The discovery means that some of the 10 billion pills containing valsartan sold worldwide last year to prevent heart attacks and strokes had traces of N-nitrosodimethylamine (NDMA), classified as a probable human carcinogen.
SHANGHAI/LONDON – A toxin inadvertently produced in the manufacture of a widely prescribed medicine but not spotted for years raises questions about regulators’ ability to detect risks in a sprawling global drug supply chain increasingly reliant on factories in China.
China’s Zhejiang Huahai Pharmaceutical, which produces bulk ingredients for drugmakers, told its customers in late June it had found NDMA in its valsartan, an off-patent blood pressure drug originally developed by Novartis.
The discovery means that some of the 10 billion pills containing valsartan sold worldwide last year to prevent heart attacks and strokes had traces of N-nitrosodimethylamine (NDMA), classified as a probable human carcinogen. No one has been reported as sickened by the toxin, once used in the production of liquid rocket fuel.
Regulators and industry experts say the toxin almost certainly was introduced when Huahai changed the way it produced valsartan in 2012 – a modification that was signed off on by the European body that sets standards. Subsequent inspections by European, U.S. and Chinese regulators also found no problem.
"Everyone failed – the company, the inspectors, the FDA (U.S. Food and Drug Administration), the Europeans, the Chinese," said Philippe Andre, an independent pharmaceutical auditor who inspected two Huahai facilities last August and found no critical concerns. "It’s a system failure."
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Reuters was unable to determine how Huahai first discovered the problem. In a July 7 statement released through the Shanghai Stock Exchange, it said it detected the toxin during the "optimization and evaluation" of its manufacturing process.
A Novartis spokesman told Reuters that its generic drugs arm, Sandoz, spotted the NDMA in the course of intensive testing to prepare for expanding its purchases of valsartan. He declined to comment further, including on the identity of the manufacturer or when the tests took place.
Two other smaller bulk suppliers – Zhejiang Tianyu Pharmaceutical and a unit of India’s Hetero Drugs – have since also discovered traces of NDMA in some of their valsartan.
The three companies declined to comment to comment about the case.
Huahai said in a document released through the Shanghai Stock Exchange it changed the production process to reduce waste and improve yields.
"The NDMA impurity was produced in trace amounts during the normal manufacturing process according to the company’s current registered process," it said in a statement on July 24.
"All changes in the company’s valsartan manufacturing process have been approved by each country’s drug regulator, and the company manufactures in compliance with legal and regulatory standards."
The European Medicines Agency (EMA) regulator, which first publicly raised the alarm in a statement on July 5, told valsartan suppliers in a subsequent memo dated July 16 that the NDMA may have been connected to the combined use of the solvent dimethylformamide and sodium nitrite.
The FDA is also going on that hypothesis, said Janet Woodcock, director of its Center for Drug Evaluation and Research. She stressed the investigation was still going on.
"This (NDMA) was not what you look for in an inspection," Woodcock said in an interview. "If you don’t test for this you’re not going to have an idea that it’s in there, and you’re not going to see it on an inspection."
The European Directorate for the Quality of Medicines (EDQM), responsible for setting manufacturing standards, told Reuters it was aware the solvent was being used when it approved the changed process, but that NDMA as a by-product was unexpected and not tested for.
Detecting NDMA would have required gas chromatography coupled with mass spectrometry, a very sensitive level of testing, an EDQM spokeswoman said.
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"These techniques are not normally used routinely to test pharmaceutical products," she said.
Built by Novartis into the $6 billion-a-year brand Diovan, valsartan’s European and U.S. patents expired in 2011 and 2012.
Global sales totaled 10.4 billion pills last year, including combination products, healthcare data consultancy IQVIA estimates. People with high blood pressure typically take one pill daily and heart failure patients two.
More than 50 companies around the world making finished tablets from the tainted valsartan have recalled products in recent weeks, according a Reuters analysis of national medicines agencies’ records. They include major generic drug manufacturers such as Teva Pharmaceutical Industries, Ranbaxy Laboratories and Sandoz.
Based on the average NDMA impurity detected at Huahai of 60 parts per million (ppm), the EMA says there could be one additional case of cancer in every 5,000 people taking the highest dose for seven years.
The contamination puts a spotlight on manufacturers in China and India, which supply more than two-thirds of all active pharmaceutical ingredients used in medicines, industry executives estimate. China accounts for the lion’s share.
Huahai, founded in 1989 and listed in Shanghai in 2003, was one of the first Chinese companies to get drugs approved in the U.S. market.
The FDA has inspected the site that made the contaminated valsartan three times since 2010, its records show. European inspectors also visited regularly.
The provincial branch of the Chinese FDA (CFDA) also inspected Huahai facilities 10 times in connection with new drug applications between January 2016 and June 2018, the national online database shows.
U.S. and European regulators have increased scrutiny of Chinese and Indian drug factories after the adulteration of the blood thinner heparin sickened hundreds and caused the deaths of at least 81 Americans in 2007 and 2008.
The CFDA is also on alert.
Last month, it revealed that Changsheng Bio-technology, a vaccine maker, had fabricated data and sold ineffective vaccines for children. It also found that a diphtheria, tetanus and pertussis vaccine sold by the state-owned Wuhan Institute of Biological Products was substandard.
The fact that international inspections do not appear to have detected the NDMA contamination alarms Anders Fuglsang, a former European medicines regulator who runs a pharmaceutical consultancy in Denmark.
"We need to ask ourselves how it is possible – despite pharmacopoeias and agency guidelines, inspection programs with coordination across continents, a system of public quality control, and companies complying with all rules – that a nasty carcinogen can find its way into our drugs and be there for years without anyone noticing," he said.