Actavis Totowa nets warning for QC, cleaning validation.

A July 10-Aug. 10, 2006 inspection of Actavis Totowa, Little Falls, NJ, a prescription drug manufacturer, found significant deviations from GMP regulations which included the following:

Significant deficiencies in the company's quality control unit; laboratory notebooks did not include all raw test data generated during testing; failure to check for accuracy the inputs to and outputs from the "Total Chrom Data Acquisition System," which is used to run the firm's HPLC instruments; quality control failed to recognize that some tablets that did not meet in-process specifications; lack of adequate procedures for conducting bulk product holding time studies; cleaning validation studies were found to be inadequate; master and batch production and control records were found to be deficient; and equipment used in the manufacture of Benztropine Mesylate tablets and other drug products was not adequately qualified.

Regarding quality control, FDA investigators noted in the Feb. 1 warning letter numerous instances where the quality control unit failed to adequately investigate and resolve laboratory deviations and out-of-specification (OOS) test results involving drug products that ultimately were released for distribution into interstate commerce. Additionally, investigators uncovered out-of-specification test results in laboratory raw data that were not documented in laboratory notebooks, and found that products were released based on retesting without any justification for discarding the initial out-of-specification test results.

Numerous instances were observed where manufacturing process deviations occurred and in-process specifications were not met, yet there was no indication that action was taken promptly to investigate or to correct the deviations and the products were approved for release and distribution by the quality control unit, the agency wrote.

Next, auditors observed that the firm's laboratory notebooks did not include all raw test data generated during testing and that analysts did not always document the preparation, and testing of samples in their notebooks at the time they were done.

Further, instances were found where analysts aborted and failed to complete chromatographic testing runs after an OOS test result was obtained. The chromatographic test data reflecting the OOS test results were not recorded in laboratory notebooks.

FDA investigators also uncovered numerous instances where OOS test results obtained during the testing of the firm's drug products were not adequately investigated.

Regarding failure to check for accuracy the inputs to and outputs for the HPLC instruments, electronic data files were not routinely checked for accuracy, and investigators found numerous discrepancies between the electronic data files and documentation in laboratory notebooks.

Next, the letter cited the company because of failure to meet in-process specifications during tablet compression operations, which was not always documented in production records, and there was no indication that the process deviations were promptly corrected during compression operations to avoid releasing tablets that did not have their appropriate quality. Instead, investigators found instances where compression problems were documented in investigation reports several weeks after they occurred.

For example, on Nov. 11, 2005, during the compression of Carisoprodol, Aspirin & Codeine tablets, batch 5904A, one tablet was documented as having a hardness value of 8.9 kp. The tablet hardness specification was a different value, FDA stated. Additional tablets were not tested to determine the extent of the batch that did meet specifications, as required by the firm's SOP.

Also, the following bulk holding time studies initially were generated from the testing of finished products instead of from samples of bulk products held for the holding time studies: Benztropine Mesylate tablets, USP, 0.5mg, 1mg, 2mg; Buspirone HCl tablets, USP, 30mg; Imipramine HCl tablets, USP, 10mg, 25mg, 50mg; Methimazole tablets, USP, 5mg, 10mg; and Phendimetrazine Tarate tablets, USP, 35mg.

The firm further failed to identify and control rejected in-process materials to prevent their use in manufacturing or processing operations. For example, according to the firm's investigation reports, some batches were rejected because they failed to meet blend uniformity or dissolution specifications. Yet FDA observed that the batches were stored in the firm's work-in-progress warehouse labeled as in-process materials.

The warning letter also stated that regarding cleaning validation that cleaning validation was performed for the process trains without evaluating for sample recovery for numerous products, including: Amidal Nasal Decongestant; Amigesic Caplets, 750mg; Carisoprodol and Aspirin tablets, USP, 200mg/325mg; Carisoprodol tablets, USP, 350mg; Chlorzoxazone tablets, USP, 250mg and 500mg; Digoxin tablets, USP, 0.25mg.

Next, although the firm's procedures required the collection of in-process blend uniformity samples of three times the weight of finished product tablets or capsules, master production records did not require, and batch records did not contain, documentation that the samples were being collected accordingly, the agency noted.

Additionally, FDA auditors stated that equipment used in the manufacture of Benztropine Mesylate tablets and other drug products was not adequately qualified. For example, the requalification of an undisclosed ingredient, which was used in the production of Benztropine Mesylate tablets, batch RBR-2137, did not have clearly defined acceptance criteria. In addition, there was no discrepancy report to explain why equipment drawings, equipment schematics, equipment manuals, and purchase orders were not available, what steps had been taken in an attempt to obtain these materials, and why the re-qualification was acceptable without this information.

FDA stated that it had reviewed the firm's corrective actions promised in a letter dated Aug. 29, 2006. The agency found that while corrections the firm promised in its correspondence appeared to adequately address many of the GMP violations, FDA reiterated its concern about the quality of drug products that were released from the facility under the serious lack of GMP controls found during the inspection.

Further, the agency stated that the company should promptly initiate an audit program by a third-party having appropriate GMP expertise, to provide assurance that all marketed lots of drug products that remain within expiration have their appropriate identity, strength, quality, and purity.

The company could not be reached for an update. Doc. 14080W