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 China's Zhejiang Huahai Pharmaceutical <600521.SS>, 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 <NOVN.S>.
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
André, an independent pharmaceutical auditor who inspected two
Huahai facilities last August and found no critical concerns. "It's
a system failure."
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
<300702.SZ> 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.
For a graphic on heart drug widely used, click https://tmsnrt.rs/2KnaxAx
REDUCE WASTE
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.
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Detecting NDMA would have required gas chromatography coupled with
mass spectrometry, a very sensitive level of testing, an EDQM
spokeswoman said.
"These techniques are not normally used routinely to test
pharmaceutical products," she said.
RECALLS
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 <TEVA.TA>, 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.
SCRUTINY
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 <002680.SZ>,
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.
(Additional reporting by Shanghai newsroom, Zeba Siddiqui in Mumbai
and Sharnya G in Bengaluru; Editing by Sonya Hepinstall)
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