FDA issued heparin-related warning letters last month to two Chinese API suppliers - one for posing as a heparin API supplier, and the other for supplying adulterated heparin to the U.S. in violation of cGMP requirements.

The first letter went to a so-called "show" factory, Shanghai No. 1 Biochemical and Pharmaceutical Co. Ltd and the other to a "shadow" factory, Qingdao Jiulong Biopharmaceuticals Co. Ltd. The heparin lots were spiked with over-sulfated chondroitin sulfate, which is much cheaper than heparin but looked like it in then-standard compendial tests, and were later imported into the U.S. FDA officials conducted inspections of the two Chinese API suppliers last summer.

In a strongly worded warning letter to the Shanghai facility, FDA investigators noted that "the inspection revealed that the facility was not manufacturing, and did not appear to have ever manufactured, heparin sodium USP (or heparin sodium) for the U.S. market. The investigators also determined that, contrary to your firm's claims, manufacturing of heparin sodium was conducted at facilities other than the one identified in your DMF. In addition, our review of information submitted to the agency in your DMF 12281, as well as documents collected during FDA's inspections of both your facility and of subcontractor Qingdao Jiulong, along with additional information, uncovered untrue statements and information submitted by your firm to the agency with respect to the actual manufacturer(s) of heparin sodium."

While the Shanghai firm had for years informed the FDA that it was manufacturing heparin for a U.S. importer, U.S. inspectors found that the company was actually sourcing its raw heparin from Qingdao, and simply repackaging the API before sending it to the U.S.

FDA inspectors "uncovered untrue statements and information submitted by your firm to the agency with respect to the actual manufacturer(s) of heparin sodium," the letter states. That, in turn, prevented the FDA from inspecting the actual manufacturing site.

"We learned that lots of heparin sodium shipped from your facility were found to be contaminated with over-sulfated chondroitin sulfate," the FDA warning states. "In addition, your firm failed to conduct an investigation into the cause of this repeated, unacceptable contamination."

In its warning letter to Qingdao Jiulong Biopharmaceuticals Co. Ltd. located in the east coast resort city of Qingdao, FDA officials state "the inspection and other information revealed significant deviations from U.S. current good manufacturing practices (cGMP) requirement in the manufacture of drugs." FDA also complained that even after notifying the Qingdao company that it had supplied contaminated heparin to the U.S., the API producer never "initiated an investigation to determine the root cause of the contamination, identified whether other lots were implicated or taken appropriate corrective actions to prevent recurrence of this contamination."

- Joanne S. Eglovitch (j.eglovitch@elsevier.com)

'Show' and 'Shadow' Heparin Facilities Targeted in Pair of FDA Warning Letters

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