FDA is recommending that Actavis "promptly initiate" a third-party audit program to oversee the correction of manufacturing discrepancies at the firm's Little Falls, N.J. facility, following the second warning letter for the plant in less than five months.

"Significant deviations" from current good manufacturing practices were uncovered during a round of FDA inspections from July 10, 2006 through Aug. 10, 2006. A Form 483 citation was issued on Aug. 10. Actavis promised corrective actions in Aug. 29 and Aug. 30 letters to the agency while disputing "several specific observations" made during the inspection.

In response, in a Feb. 1 warning letter FDA disagreed with Actavis' "assertions...that certain of the observations listed in the FDA 483 are not accurate," and noted that Actavis itself, in a Nov. 17 follow up letter to the agency, referred to all observations on the FDA Form 483 as "correct and constructive." The generic drug maker also submitted a Quality System Improvement Plan on Oct. 18.

Actavis's Little Falls facility was the subject of a separate warning letter dated Aug. 15, based on inspections conducted from Jan. 10 to Feb. 8, 2006. The August letter addressed compliance problems with postmarketing adverse drug experience reporting. FDA found at that point that the Icelandic generics company revised its pharmacovigilence and adverse drug event procedures.

However, in the Feb. 1 letter, FDA indicates that it has concerns about the steps that Actavis is proposing to rectify the GMP issues. The letter says that while corrections promised in Actavis' correspondence "appear to adequately address many of the cGMP deviations found" during the inspection, "we are concerned about the quality of drug products that have been released from your facility under the serious lack of cGMP controls found during the inspection."

"Your response provides no assurance that the records and conditions of manufacture and testing of each such lot of drug products released and marketed by your firm will be evaluated to assure that the released drug products have their appropriate identity, strength, quality and purity."

Among the discrepancies observed during the inspection, the agency found "significant deficiencies" with the company's quality control unit.

"Our investigators observed numerous instances where the quality control unit failed to adequately investigate and resolve laboratory deviations and out-of-specification test results involving drug products that ultimately were released for distribution into interstate commerce," the agency said in the letter.

Additionally, FDA determined that out-of-specification results that were uncovered in laboratory raw data were not documented in lab notebooks. Investigators also noted that "products were released based on retesting without any justification for discarding the initial out-of-specification test results."

One example of problems with appropriate documentation in laboratory notebooks occurred with content uniformity testing of ursodiol capsules. The warning letter reports that an analyst aborted the run after the first two capsules were found out-of-specification. However the audit trail for the laboratory data acquisition system failed to reflect the aborted run, and the analyst failed to print the sample results or record the failing results in the lab notebook.

"A review of the laboratory notebook shows the sample dilution value in the laboratory notebook was overwritten without being signed and dated," FDA noted. "Additionally, there were differences between the lab notebook page showing the sample preparation and a photocopy of the same page in the investigation. Changes were made in the laboratory notebook after it was signed and approved."

Actavis is also cited for "numerous instances" when the quality control unit "either ignored or failed to recognize that some tablets did not meet in-process specifications" during tablet compression operations, and the failure to meet specifications was not always documented. "There is no indication that the process deviations were promptly corrected during compression operations to avoid releasing tablets that did not have their appropriate quality," the letter adds.

With one batch of quinapril hydrochloprothiazide tablets that did not achieve the target hardness value, there was no documentation of problems with the compression run. FDA reports that although tablet hardness limits were not met, the compression was approved by Quality Assurance. When an investigation was later initiated because the match did not meet yield specifications, the low yield was attributed to broken tablets. "This batch was released," FDA said.

FDA observed that out-of-specification results for high impurities were invalidated without scientific justification. Batches were released on retest results, which were done without prior approval as required, according to FDA inspectors.

Actavis additionally failed to identify and control rejected in-process materials to prevent them from being used in manufacturing and processing operations, FDA detailed in the letter.

The company's cleaning validation studies were also found to be inadequate, "and, as a result, there was no assurance that equipment is adequately cleaned between the manufacture of different drug products." Affected products included: Amidal nasal decongestant, Amigesic caplets; carisoprodol and aspirin tablets; carisoprodol tablets; chlorzoxazone tablets; and digoxin tablets.

FDA also found that the company did not adequately qualify equipment used to manufacture benztropine mesylate tablets and other drug products. It additionally failed to establish and follow written procedures for the maintenance of manufacturing equipment.

In one instance, FDA investigators found duct tape on the feed throat of one machine. "It appeared that the duct tape was being used to prevent powder from escaping through the feed throat during production," the agency said in the letter.

Warning letters require a response within 15 days. Actavis Totowa President Divya Patel told "The Pink Sheet" that the company assured FDA "that we had programs underway at the site to meet the needs that they addressed in the 483 and subsequent letters."

Patel noted that the letter focuses primarily on the laboratory systems and procedures. "And while most of our efforts are focused on improving procedures, documentation and systems within the laboratory, we have even outside of that voluntarily taken a review of the entire operation," he said.

"The newly implemented procedures will certainly affect productivity - they already have, to be quite frank."

He reported that they do not expect any products on the marketplace will be affected. "However, we are still doing a confirmatory review of everything out there just to assure FDA that that is the case."

- Steve Brown (steven.brown@elsevier.com)

FDA Calls For Third-Party Auditor To Rectify Actavis Manufacturing Problems

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