FM OCTOBER 2018 ISSUE - digital edition

Medicines Agency (EMA), European
Directorate for the Quality of Medicines
(EDQM), Regulatory Operations and
Regions Branch and Therapeutic
Products Directorate of Health Canada,
and the Pharmaceuticals and Medical
Devices Agency (PMDA) in Japan,
sharing the developments on the
investigation.
International regulators have since
identified another API manufacturer,
Zhejiang Tianyu Pharmaceutical Co., with
NDMA in its valsartan API. The USFDA
said that no valsartan products in the US
market use this API.
The FDA estimates that if 8,000
people took the highest valsartan
dose (320 mg) from NDMA-affected
medicines daily for four years (the
amount of time it believes the affected
products have been on the U.S. market),
there may be one additional case of
cancer over the lifetimes of these 8,000
people beyond the average cancer rate
among Americans.
“This estimate represented the
highest possible level of NDMA
exposure. It was a measure of the risk
under the most extreme circumstances.
Most patients who were exposed to the
impurity through the use of valsartan
received less exposure than this worstcase
scenario,” it said.
Difficult to determine
NDMA’s properties make it difficult to
find. To determine if valsartan products
do contain this impurity, CDER’s
scientists have developed the gas
chromatography-mass spectrometry
(GC/MS) headspace testing method.
It has posted this method to the web
to help manufacturers and regulators
detect NDMA in valsartan API and
tablets.
“Specifically, a combination of
conditions, which include certain
chemicals, processing conditions and
production steps, could lead to the
formation of the NDMA impurity. We
believe that these risks are introduced
through a specific sequence of
steps in the manufacturing process,
where certain chemical reactions are
needed to form the active ingredient.
Before we undertook this analysis,
USFDA finds second impurity
The US FDA has found an
additional unexpected impurity
N-Nitrosodiethylamine (NDEA) in the
active pharmaceutical ingredient (API)
valsartan.
NDEA, a known animal and
suspected human carcinogen,
was found in three lots of Torrent
Pharmaceuticals’ recalled valsartan
drug products, the USFDA said while
updating the public on the agency’s
ongoing investigation surrounding the
recent voluntary recall of several drug
products containing valsartan API.
These Torrent products were included
in the company’s recall on August 23,
2018
Like N-Nitrosodimethylamine
(NDMA), which was found in the
recalled valsartan products, NDEA is
also formed from a specific sequence
IF 8,000 PEOPLE TOOK THE
HIGHEST VALSARTAN DOSE
(320 MG) FROM NDMA-
AFFECTED MEDICINES DAILY
FOR FOUR YEARS, THERE
MAY BE ONE ADDITIONAL
CASE OF CANCER OVER
THEIR LIFETIMES,
THE FDA ESTIMATES.
neither regulators nor industry fully
understood how NDMA could form
during this process,” said the FDA
officials.
The US drug watchdog has been
conducting a review of ARBs from
2010, according to the documents. In
light of the valsartan issue, the FDA is
conducting a study on all ARBs to check
for the presence of NDMA.
Low risk potential?
The EMA officials in August said that
the NDMA levels detected in batches of
valsartan from Zhejiang Tianyu are much
lower than the levels seen in the active
substance from Zhejiang Huahai, which
of manufacturing steps and chemical
reactions.
In addition to the FDA’s testing, the
agency will post a preliminary method
for detecting NDEA. Manufacturers and
global regulators can use this method
to screen other products for the
potential presence of this impurity.
triggered a recall of several valsartan
medicines in July 2018.
While the DCGI assures that the
contaminated batches of the ingredient
has not touched Indian shores, experts
say that there are alternatives available
for the drug and that doctors can switch
to other products in order to avoid any
possible risk.
In India, valsartan is available
as a single drug as well as in fixeddose
combinations. Patients taking
this drug should not stop the drug
without consulting their doctors for
two reasons: First, not all valsartan
containing products are recalled and
second, many equally efficacious
alternatives to valsartan are available,
alert experts. "Physicians should take
caution prescribing drugs containing
valsartan unless they can confirm that
the particular API is not sourced from
the companies mentioned above,''
says Dr Anoop Agrawal, Consultant,
Interventional Cardiology, CARE
Hospitals, Hyderabad. FDA has listed the
recalled manufacturers on their website.
He suggests that in India, authorities
should aggressively test the available
drugs for the said impurity and put out
our own list of recalled and not-recalled
brands.
OCTOBER 2018 / FUTURE MEDICINE / 63