FDA Issues Warning Letters To Two Chinese Producers Of Adulterated Heparin: Could Prosecution Lie Ahead?

BEIJING - In a move that could ultimately lead to civil or criminal prosecution, U.S. FDA has issued warning letters to two Chinese producers of raw heparin that was discovered to be contaminated with a look-alike chemical.

FDA's Center for Drug Evaluation and Research sent the formal warnings after initially discovering heparin adulterated with over-sulfated chondroitin sulfate, whose molecular structure closely resembles that of heparin, sold by the companies and imported into the U.S. FDA officials then conducted inspections of the two Chinese API suppliers last summer, and found serious violations of GMP standards.

In a written notification 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) requirements in the manufacture of drugs."

"These and other CGMP deviations cause your heparin sodium to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act," the warning states.

The FDA also complained that even after notifying the Qingdao company that it had supplied hazardously 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."

And while the Qingdao outfit claimed it never exported heparin to the U.S., the FDA warning stated: "During an inspection conducted at a U.S. facility, we found purchase orders and information indicating that since 2005, heparin sodium manufactured at your facility was being shipped into the U.S."

The U.S. regulators also stated that the Qingdao company had supplied contaminated heparin to Shanghai No. 1 Biochemical & Pharmaceutical Co., Ltd., which received the other warning letter.

During an inspection of Shanghai No. 1 Biochemical last August 4-7, FDA agents "identified significant deviations from U.S. current good manufacturing practices (CGMP) requirements in the manufacture of drugs," the second letter states.

"We have also determined that you had made untrue statements to FDA relating to the manufacture of Heparin Sodium USP," the April 14 warning letter states.

While the Shanghai firm had for years informed the FDA that it was manufacturing heparin for a U.S. importer, American 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 [Shanghai No. 1] 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."

Each of the twin warning letters states that following the Chinese company's violation of U.S. GMP standards and supply of dangerous, contaminated heparin to the U.S, its products would in the future be subject to refusal of admission at all U.S. borders.

But there could be stronger repercussions.

"These warning letters could be the prelude to a criminal prosecution," said a former FDA official who asked not to be identified (The Gold Sheet, April 2009).

In the case of the Shanghai company that the FDA accused of making "untrue statements," the API supplier could be subject to criminal charges.

The U.S. government may be considering criminal charges against the firm under the "False Reports to the Government Act," 18 USC 1001. "It's against the law to intentionally lie to the U.S. government," said the former FDA official.

At the same time, an agreement signed by China's State FDA and the U.S. Department of Health and Human Services in December of 2007 requires each to speedily report any adverse reactions triggered by drugs or devices slated for export.

One section of the agreement provides: "SFDA and HHS/FDA shall respond rapidly to, and investigate reports of, drugs, excipients, and medical devices suspected of being misbranded, adulterated, or counterfeited. SFDA and HHS/FDA shall also notify each other of any such reports and the steps they have taken or plan to take to investigate the report."

It also obligates each side "to actively investigate and prosecute individuals or entities that manufacture, sell, distribute, handle, test, trade, or export misbranded, adulterated, or counterfeit drugs, excipients, and medical devices."

And whether or not China fufills its obligation under this agreement to investigate any manufacturers of adulterated products, "this would not preclude the U.S. from taking action," said Linda Horton, a partner at the Washington, D.C. office of the international law firm Hogan & Hartson who focuses on life sciences-related issues and legislation (Also see "In Wake Of Heparin Deaths, FDA Set To Launch Pilot Project Aimed At Preventing Imports Of Adulterated Drugs" - Scrip, 13 Feb, 2009.).

Horton, who was FDA Deputy Chief Counsel for Regulations for 14 years and the head of FDA's international policy office for eight years, explained: "The agreement does not affect the ability of either country to take enforcement actions."

"The purpose of the agreement is to promote regulatory cooperation," she added.

"Obviously it's much more difficult to prosecute people overseas," the Washington lawyer observed.

Yet she added, "The FDA has criminally prosecuted foreign companies in the past."

- Kevin Holden ([email protected])