QA failures including OOS trip up DSM Pharma.

DSM Pharmaceuticals, Greenville, NC, received a 13-item 483 because its quality assurance unit did not capture quality issues, including an out-of-specification (OOS) result that did not initiate a report nor an investigation.

The audit was conducted by investigators Cynthia Jim and Rose Ashley from Center for Drugs. The EIR was not available at press time.

"No QA review of raw data is conducted for shipping temperature data for biologics. Raw data is reviewed by the analyst and lab supervisor," FDA wrote.

One lot was received with an OOS result for shipping temperature on July 21, 2004, but the OOS was not noted by the analyst or reviewing supervisor, according to FDA records. Also, an OOS or deviation report was not initiated for the event.

Next, an equipment log for one freezer made note of freezer alarms and temperature discrepancies, but these events were not captured in the deviation system, the report stated.

Specifically, the 483 noted: "On March 11, 2004, the freezer alarmed, but the graph did not show any temperature excursion; on March 31, the freezer alarmed and temperature was noted as -58 degrees Celsius." The report also stated that deviation reports did not address missing graphs for December 2003.

Further, there was 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 was thoroughly distributed.

For example, FDA wrote that root causes were not identified and corrective actions were not implemented for five OOS events involving bulk drug substances that were shipped out of temperature specification.

In a related observation, root causes were not identified to address recurring deviations associated with bulk drug substance thaw cycles.

One occurrence noted that the thaw cycle was initiated and stopped two times due to an undisclosed malfunction. An alarm indicated a high temperature for the condenser temperature sensor, but the cause was not determined, the report stated.

Further, FDA reported that the firm did not maintain equipment at appropriate intervals to prevent malfunctions that would alter the safety, identity, strength, quality and purity of the drug product.

"Equipment vendor recommended semi-annual and annual planned maintenance requirements to avoid operational problems are not conducted for the [undisclosed] units which are used for bulk drug substance thaw cycles," the 483 noted.

Also, the post-filtration product integrity bubble point for an undisclosed procedure was not determined. "The acceptance criteria for filter integrity testing is based on the WFI bubble point testing, and product bubble points are currently taken for informational purposes. Therefore a true minimum product bubble point is not currently available," the FDAer wrote.

Next, the report stated that batch production and control records did not include the results of any investigation made into any unexplained discrepancy, whether or not the batch of drug product had already been distributed.

Specifically, the 483 added, "the SOP for sterile batch record review and disposition does not require review of deviation and OOS investigations associated with bulk drug product to be included in the batch review and disposition."

Further, the 483 stated that the responsibilities and procedures applicable to the quality control unit were not in writing and not fully followed.

For example, the SOP for handling OOS results did not clearly define the procedure for developing test plans for retesting OOS samples. Discrepancies were noted in the firm's retesting practice for three OOS tests for protein identification, FDA documents noted.

Next, deviation management procedures were not followed in that a deviation report was not initiated for a shipping temperature excursion with a temperature result of -29.2 Celsius during shipment, the report stated.

"Procedures are not taken to exclude extraneous infectious agents from manufacturing areas," the document continued. The SOP for requesting the creation of a new raw material master record required BSE/TSE information from the vendor for raw materials. This requirement was initiated by the firm on Dec. 2, 2002, but the firm could not provide verification during the audit that TSE/BSE evaluation forms were received from vendors for all materials used in the manufacture of drug products.

The company could not be reached for comment. DSM Pharmaceuticals, Greenville, NC, 5/3-12/05, Doc. 109955M, $5 plus retrieval.

[check] The Checklist--DSM Pharma

[check] QA did not capture quality issues

[check] OOS result did not initiate report or investigation