Nitrosamine impurities like NDMA and NDEA have been found in several generic drugs like ARBs which are used to treat hypertension. These impurities are classified as Class 1 mutagens and carcinogens. They can form during drug manufacturing through reactions between amines and nitrites in raw materials, solvents, or other process components. To prevent nitrosamine formation, manufacturers should avoid using amines and nitrites together, ensure raw materials and equipment are free of contamination, modify processes to remove potential impurities, and implement controls to detect and limit nitrosamines in drugs.

1. NITROSAMINE IMPURITIES
Generation &t
-An Introduction,
Control(Prevention)
A Presentation By:
NEERAJ KUMAR RAI
AGM-API Production
(Black Belt in Lean Six Sigma)

2. Introduction
Food and drug administration (FDA) and
European Medicines Agency (EMA) in July 20 18
announced that a carcinogenic impurities N•
Nitrosodimethylamine (NDMA) and N•
Nitrosodiethylamine (NDEA) are said to be
present in generic drug substances and drug
product, especially in angiotensin II receptor
blockers (ARBs) or 'Sartans'class medicines
which are used to treat patients with
hypertension (high blood pressure) and heart
failure.
•

3. Introduction
This announcement leads to voluntarily recall
hundreds of batches of these generic versions by
pharmaceutical distributor worldwide. Further,
the FDAand EMAinvestigation in year 2019 led
to the detection of these Nitrosamine impurities
in Pioglitazone used for the treatment of
diabetes and Ranitindine an H2 (histamine-2)
blocker used for the treatment of acidity of the
stomach. Presently, low level of NDMA impurity
found in Metformin also brought this drug
under FDA and EMA investigations.
•

4. Introduction
(R1) classifies Nitrosamine impurities
1, which is known to be mutagenic and
• ICH M7
as Class
carcinogenic. These Nitrosamine impurities
impact the genetic material by means of
mutations through chromosomal breaks,
rearrangements, covalent binding or insertion
into the DNA during replication.

5. What are the Nitrosamine impurities?
Nitrosamines, or N•
nitrosoamines, refer to any
molecule containing the
nitroso functional group.

7. - = l
Why Nitrosoamine impurities are part
of discussion as on date?
• Nitrosamine impurities are known to be
mutagenic and carcinogenic, very small
exposure of these impurities can lead to cancer.
These impurities may be formed and get
incorporated into drug substance or drug
product through reagent, catalyst, solvent or raw
materials used in the process of manufacturing.
The various regulatory authority has published
the press release or notice regarding the control
of these impurities with the interim limit.

8. Structures of Sartans
CH,
CH,
y'0
.:
N
N, I
H
N
N - ·
N
0
0
OH
Candesartan Irbesartan Los artan
N
N N
N
0Imesartan Valsartan
Telmisartan

9. How Nitrosamine
generated?
0
II
impurities are
acidiccondition
NaN +
-
0
Sodiumnitrite Amine N-nitrosamine
C C ,
H
,C
, 0
3 NaN0,HNO, N
I
N
]
H
N-nitrosodimethylamine
(NDMA)
Dimethyformamide(DMF) Dimethylamine

10. Amines and corresponding Nitrosamine impurities
Amines
Dimethylamine
Diethylamine
Dipropylamine
Diisopropylamine
Dibutylamine
Ethylmethylamine
Corresponding Nitrosamine impurities
N-nitrosodimethylamine (NDMA)
N-nitrosodiethylamine (NDEA)
N-nitrosodipropylamine (NDPA)
N-nitrosodiisopropylamine (NDIPA)
N-nitrosodibutylamine (NDBA)
N-nitrosomethylethylamine (NMEA)
•
•
•
•
•
•
• 4-(methylamino)butanoic acid N-nitroso-N-methyl-4•
aminobutyric acid (NMBA)

11. Sources of Nitrosamine impurities
• Nitrosamine impurities can get incorporated
into the drug substance and drug product
basically through process formation, direct
introduction, degradation or cross•
contamination.
Manufacturing of drug substances involves raw
material, intermediates, solvents, chemicals and
reagents. Through these stages, if this impurity
is formed or present it may get incorporated and
carried forwarded to drug product.
•

12. Sources of Nitrosamine impurities
,,,,. ~ r----------------------~
N-nitrosaming impurities
~
r°
I
Starting material Starting material and its Impurities
i
...
.
l
Intermediate
w
'I'
Catalyst, reagent, solvents, by•
product and int ermediat es carry
over
Product I
I
I
I
I
I
I
I
I
I
I
I
'
'"
l
..-
7p
Degradation product on storage
and shipment
Drug substances / Drug
product -
l
....
....
~------------------------~'

13. How to avoid Nitrosamine impurities?
Following precautions should be taken to avoid
the formation of nitrosating impurities.
• Avoid the use of primary, secondary and tertiary
amines and quarternary ammonium salts
alongwith nitrosating agents in same process or
different stages of process.
Use of recovered solvents should be avoided in
process without washing as impurities may be
stuck in solvents.
•

14. How to avoid Nitrosamine impurities?
• Contaminated raw material, intermediate and
reagents used in manufacturing are also the
potential source of Nitrosamine impurities. The
degradation product of raw materials and
intermediate on storage in the presence of traces
of nitrites may lead to the formation of
Nitrosamine impurities. Hence, these materials
should be properly stored and tested for
Nitrosamine impurities.

15. How to avoid Nitrosamine impurities?
• Equipment should be properly cleaned and
checked for any contamination before use in
next product as any previous contamination may
lead to formation of nitrosamine impurities.
The drug substances manufacturer should test
and check the carryover of Nitrosamine
impurities in various intermediate stages and if
it is present, it should be controlled with the
proper limit.
•

16. How to avoid Nitrosamine impurities?
• The manufacturer should modify the process to
purge out amines, nitrites and Nitrosamine
impurities at various stages. Control strategies
should be implemented to detect and control
Nitrosamine impurities in intermediate or drug
substances.