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Umesh et.al International Journal of Drug Regulatory Affairs. 2021; 9(2): 77-80
e-ISSN: 2321-6794 [77]
Available online on 15 Jun, 2021 at https://ijdra.com/index.php/journal
International Journal of Drug Regulatory Affairs
Published by Diva Enterprises Pvt. Ltd., New Delhi
Associated with Delhi Pharmaceutical Sciences & Research University
Copyright© 2013-21 IJDRA
Review Article Open Access
Nitrosamine Impurities: Origin, Control and Regulatory Recommendations
Umesh Dobariya*, Narendra Chauhan, Himani Patel, Nidhi Pardeshi
Department of Regulatory Affairs, Isazi Pharma and Techno Consultancy Private Limited, Vadodara, Gujarat, India – 390007
Abstract
The unexpected finding of presence of nitrosamine impurities, by USFDA and EMA in year 2018, in drugs such as Angiotensin-II
Receptor Blockers (ARBs), Ranitidine, Nizatidine and Metformin, has triggered the need for a risk assessment strategy for evaluation
and control of these probable human carcinogen - nitrosamine in pharmaceutical product that are at risk. This finding leads to voluntarily
recall of products worldwide. The finding of nitrosamines in some types of drug products led FDA and other international regulators to
conduct a detailed risk assessment of these impurities in APIs and drug products. Although nitrosamine impurities have been found in
only some drug products, regulatory agencies recommended to extend risk analysis in other chemically synthesized APIs and drug
products also.
Keywords: Nitrosamine, Risk Assessment, USFDA, EMA, EDQM, Amines, Nitrous Acid, Azide
Article Info: Received 27 May. 2021; Review Completed 14 Jun. 2021; Accepted 15 Jun. 2021
Cite this article as:
Dobariya U, Chauhan N, Patel H, Pardeshi N. Nitrosamine Impurities: Origin, Control and Regulatory Recommendations.
Int J Drug Reg Affairs [Internet]. 2021 Jun 15 [cited 2021 Jun 15]; 9(2):77-80. Available from:
http://ijdra.com/index.php/journal/article/view/472
DOI: 10.22270/ijdra.v9i2.472
*Corresponding author
1. Introduction
In July 2018, health agencies were informed about
presence of probable carcinogenic impurity identified as
N-nitrosodimethylamine (NDMA) in Valsartan
(Angiotensin-II Receptor Blockers (ARBs)). Since then,
WHO, USFDA, EMA and other health agencies have
been investigating the presence of nitrosamine impurities
in certain drug products. Because the nitrosamine
impurity issue is not limited to some region of world,
USFDA and other regulatory authorities partnered to
share investigation information, inspection coordination,
communicate effective analytical methods to detect and
identify various nitrosamines, and to develop rapid
solutions to ensure the safety and quality of the drug
supply. (1-4)
Regulators with which USFDA collaborated include the
European Medicines Agency (EMA), European
Directorate for the Quality of Medicines and Healthcare
(EDQM), Health Canada (HC), Therapeutic Goods
Administration (TGA, Australia), Ministry of Health,
Labour and Welfare/ Pharmaceuticals and Medical
Devices Agency (PMDA/MHLW, Japan), Health
Sciences Authority, Singapore (HSA, Singapore), and
Swissmedic (Switzerland). (1)
Nitrosamine are the molecule containing nitroso
functional group and is of concern because these
molecules are classified as probable carcinogens by
International Agency for Research on Cancer [IARC]
based on animal studies. Nitrosamine are common in
water and foods, cured and grilled meats, dairy products
and vegetables. Importantly, formation of Nitrosamine in
Medicinal products is process driven and not relate to
any particular molecule. (1,2)
There are seven nitrosamine impurities (Figure 1) that
could be present in drug products theoretically and five
of them (NDMA, NDEA, NMBA, NIPEA, and NMPA)
have actually been detected in drug substances or drug
products. (1)
2. Origin of Nitrosamine
The most common pathway for the formation of
Nitrosamine is Nitrosating reaction between amines
(secondary, tertiary, or quaternary amines) and nitrous
acid (nitrite salts under acidic conditions). Amines and
nitrous acid can be present in the reaction process by
various reasons.
Secondary, Tertiary and Quaternary Amines, present as a
functional group in the API, intermediate and starting
materials or added intentionally as a reagents or
catalysts, can react with nitrous acid or other nitrosating
agents to form nitrosamines.
Amide solvents, N-methylpyrrolidone, N,N-
dimethylacetamide, and N,N-diethylacetamide are
susceptible to degradation under certain reaction
Umesh et.al International Journal of Drug Regulatory Affairs. 2021; 9(2): 77-80
e-ISSN: 2321-6794 [78]
conditions to form secondary amines. Tertiary and
quaternary amines used as reagents in the synthesis of
APIs may contain other amine impurities. Secondary and
tertiary amines may be present as impurities or
degradants formed by dealkylation of quaternary amines.
Figure 1. Structure of Different Nitrosamine impurities
NDMA can occur in drinking water as it is a by-product
of several industrial processes and is a contaminant of
certain pesticides. Nitrosamine impurities can be
introduced when vendor-sourced materials, including
starting materials and raw materials, are contaminated.
The agency has observed incidents where starting
materials and other raw materials are contaminated
during shipment from vendors, nitrite impurities present
in some starting materials and raw materials, secondary
and tertiary amines present as impurities in some raw
materials and fresh solvents, and cross-contamination of
out-sourced starting materials and intermediates
manufactured at sites where nitrosamine impurities are
produced in other processes and equipment is not
adequately cleaned.
Recovered materials such as solvents, reagents, and
catalysts may pose a risk of nitrosamine impurities due
to the presence of residual amines. These nitrosamines
may be entrained if they have boiling points or solubility
properties similar to the recovered materials, depending
on how recovery and subsequent purification takes
place.
Quenching process for decomposition of residual azide
by addition of nitrous acid directly into reaction mixture,
where nitrous acid, despite purification operations, can
carry over into subsequent steps and comes into contact
with residual amines in the raw materials and forms
nitrosamine. Lack of optimization of the manufacturing
process for APIs, where reaction conditions such as
temperature, pH, or the sequence of adding reagents,
intermediates, or solvents are inappropriate or poorly
controlled, is another potential source of formation of
nitrosamine impurities.
Nitrites are common nitrosating impurities present in
commonly used excipients which may lead to formation
of nitrosamine impurities in drug product during
manufacturing process as well as during storage.
Processes that use nitrites in the presence of secondary,
tertiary, or quaternary amines are at risk of generating
nitrosamine impurities. Some drug products may
undergo degradation pathways to form nitrosamine
impurities during storage. (1, 2, 4, 7, 8)
3. Controls Strategies and Regulatory
Recommendations
As per ICH M7(R1): Assessment and Control of DNA
Reactive (Mutagenic) Impurities in Pharmaceuticals to
Limit Potential Carcinogenic Risk (March 2018), control
of any known mutagenic carcinogen, such as nitroso-
compounds, at or below a level such that there would be
a negligible human cancer risk associated with the
exposure to potentially mutagenic impurities. (5)
Umesh et.al International Journal of Drug Regulatory Affairs. 2021; 9(2): 77-80
e-ISSN: 2321-6794 [79]
Regulatory agencies, including USFDA, EMA and
EDQM, recommends that manufacturers consider the
potential causes of nitrosamine formation and evaluate
the risk for formation and contamination of nitrosamine
impurities in their APIs and drug products based on
factors such as maximum daily dose, duration of
treatment, therapeutic indication, and number of patients
treated. Manufacturers of APIs and drug products should
take appropriate measures to prevent unacceptable levels
of nitrosamine impurities in their products. (1-3)
Nitrosamines are not expected to be formed during the
manufacture of the vast majority of APIs. However, it is
now known that these impurities can form during
production under certain conditions and when certain
solvents, reagents and other raw materials are used. In
addition, impurities can be carried over during the
manufacturing process when using already-contaminated
equipment or reagents. Furthermore, in cases where
nitrosamines can form or are carried over during
production, the impurities should normally be controlled
and removed during the manufacturing process.
Therefore, despite the low risk of nitrosamines being
present, manufacturers were asked to take precautionary
measures to mitigate the risk of nitrosamine formation or
presence during the manufacture of all medicinal
products containing chemically synthesised APIs. (1, 2)
Active Pharmaceutical Ingredients Committee (APIC)
recommended criteria of the risk assessment for presence
of N-nitrosamines in APIs to prioritize the evaluations,
as provided below. (6)
Higher daily dose taken
Long duration of treatment
Therapeutic indication
Higher number of patients treated
Commercial APIs > APIs used for clinical trials
API manufactured in multipurpose equipment >
dedicated equipment
API manufactured in multipurpose equipment
exposed to nitrosating agents
API > Intermediate > RSM (for companies
manufacturing the three categories)
APIs still manufactured > APIs no longer
manufactured but still on the market
APIs sold to markets where risk assessment has
already been requested by authorities > APIs
sold to other markets
Knowledge of the likelihood of a risk based on
the chemistry of the process (presence of amine,
nitro functionalities, nitrosating agents)
USFDA recommends the acceptable intake (AI) limits
for the nitrosamine impurities NDMA and NMBA as 96
ng/day and for NDEA, NMPA, NIPEA and NDIPA 26.5
ng/day. These limits are applicable only if a drug
product contains a single nitrosamine. FDA suggested, if
more than one nitrosamine impurities is detected and the
total quantity of nitrosamine impurities exceeds 26.5
ng/day based on the maximum daily dose (MDD), the
manufacturer should contact the Agency for evaluation.
If nitrosamines without published acceptable intake
limits are found in drug products, manufacturers should
use the approach outlined in ICH M7(R1) to determine
the risk associated with the nitrosamine and contact the
Agency about the acceptability of any proposed limit. (1)
Sensitive methods with limits of quantitation (LOQ) in
the parts-per-billion (ppb) range are needed to meet the
low acceptable intake recommended for nitrosamines.
Manufacturers should use methods with LOQs at or
below 0.03 ppm. If more than one nitrosamine is
detected, then the analytical method should be validated
for LOQs below 0.03 ppm to accurately quantify a total
nitrosamine level of not more than 26.5 ng/day. (1, 2)
4. Conclusion
Manufacturer should identify potential sources for
formation of Nitrosamine impurities such as raw
material, reagent, catalyst, solvents and cross-
contamination in chemically synthesized drug substance
and drug products manufactured thereof. Regulatory
agencies are publishing instruction notes and guidance
periodically to guide manufacturers to identify and
evaluate Nitrosamine in their product and control within
its acceptance limit. Regulatory agencies are still
collecting updated evaluation data from manufacturers to
update recommendations provided in guidance as more
information becomes available. All regulatory agencies
and pharmaceutical manufacturers are working so
closely with each other that elementary information
about chemistry, origin, evaluation and control strategies
are now well known for further assessment.
Acknowledgements
The authors are very much thankful to Isazi Pharma
and Techno Consultancy Private Limited for their
support and constant encouragement.
Financial Disclosure statement: The authors received
no specific funding for this work.
Conflict of Interest
The authors declare that there is no conflict of interest
regarding the publication of this article.
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