Changzhou fails to remove impurities, check OOS results.

Changzhou SPL Company, the company implicated in Baxter's heparin recall, received an 11-item 483 in a February audit because of its evaluation of the steps it takes to remove impurities; its investigation of out of specification (OOS) results; issues related to waste material flow; and deficiencies related to equipment.

The EIR had not been released at press time. Conducting the audit for CDER were investigator Regina Brown and chemist Zi-Qiang Gu. The firm is based in Wujing, Changzhou City, China.

The company's APIs were linked to hundreds of allergic reactions and possibly 19 deaths in the United States.

According to inspection records, FDA wrote:

"There have been no critical processing steps identified for the Heparin Sodium USP process, and the repeated and efficient removal of impurities, such as, proteins, nucleotides, virus, endotoxins, bacterial and heavy metals at the appropriate, specified process steps has not been evaluated. There was no report for annual [undisclosed] test results available."

The 483 also stated there was no impurity profile established for Heparin Sodium USP and no evaluation for degradants during stability program testing.

Also, "the manufacturing instructions for Heparin Sodium USP are incomplete in that they do not include a description of manual manipulation of the [undisclosed] during processing steps, they do not include the actual, manually entered [undisclosed] set temperatures and times, and operator observations, such as, level measurements, used in calculations, during the [undisclosed] step are not recorded."

Further, the report stated there were no test method verifications performed for the reported USP test methods--Nitrogen Determination, Protein and Total Aerobic Microbial Count--employed in testing of Heparin Sodium USP and Heparin Crude material, to show that the methods are suitable under actual conditions of use. In addition, there was no routine test for an undisclosed residue amount at the line of release.

Next, the 483 addressed the inside surface of large "cleaned" tanks used in an undisclosed step: "After both [undisclosed] were very scratched with unidentified material adhering to the insides, and the inverted handles held liquid, which spilled to the bottom of the tank when it was uprighted. There was no written procedure showing that the tanks were dedicated to a particular process step. There was no data collected to verify marker and tap volume markings on the outside of the tanks."

The cleaning method also was not validated. "It was noted that equipment cleaning tags were made of paper and taped to the piece of equipment unprotected from liquids used in the processing room environments," the 483 noted.

In addition, FDA documented that raw material inventory records were incomplete in that samples removed from the containers and the status and amount of materials returned from use by the production processing department were not recorded.

"Control of material flow in the processing area was inadequate in that waste was carted through a door to the outside in the processing area and not provided for by the material flow written procedure."

Changzhou SPL Company, Wujing, Changzhou City, China, 2/20-26/08, Doc. 110017M, $3 plus retrieval.

[check] The Checklist--Changzhou SPL

[check] Lack of critical processing steps for heparin

[check] Cleaning methods not validated

By Joseph Pickett, Managing Editor