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Weekly UpdatesPharmaceutical Laboratories and Consultants, Des Plaines, IL Chicago District
Contract testing laboratory Pharmaceutical Laboratories and Consultants (PLC) received a 14-item 483 from FDA investigator Bruce McCullough for significant deviations from laboratory control and quality system regulations.
McCullough found that PLC had reported incorrectly calculated test results for approximately 12 batches of tested product. "When the results are recalculated correctly, approximately six of the 12 batches fall out of specification for content," the inspector wrote in the 483 he issued after his inspection April 16-May 3, 2007.
In addition, the company's test procedure for the assay of an active pharmaceutical ingredient was not scientifically sound, the FDAer wrote, because the calculation included a factor that should not have appeared in the denominator of the equation. "PLC has analyzed and reported the results for approximately 25 batches using the incorrect equation," he stated.
The investigator faulted the company for performing microbial limit testing via the Plate Method using a single plate per sample, when USP "requires plating sample preparation aliquots in duplicate, on two separate plates. Use of a single plate has not been shown to be equivalent to the USP method," McCullough reported.
Neither a previously-used autoclave cycle nor the cycle being used at the time of inspection had been validated, the report noted. Further, PLC had no controls in place to prevent or track the printing out of multiple blank Work Order forms, which are used for recording raw data; there were no written instructions for the number of units to test for sterility in newly prepared batches of broth media; and the reference standard used in one assay was not assayed for purity. The standard was also used without drying or determining its moisture content, the inspector added.
The company had not conducted validated studies for four analytical methods routinely used to test drug products for active ingredients, the investigator found. In addition, laboratory records were deficient because they did not include a complete record of all data obtained during testing. There were no records of raw data for sterility testing and growth-promotion testing of media batches, and actual sample weights were not recorded.
The method used to test stability samples for a drug product had not been shown to be stability-indicating. In addition, PLC's procedures did not include a system suitability test requirement for one system.
Deviations from written procedures were not recorded and justified, McCullough found. The procedure for USP growth promotion testing required recording growth promotion test data on a form, which the laboratory's personnel were not using. The same was true of a form used to record media preparation and test data.
Although the company had been informed of a calculation error in the analysis of 12 batches of drug product a week earlier, it had not yet initiated a written investigation into the cause of the error.
Responsibilities and procedures applicable to the company's quality control unit were not in writing and fully followed, McCullough observed. He noted that employees had been told not to use a form when making up batches of media, but the procedure had not been changed to reflect the change of form.
"There is a pattern of failure to follow written analytical methods," McCullough wrote, and "a pattern of failure to investigate deviations from analytical methods." He noted several work orders for which analysts deviated from the written method but did not initiate deviation forms as required by procedure. Further, he wrote, "the instructions for performing data reviews for chemical analyses (including review of chromatograms) by a second person are not stated in writing."
The FDA inspection found that individuals responsible for supervising the manufacture of drug products lacked the education, training and experience to assure that the drug products met their specifications. "Specifically," McCullough wrote, "although the President/ Laboratory Manager signed as Reviewer for multiple assays via HPLC and GC, he stated that he does not have experience or background in HPLC or GC analyses." Further, there was no documentation that employees were trained for the operations they performed in their assigned duties; the president and laboratory manager told the FDAer that all training records prior to a certain date had been discarded.
McCullough found the company's GMP training had not been conducted "with sufficient frequency to assure that employees remain familiar with GMP requirements." He noted that PLC's training did not include instruction in how to appropriately make raw data corrections and completely document raw data.
The firm did not perform installation and operation qualification studies for its HPLC and GC instruments as required by its procedures, although these instruments were being used routinely to analyze drug samples. There were no established calibration and preventive maintenance procedures for some instruments, and procedures for calibration were deficient or not followed.
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