190 tablets passed; the investigation was closed, with no attempt to determine the root cause of the original OOS result or investigation into whether additional distributed lots should be investigated further.

The investigators noted instances in which Pharmaceutics did not complete investigations into OOS results when an assignable cause was determined. The company found that its oxandrolone USP reference standard had been inappropriately dried due to conflicting directions on the reference standard label and in the USP guidelines. The FDAers noted that the investigation "did not extend to other analyses in which the oxandrolone reference standard might have also been inappropriately dried." In addition, an investigation into an OOS results for unknown impurities in nimodipine API determined that the THF used to make the standard came from an almost-empty bottle and the reagent could have been contaminated. A re-test with a new bottle of THF met acceptance criteria. The original results were invalidated but the company did not extend its investigation to other runs that might have used the same possibly contaminated THF.

Nieves and Gooen found that during laboratory investigations, Pharmaceutics had invalidated OOS results on the basis of passing results in re-tests, "with no other evidence for an assignable cause." The firm's standard procedure for lab OOS investigations stated that if no laboratory error or assignable cause was initially found and re-tests are within specification, an assignable cause is identified and the original OOS is invalidated.

FDA added: "However, if the initial OOS result cannot be invalidated for an assignable cause after these steps, the OOS result is averaged with passing results from the re-test and is not reported separately for consideration by the quality assurance unit in the batch release decision." The FDAers noted two incidents in which no assignable cause was found but no quality assurance or secondary review was conducted.

The inspection also found the company's laboratory controls did not include the establishment of scientifically sound and appropriate test procedures designed to assure that in-process materials and drug procedures conform to standards. The investigators wrote that Pharmaceutics' quality control managers applied the "Inhibit Integration" function in processing HPLC chromatograms "without scientific justification or rationale. There is no approved written procedure for this reprocessing."

The company also had no scientific rationale "for the practice of compositing individual drug samples to perform incoming raw materials identification testing," Nieves and Gooen wrote. "There is no assurance that impurities and subdivisions are not masked in the identification testing when samples are composited."

The FDA team also faulted the company for failing to establish time limits as appropriate for the completion of each production phase to assure the quality of its drug products. They noted that the company had not set parameters for the maximum time for the drying phase of bulk-filled softgel capsules, and further, that no set time points had been established for sample and testing these capsules.

Pharmaceutics International, Hunt Valley, MD, 6/4-26/07, Doc.110124M, $52 plus retrieval

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