Andrx Pharma on receiving end of 9-item 483 for OOS, QC violations, control procedures.

Andrx Pharmaceuticals, Ft. Lauderdale, FL, was slapped with a nine-item 483 in a March-April inspection because it did not perform investigations of OOS results. Also, the firm's quality control unit was inadequate, and the firm had faulty control procedures, which did not validate the performance of manufacturing processes.

The audit was performed by investigators Ileana Barreto-Pettit, Jennifer Menendez, Rebeca Rodriguez and analyst Jennifer Hollstrom from FDA's Maitland, FL, District Office. The FIR was not available at press time.

According to the report, Andrx failed "to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been thoroughly distributed."

Specifically, the firm did not perform adequate investigations with scientifically justifiable conclusions to incidents of OOS results or production deviations and/or failed to implement appropriate corrective actions for the root cause determination.

The report stated that the QC unit "failed to adequately review Ketoprofen Validation Protocol and Report No. 002PV005 and, as a result, it released and distributed between March and July 2005 six batches of Ketoprofen ER capsules (lot #'s: 520E017, 520F0368, 520E018, F520F0840, F520F1030, and F520F1031) that were manufactured with a process that showed significant variability and was not adequately validated."

Next, the QC unit did not ensure that Phase I Laboratory Investigations were adequately investigated, documented and trended after they were removed from an undisclosed system in September 2005 and transferred to a manual logbook.

Regarding control procedures, FDA documents noted that the QC unit approved Doc. No. 0002PV05 titled "Process Validation Protocol-Manufacture of Ketoprofen" to evaluate the accuracy of scale reading versus an undisclosed type of reading for the sustained-release coating process as the difference in dissolution performance at the eighth hour.

FDA added: "Five commercial batches of [an undisclosed product] were manufactured under this validation protocol, which resulted in three batches (52050, 55797 & 520E018, sublot#4) that failed dissolution specifications at the eighth hour, and a batch (57043) that deviated from the target capsule fill weight specified in the manufacturing batch record in order to meet dissolution specification at the eighth hour."

Next, FDA cited the use of instruments and apparatus not meeting established specifications. "Specifically, in December 2005," the report stated, "the QC unit determined the need to replace the flow rate valves of all [undisclosed] apparatuses as a result of frequent clogging, flow rate problems and increased bubble formation that randomly caused 'erratic' dissolution results."

However, the quality unit failed to adequately monitor the implementation of its corrective action and, as a result, the valves were not installed and the use of these dissolution baths with potentially malfunctioning valves continued for dissolution testing of all cartia, diltia, taztia, metformin, naproxen sodium, and ketoprofen drug products."

Further, written records of investigations into unexplained discrepancies did not include the conclusions and follow-up. For example, the 483 stated, "the cleaning swab failure investigations reported under TWRs 1545, 1555, 2194, 2259 disclosed that the root cause was the failure to thoroughly rinse or clean equipment or that the cleaning procedures were not specific enough."

The agency added that the QC unit also failed to follow up on these findings and none of the SOPS involved in these investigations had been revised to make the rinsing and/or cleaning instructions more specific.

Additionally, the FDAers wrote, "there is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been thoroughly distributed."

Specifically, the firm did not perform adequate investigations with scientifically justifiable conclusions to incidents of OOS results or production deviations and/or failed to implement appropriate corrective actions for the root-cause determination.

The deficiencies included the following: The investigation report TWR #1691 for finished product testing of metformin HCl extended-release tablets, 500 mg lot no. F571F0692 was specifically for content uniformity testing. During analytical testing, one of the capsules failed to meet the Stage 1 established specification of an undisclosed ingredient label claim and another tablet was toward the low end of the specification range.

The root-cause analysis indicated analyst error and two additional capsules were extracted with the results replacing the original OOS capsules, the 483 stated. The investigation revealed that the analyst observed a gelatin like mass of material at the bottom of one of the flasks and a piece of undissolved gel at the bottom of the other flask after adding diluting solvent A.

As a result, these two flasks were stirred for an additional 60 minutes, which is longer than the procedure or the eight other flasks, according to FDA documents. The analyst who performed the QC method transfer stressed the importance of full tablet disintegration before adding diluting solvent A or the material will clump. "The firm concluded that based on the physical observation of the two stock solutions in question proper active extraction did not take place."

Following the audit, Andrx said in a press release that it "provided FDA with a detailed response to the 483, which included a proposed corrective action plan. FDA has not commented on the company's response or corrective action plan. Andrx is working to resolve the cGMP issues at its facility as quickly as possible. The timing of that resolution is uncertain, and is not solely in our control."

Andrx Pharmaceuticals, Ft. Lauderdale, FL, 3/16-4/18/06, Doc. 109849M, $5.50 plus retrieval.

[check] The Checklist--Andrx Pharmaceuticals

[check] Quality audits inadequate

[check] No corrective actions for OOS results

By Joseph Pickett, Managing Editor