Valsartan medications were recalled in 22 countries after NDMA, a probable human carcinogen, was found in some products. The NDMA was detected in valsartan active pharmaceutical ingredients supplied by Zhejiang Huahai Pharmaceuticals. NDMA is believed to form as an unintended byproduct during valsartan synthesis when dimethylamine and sodium nitrite are used to form the tetrazole ring under acidic conditions. Regulatory agencies estimate that long-term use of affected valsartan batches could potentially lead to 1 additional case of cancer for every 5,000-8,000 patients treated based on average NDMA levels detected. Further investigation also uncovered a second carcinogenic impurity, NDEA, in some

1. NDMA, a new impurity identified in
Valsartan drug product
Presented by
Dr. Narender Rao Somisetti

2. VALSARTAN RECALL FROM MARKET
 On July 13, 2018, FDA pulled valsartan drug products after NDMA was
identified in some medications.
 The recall was initiated after N-nitroso dimethylamine (NDMA), which is classified as a
probable human carcinogen based on laboratory tests.
 To date, 22 countries have recalled valsartan-based medications after the impurity
was identified. FDA, EMEA & Canada recalled drugs containing valsartan supplied by
Zhejiang Huahai Pharmaceuticals after NDMA was detected in the active
ingredient.
N D M A
(N-Nitroso dimethylamine)
NDMA is classified as a probable human
carcinogen based on animal tests.
Zhejiang Huahai
Pharmaceuticals
Valsartan Global Recall due
to unexpected impurity,
NDMA

3. VALSARTAN RECALL FROM MARKET
Medicine Company
Valsartan Major Pharmaceuticals
Valsartan Solco Healthcare
Valsartan Teva Pharmaceuticals Industries Ltd.
Valsartan/Hydrochlorothiazide (HCTZ) Solco Healthcare
Valsartan/Hydrochlorothiazide (HCTZ) Teva Pharmaceuticals Industries Ltd.
Recalled Products:
The companies listed above are recalling all lots of non-expired products that contain the ingredient
valsartan supplied to them by Zhejiang Huahai Pharmaceuticals, Linhai,China. Not all valsartan-
containing medicines distributed in the United States have valsartan active pharmaceutical
ingredient (API) supplied by this specific company.
NDMA is an unexpected impurity that was not detected by routine tests carried out by
Zhejiang Huahai. EMA is now gathering details of the company’s manufacturing processes,
following changes introduced in 2012 that are believed to have produced NDMA as a side
product.

4. IMPACT ASSESSMENT AND ACTION BY
REGULATORY AUTHORITIES
EMA estimates that there could be one extra case of cancer for
every 5,000 patients taking the affected medicines at the
highest valsartan dose (320 mg) every day for 7 years. This is
based on average levels of this impurity detected in the active
substance from Zhejiang Huahai Pharmaceuticals (60 parts per
million).
FDA scientists estimate that if 8,000 people took the highest
valsartan dose (320 mg) from the recalled batches daily for the full
four years, there may be one additional case of cancer over the
lifetimes of these 8,000 people. This assessment led to FDA’s
decision to have these batches recalled.
Based on the toxicity data, the tentative limit for NDMA in Valsartan
designated by EDQM, is 0.3 ppm according to the requirements of ICHM7,
and further assessment was still being conducted by EMA. The final acceptable
limit index has not been determined.
FDA placed Zhejiang Huahai Pharmaceuticals on import alert on
September 28, 2018, entering the United States. FDA’s action
follows a recent inspection at ZHP’s facility.

5. TOXICITY CLASSIFICATION OF NMDA

6. WHAT IS NDMA ?
Valsartan
NDMA
(N-Nitroso dimethylamine)
 NDMA is water-soluble, yellow in
color, It is toxic to the liver and other
organs, and is a probable human
carcinogen.
 By-product of industrial processes.
 Organic nitrogen-containing
wastewater can lead to the
production of NDMA and can form or
be leached during treatment of water
by anion exchange resins.[
 NDMA is found at low levels cured
meat, fish, beer, tobacco smoke and
as an impurity in pharmaceuticals.

7. HOW IT IS FORMED IN
VALSARTAN SYNTHESIS ?

8. HOW IT IS FORMED IN
VALSARTAN SYNTHESIS ?
“NDMA appears to be generated during the formation of the tetrazole ring by
reaction of dimethylamine (which may be present as an impurity or degradant in
the solvent dimethylformamide (DMF) and sodium nitrite under acidic conditions
(where nitrous acid is formed). It can also not be excluded that other N-
nitrosamines could be generated with other solvents or under other specific
reaction conditions where other amines are present”
Ref: EMA release; CHMP List of questions (EMA/CHMP/467845/2018; dated 16 July
2018).
a) Quenching the excess sodium azide left unreacted in the tetrazole ring formation
2NaN3+2HNO2 → 3N2+2NO+2NaOH
b) Preparation of tetrazole ring formation upon reacting with the aminoamidine
obtained by
reacting hydrazine with methyl N-valeryl-N-[(2'-cyanobiphenyl-4-yl)methyl]-
L-valinate
R–CN + N2H4→R–C(=NH)NHNH2
R–C(=NH)NHNH2+ HNO2 → R–Tetrazole.
NH(CH3)2+NO or HNO2 →NDMA

9. METHODS FOR DETECTION AND
QUANTIFICATION OF NDMA
FDA is releasing a gas chromatography-mass spectrometry (GC/MS)
headspace method for manufacturers and regulators to detect and quantify
NDMA in valsartan API and finished drug products

10. HOW TO ELIMINATE OR AVOID FORMATION
OF NDMA IMPURITY IN VALSARTAN
Use of alternate methods for tetrazole
formation in place NaN3/DMF system like
tributyl tin azide in xylene/toluene
Use of NaOCl for quenching excess NaN3
instead of nitrous acid.
Preparation Barium salts of Valsartan for
final purification.
Preparation of Tetrazole ring in the initial
stages/ Using advanced intermediates
having Tetrazole ring

11. PROBLEM CONTINUES: ONE MORE
NEW IMPURITY IN VALSARTAN
 A second unexpected impurity was shown in 3
lots of Torrent Pharmaceuticals’ recalled drug
products during an ongoing FDA investigation.

This second impurity, N-Nitrosodiethylamine
(NDEA), is a known animal and suspected
human carcinogen.
 According to the FDA, its testing discovered
NDEA in some of ZHP’s valsartan API. The
additional impurity also was found in Torrent’s
valsartan 160mg (lot BV47D001) and 320mg
(lots BV48D001 and BV48D002) tablets, which
were made using API from ZHP and were part of
the earlier recall. The FDA’s testing shows that
not all products made using ZHP valsartan API
contain the NDEA impurity.

12. Curiosity
Chemistry
Creativity