Increasing globalization of drug manufacturing has the U.S. Food and Drug Administration playing catch-up in its efforts to temper the entrance of tainted drugs from foreign sources into the U.S. market, a problem that poses risks to public health as well as to worldwide pharmaceutical markets.
In late 2018, Mylan NV and Teva Pharmaceutical Industries Ltd.'s voluntary recall of tainted batches of the blood pressure medication valsartan underscored the need for a review of international manufacturing processes and the steps companies and regulators are taking to ensure product safety.
Novartis AG's valsartan product, Diovan, was first approved by the FDA in 1996. After its patent expired, Mylan's generic valsartan entered the market in 2012, followed by several more copycats from Israel's Teva, New Jersey's Prinston Pharmaceutical Inc., India's Torrent Pharmaceuticals Ltd., Tennessee's Avkare Inc and more.
While these companies market the drug, valsartan and its active pharmaceutical ingredients are shipped mostly from two sources, according to data from Panjiva Research, an affiliate of S&P Global Market Intelligence. Sixty-eight percent of the world's valsartan supply comes from India and 13% is from China.
In July, the European Medicines Agency first recalled valsartan pills that contained ingredients from China's Zhejiang Huahai Pharmaceutical Co. Ltd., known as ZHP, which revealed levels of a probable carcinogen in its export. Shortly thereafter, the FDA announced it was also reviewing valsartan products, a process that began a month earlier when Prinston Pharmaceuticals brought the impurity to the agency's attention.
The manufacturing process of the ingredient can result in the introduction of N-nitrosodimethylamine, referred to as NDMA, or N-nitrosodiethylamine, known as NDEA. The FDA is still investigating why these impurities are being produced. So far, the level of impurity discovered in valsartan products has been very low.
In late November, drugs from several more companies, including Mylan and Teva, were recalled for the contamination, which included products containing ingredients from ZHP and another Chinese company, Zhejiang Tianyu Pharmaceutical Co. Ltd.
Although the ingredient came from the Chinese companies, Mylan's recall of the finished product was linked to a plant in Hyderabad, India, which had received shipments of the tainted material. Mylan was required to recall valsartan in the European market in November and has since voluntarily recalled 15 batches of its U.S. products. The company expanded the recall in early December to all batches of valsartan-containing products.
"Mylan is committed to ensuring a reliable supply of high-quality medicines for patients and customers in the markets it serves," a Mylan spokesperson told S&P Global Market Intelligence.
Teva did not respond to a request for comment.
The FDA continues to investigate the impurity and better ways to test for the trace chemicals, according to the latest Dec. 11 statement from the agency that included a warning letter to ZHP.
"Under the agency's long-standing policies, manufacturers are required to test for impurities that may be introduced or develop during their manufacturing processes," FDA Commissioner Scott Gottlieb said in an earlier statement. "We review that information in product applications, including requests to change the manufacturing process."
Striving for better oversight
Globalization of drug manufacturing has grown at a fast pace in the last 20 years, and the FDA has had trouble keeping up, according to the Government Accountability Office, Congress' investigative arm.
"The U.S.'s increasing dependence on global markets has been challenging for FDA," the agency wrote in its most recent report in 2016. "The rapid pace of globalization has complicated the agency's efforts to ensure the safety of our drug supply. Our concerns with the FDA's response to globalization go back two decades."
The FDA responded to globalization by inspecting more and more overseas manufacturers. The number of overseas inspections was higher than the number of domestic inspections for the first time in 2015 following a rapid rise.
But the agency also failed to inspect some overseas manufacturing facilities altogether, despite inspections being one of the only lines of defense in determining the quality of drugs entering the U.S., the GAO said.
The GAO analysis said that of the 572 drug establishments in India slated for inspection in 2017, the FDA could not identify a previous surveillance inspection at 189 of them, a 33% failure rate. In China, 45% of inspections were unaccounted for, and in South Korea, 90% of drug establishments were not inspected.
The FDA uses a risk-based model to inspect manufacturing facilities that pose the greatest potential risk for problems that could harm patients, the agency wrote in September.
In the case of valsartan, the contamination is of a nature that tests were not sensitive enough to identify. But the fact that so many manufacturing facilities go unnoticed speaks to a larger problem at the FDA, the GAO said.
The most pressing concern for the FDA is contending with the volume of overseas manufacturers, and a workforce incapable of addressing that volume, the GAO found. In 2016, 46% of FDA foreign office positions remained vacant.
"Given that one of the reasons for opening the foreign offices was to conduct inspections, the large number of vacant investigators is concerning," the GAO said. "FDA officials have stressed that there are significant benefits to having investigators stationed overseas."
But the agency is improving, GAO Healthcare Director John Dicken said in an interview. The GAO will release a new report on FDA inspections in February, he noted.
One way the FDA has increased its regulatory reach is by entering international mutual agreements allowing regulatory cooperation with 20 European countries since November 2017. The agreements enable the FDA to recognize drug inspections conducted by foreign regulatory authorities in those countries, expanding the workforce in response to the volume of foreign manufacturers.
"FDA is reaching agreements with a number of EU countries to rely on the inspections those countries have done and vice versa," Dicken said. "And that's a major step that FDA has been taking to address the challenges faced with the globalized manufacture of drugs."
As for the FDA's specialized workforce, progress has been made, albeit slowly.
"They're still relying on domestic inspectors and some foreign inspectors who may have been assigned to foreign offices, or developed a cadre of individuals that work across all different foreign inspections, so certainly there have been challenges in having a stable and trained workforce that can do that," Dicken said. "That's the area where we did see progress since 2016, and they're developing a plan to reduce the gaps that they've had in the workforce that performs foreign inspections, but that does certainly remain a challenge."