U.S. FDA Set To Strengthen Inspections Of Chinese Drugmakers, Search For Adulterants In Aftermath Of Heparin Deaths – CDER Official

BEIJING - As U.S. FDA leaders select inspectors to deploy across three new offices being set up in China, the organization is also preparing to ramp up the number of inspections and the level of scrutiny of Chinese drugmakers that export to the U.S.

The program of heightened monitoring of Chinese makers of active pharmaceutical ingredients via new FDA outposts in Beijing, Shanghai and Guangzhou is being launched one year after adulterated heparin components sourced from China began triggering a spike in extreme adverse reactions and deaths across the United States (Also see "U.S. FDA Triples Estimate On Deaths Following Allergic Reaction To Blood Thinner Heparin" - Scrip, 14 Apr, 2008.).

A senior FDA official who is screening inspectors to be sent to China indicated the new outposts would help the administration keep pace with China's growing role as a main supplier of APIs to pharmaceutical giants across the Pacific and prevent other adulterated drug ingredients from entering U.S. hospitals.

During a recent teleconference co-hosted by PharmAsia News on FDA's expanding presence in China, FDA official Nicholas Buhay said the agency currently carries out about 15 inspections each year of Chinese sites making drug components for the U.S. market.

After the new FDA offices are established, "there will be many multiples of the past number of inspections," said Buhay, who is deputy director of the manufacturing and product quality division under FDA's Center for Drug Evaluation and Research.

"These inspections will include surveillance for compliance with GMP standards," he said. "There will be initial inspections and surveillance inspections that will be periodic," Buhay added.

Pharmaceutical multinationals operating China-based drug manufacturing sites, or foreign companies sourcing Chinese-produced components, must be extremely careful to ensure medicines are produced under the highest GMP standards, according to Ray Bonner, a lawyer at the Washington office of law firm Sidley Austin. Sidley Austin, which also has offices in Beijing and Shanghai, co-hosted the teleconference on FDA inspections in China.

"You are being regulated not just by FDA, but also by [China's State FDA] and by the U.S. Congress," Bonner said of companies that manufacture in China and export to the U.S. market.

Meanwhile, Buhay said FDA is also pressing its Chinese counterpart, SFDA, to allow U.S. inspectors to carry out unannounced inspections of the operations of Chinese API makers.

"There will be a major new program objective to find and act against mixing, packing and substituting substances into drug components … an essential definition of adulteration," Buhay said.

Seven months after a nationwide recall was ordered in the U.S. of all heparin containing Chinese components, "Heparin is on all our minds," the FDA deputy director said. He explained that the high-risk, adulterated heparin had not been brought under control until fairly recently.

"The contaminant [found in heparin] mimics heparin activity so closely that it was not recognized by routine testing. FDA now has in vitro and animal data demonstrating a solid mechanistic link between the oversulfated chondroiton sulfate and the adverse events observed," according to FDA's Center for Drug Evaluation and Research.

FDA stated in its most recent adverse events report on heparin that 146 deaths involving one or more allergic symptoms or symptoms of hypotension following the administration of the drug were reported in the first half of 2008.

Buhay indicated that the inspectors slated to be stationed in northern, eastern and southern China would set out to detect drugs contaminated from negligent failure to comply with cGMP standards or from willful adulteration of APIs.

Inspections will include a "search for any substances used in adulterations," he said. "We will investigate, we will sample and test" to detect this, Buhay added.

The deputy director also said FDA seeks a closer level of cooperation with SFDA in inspecting drug manufacturing sites, cross-training and information sharing on any pharmaceutical products or medical devices that trigger adverse reactions.

An agreement signed by SFDA and the U.S. Department of Health and Human Services last December paves the way to improve exchanges between the two sides and requires each to speedily report any adverse reactions triggered by drugs or devices slated for export (Also see "Import Safety Agreement Further Entwines FDA/China Regulatory Process" - Scrip, 17 Dec, 2007.).

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."

That agreement laid the groundwork for FDA's moves to set up operations across China in three mega-cities, Buhay said.

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."

- Kevin Holden ([email protected])

[Editor's note: To purchase a recording of the Oct. 15 webinar on U.S. FDA inspections in China sponsored by PharmAsia News and Sidley Austin LLP, click here.]