FDA cites heparin producer for outsourced manufacturing.

April 14--CDER

An Aug. 4-7 inspection of Shanghai No. 1 Biochemical & Pharmaceutical Co. Ltd., which supplied some of the contaminated heparin involved in several injuries and deaths in the U.S. last year, revealed that the facility had never manufactured heparin sodium for the U.S. market as it had claimed. Instead the firm had subcontracted manufacturing to two other facilities not inspected by FDA.

The inspection conducted by FDA investigator Carl Lee and Compliance Officer Zi-Qiang Gu, Ph.D., also helped to reveal false statements made by Shanghai's management to FDA.

FDA's review of information obtained revealed that two other facilities have performed manufacturing and testing of heparin sodium in place of the Shanghai facility since 2001. These facilities were identified as Qingdao Kangyuan and Qingdao Jiulong, neither of which was listed in the DMF. Since 2001, several lots of heparin sodium were supplied by Shanghai to International Medication Systems (IMS) in the U.S. There were no manufacturing batch records at the Shanghai site to show that the company had ever produced any of this material shipped from the facility to the U.S.

Instead, FDA wrote, "we found during the inspection that heparin sodium was received at your facility packaged in 5 kg bags inside fiber drums, labeled with the name of the manufacturers (Qingdao Kangyuan or Qingdao Jiulong). The investigators also found that the manufacturers' labels had been removed from the 5 kg bags during the repackaging operation and the bags were placed inside aluminum drums used to ship the heparin sodium to the U.S.; the bags were then sealed and identified with the Shanghai No. 1 label."

Although this heparin sodium was shipped to the U.S., FDA noted that no drug products made with these lots have been marketed in the U.S. at this time.

The firm lacked laboratory testing records for the heparin sodium released from its facility to the U.S. to demonstrate that each batch met specifications. "Significantly, our inspection found that your firm did not adhere to your DMF commitment to perform tests reported on your Certificates of Analysis (COAs)," the letter stated.

Shanghai failed to investigate discrepancies related to lots of the heparin sodium supplied to the U.S. "We learned that lots of heparin sodium shipped from your facility were found to be contaminated with Over-Sulfated Chondroitin Sulfate (OSCS). Although your firm quarantined some of the contaminated material apparently produced by Qingdao Jiulong in 2008, you permitted at least 19 lots to be shipped to the U.S.," FDA wrote.

The letter added: "In addition, your firm failed to conduct an investigation into the cause of this repeated, unacceptable contamination. Instead, you requested that Qingdao Jiulong investigate the contamination, although the product was repackaged and relabeled at your facility."

In addition to the above violations, Shanghai submitted untrue information to FDA relating to the manufacture of heparin--specifically, that the heparin sodium the company supplied was produced at Shanghai, that its operations were in accordance with GMP, and that each lot of the manufactured product would conform to the specifications and test methods described in the Drug Master File.

In its DMF the firm stated that "All manufacturing, packaging and control of Heparin Sodium USP, as well as final drug substance and stability testing, are performed at: Minhang Branch of Shanghai No. 1 Biochemical & Pharmaceutical Co." and further stated: "No contract firms are involved in the manufacturing of the drug substance, Heparin Sodium USP, that is the subject of this Drug Master File."

On June 27, Shanghai's U.S. Agent submitted a letter on the firm's behalf identifying Qingdao Jiulong (located in Shandong, China) as an "alternate. manufacturing site of heparin sodium. When FDA inspected the facility in August, "we found that Heparin Sodium USP had also apparently been produced by a second site, Qingdao Kangyuan, from approximately 2001 until 2006. This manufacturer of heparin sodium had never been inspected by the FDA, and had not been mentioned in correspondence to FDA by your firm, or your U.S. Agent, dating back to 2001," the agency stated in the warning letter.

During the inspection, Shanghai indicated that the Qingdao Kangyuan facility transferred the manufacturing of heparin sodium to Qingdao Jiulong in late 2005, and ceased production of heparin sodium. "Because of the submission of untrue statements to FDA, the Agency was never given the opportunity to inspect the conditions and practices at the Qingdao Kangyuan manufacturing facility to verify whether heparin sodium was manufactured there and determine whether it was manufactured, processed, packed, and held in compliance with GMP," FDA wrote, adding:

"We also confirmed that from late 2005 to present, the Heparin Sodium USP you supplied to the U.S. was produced, contrary to your representations to FDA, by Qingdao Jiulong and not at your facility."

The agency asked Shanghai to reply in writing and explain why it repeatedly departed from its DMF commitments, which explicitly committed to FDA that all manufacturing and testing would be conducted solely at its site and no subcontractors would be used; and why it did not report, until recently, the information regarding contract manufacturers in the DMF. QC/QS