Trashed Tests Put FDA on Notice as China Pushes Drug Exportsby
Thirty-eight facilities in China banned from exporting to U.S.
Regulators working to improve quality of manufacturing
During a visit to Zhejiang Hisun Pharmaceutical Co.’s factory in the Chinese city of Taizhou this year, FDA inspectors noticed a worrisome sign. When workers conducted quality tests on drugs for export to the U.S. they sometimes didn’t record the results. Other times, they deleted them.
It was a warning signal that led the Food and Drug Administration to ban 15 drug products from Hisun worth about $31 million, over concerns that the medicine might not meet U.S. quality standards. Hisun said it has addressed the problems.
Policing drug manufacturers abroad has become a critical task for the FDA because medicine that doesn’t meet U.S. standards could sicken patients. The idea is to avoid situations like the one that arose in 2008, when a blood thinner called heparin was made with contaminated Chinese ingredients and linked to 246 deaths in the U.S.
The FDA has worked for years to increase its scrutiny of India, another major exporter, and now China is a focus. Together, the two countries manufacture more than 80 percent of the main active ingredients in the world’s drugs, including in the U.S. and Europe, according to an Institute of Medicine report.
China has a growing drug industry, and one that increasingly wants to make not just raw ingredients but finished drugs for export. Yet there are currently only two FDA drug inspectors in the country, overseeing about 700 facilities involved in drugmaking. The FDA wanted to boost that number to a total of 26 inspectors for drugs and food, and has ended a long fight with the Chinese government over visas, but it’s been slow going to deploy the inspectors, the FDA has said.
“We’re hearing the Chinese are definitely interested in developing innovative products that aren’t just for the Chinese marketplace, but that are for the global marketplace, for the U.S. marketplace,” Leigh Verbois, the newly appointed director of the FDA’s China office in Beijing, said in an interview with Bloomberg.
Regulators want to make sure those products are safe, high-quality, and include the ingredients and strengths they claim to, for everything from seizure to heart drugs. The low point for Chinese-exported drug products may have been the deaths linked to heparin seven years ago. Regulators never found at what point the ingredients in the drug, made by Baxter International Inc., were contaminated. At the time, Baxter said it was alarmed that the contamination appeared to have been deliberate, though said it didn’t have proof of how it happened.
Now Chinese drugmakers are trying to fix problems, and the FDA’s Chinese counterpart, the CFDA, seems committed as well, Verbois said. The U.S. FDA conducted 120 inspections of drug facilities in China last year, Jeff Ventura, a spokesman for the agency, said in an e-mail.
“Companies are letting us in,” said Verbois, who has been with the FDA since 2002. Before she took over the China job last month, she ran the agency’s office that coordinates with regulatory counterparts in Canada and the Asia-Pacific region, excluding China and India. “We’re in a different place than we were in 2008.”
The CFDA didn’t respond to a faxed message requesting comment.
“It’s not just for the U.S. FDA, also the China FDA is understaffed as well,” said Jonathan Chan, an analyst in Hong Kong with Decision Resources Group, citing the size of the industry and the large number of drug applications. “It’s quite overwhelming. With agencies being understaffed, quality control and standards will get compromised.”
Even with only a handful of U.S. inspectors in the country, Chinese manufacturers are second only to India in the number of facilities that have been banned from exporting drugs and drug ingredients to the U.S. Including Hisun’s Sept. 9 prohibition, 38 Chinese facilities are on the FDA’s banned list. Some of the bans only apply to certain drug products, not the whole facility, according to the FDA.
At Hisun, certain lab employees failed to record data in a timely manner or deleted invalid data from failed tests, the company said in an e-mail. Hisun said it re-tested the batches of products in question and found that they met quality standards.
Hisun said it has taken measures to prevent similar problems in the future and is talking with the FDA to remove the import ban. The FDA declined to comment.
Along with making active ingredients for anti-infection, depression, cardiovascular and oncology drugs, Hisun and New York-based Pfizer Inc. formed a joint venture in 2012 to make generic drugs for the Chinese and global markets. Pfizer said in a statement that the import ban didn’t apply to products covered by the joint venture.
Similar problems were found last year at Zhejiang Jiuzhou Pharmaceutical Co., according to an FDA warning letter sent to the company. Jiuzhou, also based in Taizhou, says on its website its main product is carbamazepine, a drug used to treat epileptic seizures. The company says it provides 80 percent of domestic carbamazepine in China and 40 percent of the international supply.
The FDA said that Jiuzhou got active drug ingredients from a supplier, then relabeled them as its own without oversight of the company’s quality unit. The company also shipped drug ingredients without the quality unit’s sign-off, and FDA inspectors found missing and falsified data in the drugmaker’s manufacturing records. Jiuzhou was banned from exporting products from its Taizhou facility to the U.S. The FDA didn’t say whether the issues at the facility dealt with carbamazepine.
A representative for Jiuzhou declined to comment about the company’s steps to meet the FDA’s standards.
Upon her arrival in China in August, Verbois kicked off a series of workshops for drug manufacturers there on data integrity and manufacturing. She’s also being assisted by the agency’s former top drug inspector in India, Peter Baker.
China’s own drug regulators are trying to help their country’s manufacturers meet higher standards. The Chinese government released a guideline last month seeking to improve drug safety and quality. The CFDA ordered companies in July to do self-inspections involving 1,622 drug applications. Drugmakers were give a month to withdraw their applications if they found data integrity issues.
“It’s a really good example of how CFDA has not only listened to what we’ve said about data integrity, but has implemented something to address it and made industry accountable,” Verbois said.
It’s also a sign of a bumpy road ahead. After the CFDA announced the self-inspection program in July, manufacturers pulled back a fifth of all the drug applications.