IPEC Position Paper

The Role of Excipients in Determining N-Nitrosamine

Risks for Drug Products
February 2024

Purpose of Position Paper

This paper describes the IPEC Federation’s (IPEC) position on the role of excipients when conducting
N-nitrosamine (nitrosamine) risk assessments for drug products.

Executive Summary
The presence of N-nitrosamines in drug products continues to be a global concern. Contributions
excipients may or may not have on nitrosamine formation should be considered within a holistic risk
assessment for drug products. Although the risk for excipients to directly contribute nitrosamines to
a drug product is very low, some excipients may contain the reactive species that contribute to (or
inhibit) nitrosamine formation. The most likely reactive species potentially present in excipients are
nitrosating agents, like nitrites. The concentration of nitrites may differ by excipient chemistry,
manufacturer and batch. Excipient manufacturers, on their own, have no regulatory requirement to
conduct risk assessments or control reactive species within their products. The responsibility of
assessing and potentially controlling nitrosamines lies with the drug product owner/manufacturer as
part of a collaborative process. However, many excipient manufacturers provide information to
support drug product manufacturers' risk assessments and mitigation strategies (IPEC-Federation
Questionnaire).

Background Information
N-nitrosamines are a class of organic compounds that include examples that are associated with a
potential for a significant carcinogenic risk (part of the “cohort of concern” in ICH M7).1 Beginning in
July 2018, the European Medicines Agency (EMA) reported the recall of several products containing
Valsartan due to N-nitrosodimethylamine (NDMA) contamination.2 This initiated investigations by
several regulatory agencies resulting in the discovery of N-nitrosamine impurities in sartans and other
unrelated compounds.3,4 Because the presence of N-nitrosamines in final drug products is a global
issue, there have been requests from multiple regulatory agencies for drug product manufacturers to
complete risk assessments for the presence or formation of N-nitrosamines in marketed drug products
containing chemically-synthesized APIs.5 In July 2020, the EMA published an Article 5(3) assessment
report that placed all medicinal products (including, biologics, vaccines, Advanced Therapeutic
Medicinal Products (ATMPs), and recombinant therapeutic proteins) into scope of the nitrosamine risk
assessment.6,7 Other regulatory agencies, (for example, Health Canada, Swiss Medic, and ANVISA)
have also placed biologics within scope of the nitrosamine risk assessments. In September 2020, the
US Food and Drug Administration (FDA) published its guidance on nitrosamines.8
The FDA’s guidance applies to any drug product containing chemically synthesized APIs and drug
products at risk.
The most substantial risk for the presence or formation of N-nitrosamines in drug products comes from
the confluence of three factors: a nitrosating agent, a secondary or tertiary amine (vulnerable amines),

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 IPEC Position Paper
The Role of Excipients in Determining
N-Nitrosamine Risks for Drug Products

and appropriate conditions (for example elevated temperatures, acidic conditions, liquid phase) for
the reaction. This position paper does not intend to be an exhaustive review of nitrosamine chemistry
and formation. For further details on nitrosamine formation, please refer to published articles.
Excipients should be considered within a holistic risk assessment for nitrosamines in a drug product.
Risk assessments by the drug product manufacturer should be designed to evaluate the potential
sources of nitrosamine presence/formation (i.e., API including starting materials, route of synthesis,
solvents, solvents recovery, degradation of API, excipients, primary packaging material) and
contamination during manufacturing of drug products.

IPEC Federation Position

Nitrosamines in Excipients
To date, only one excipient has been known to contain a nitrosamine: trolamine (triethanolamine)
with the nitrosamine impurity N-nitrosodiethanolamine. In the European Pharmacopeia, the limit for
N-nitrosodiethanolamine is established at 24 ppb.9 While this particular excipient may contain a
nitrosamine impurity, this vulnerability is known and understood. The risk of an excipient introducing
a nitrosamine directly to a drug product is not currently envisaged for any other product.
Vulnerable Amine Compounds in Excipients
Vulnerable amines can be introduced to a drug product via the active drug substance, impurities in
the active drug substance, counterions from pharmaceutical salts, and excipients. With respect to
excipients, the questions that should be considered are: can an excipient directly introduce a reactive
amine that can convert to a nitrosamine within a drug product? The potential risk that may come from
a vulnerable amine present in trace amounts in an excipient will depend on the formulation
composition and should be evaluated accordingly.
Nitrosating Compounds in Excipients
Concern for nitrosating compounds in excipients has focused attention on nitrites and nitrates, neither
of which are powerful nitrosating compounds on their own, but, under certain conditions, can
potentially react with other materials in the drug product formulation to form nitrosamines. Nitrite can
form the reactive species nitrous anhydride (N2O3) under mildly acidic conditions.10 Solid state
mechanism of nitrosamine formation related to nitrite partitioning in water vapor and reacting with
secondary amine containing APIs have been reported.11 Nitrates can react to form nitrite through
enzymatic reduction, which then can form the reactive nitrous anhydride under acidic conditions.12 It
is very unlikely during excipient and drug product manufacturing for enzymatic reduction of nitrates to
nitrites to occur. Therefore, nitrate is not a significant contributor to nitrosamine formation in drug
products.13,14,15 Further discussion will focus only on nitrites.
The report by Wu et al. measured nitrites in samples of microcrystalline cellulose (MCC), lactose, pre-
gelatinised starch, povidone, crospovidone, sodium starch glycolate (SSG), sodium croscarmellose,
stearic acid, hydroxypropyl cellulose (HPC) and silicon dioxide.16 Reported levels of nitrites in the
excipients ranged from 0.9 ppm (in a sample of HPC) up to 285.6 ppm (in a sample of SSG). More
recently, a publication from Lhasa provides ranges of nitrites in excipients as reported by contributor
companies.14 The report indicates that nitrite levels can vary batch-to-batch and manufacturer-to-

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 IPEC Position Paper
The Role of Excipients in Determining
N-Nitrosamine Risks for Drug Products

manufacturer and are dependent on the method used to quantify nitrites. These reports highlight the
complexity that arises when assessing the potential contributions of nitrosating agents from excipients.
It is important to note that the presence of nitrites cannot always be directly inferred from the structure
or manufacturing process. Process water (e.g., material used for washing materials after processing),
raw materials, and excipient processing conditions could be sources of nitrites in excipients. Excipient
manufacturing can use potable and/or purified water. Typically, potable water has nitrite levels below
0.1 ppm and would not likely be a concern as a source of nitrosating agents.10 Where purified water
is used to manufacture excipients, it is even less likely a factor of concern. Typically, purified water
and potable water undergoes periodic testing and reporting of control levels for numerous chemical
moieties including monitoring and controls for nitrites. It is important to know that the water used for
washing the material, for instance after acid mediated processes, can be extensive and that some
materials can preferentially adsorb content from the water, so processing water needs to be of the
requisite standard (at a minimum, potable water).
While nitrites are present in commonly used excipients, removing nitrites from excipients, where
present, is not trivial. Rather than removing or limiting nitrites in excipients, the impact of nitrites in a
given excipient should be evaluated individually for each drug product for any potential risk. Whether
the presence of nitrites in an excipient is a significant risk factor will depend on the composition in the
drug product formulation and the published acceptable level for a given nitrosamine. It is possible that,
going forward, that alternate sources of water could be used for processing excipients, but this will
have an impact on how much it costs to process them with more expensive sources of water.

So, is it necessary to introduce limits for nitrites in excipients? For each drug product, the drug
manufacturer must develop control strategies based on their risk assessment, for the following
reasons:

• The presence of nitrites in an excipient alone does not directly result in the formation of
nitrosamines in a drug product, as other factors (a vulnerable amine and correct reaction
conditions) are also required. Not all drug products meet all conditions for nitrosamine
formation.
• The amount of nitrite present in a drug product because of an excipient is dependent upon the
amount of excipient used in the formulation.
• Mitigation in the form of exclusions of moisture, and conditions of oxidation, from the drug
product by formulation, processing and packaging may be possible.
However, a thorough risk assessment on the drug product by the MAH or drug product manufacturer
may conclude that the presence of nitrites in an excipient is a risk for nitrosamine formation. In such
cases where possible, the MAH or drug product manufacturer should mitigate any risk in cooperation
with the excipient supplier(s). Here, a limit for nitrites may be appropriate. However, it may not be
possible for the vendor to meet any specific limit request, and the drug manufacturer needs to take
this into account when making the risk assessment. For new products it is possible that grades, or
suppliers, of materials may be chosen which act as a mitigation, but it may not be possible to retrofit
these standards to long established materials.

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 IPEC Position Paper
The Role of Excipients in Determining
N-Nitrosamine Risks for Drug Products

Consideration of Excipients for Mitigating Nitrosamine Formation in Drug Products

There are many opportunities for drug product manufacturers to select and utilize excipients to help
reduce nitrosamine formation. Ideally this is best done as part of new product development (Quality
by Design). Many new and novel nitrosamines are emerging and the scope of potential nitrosamines
in commercial drug products is not yet fully understood. In 2021, the FDA provided updates on
possible strategies to reduce the risk of nitrosamine impurities in drug products.8 Within the update,
the FDA encourages drug product manufacturers to explore innovative strategies to reduce the
formation of nitrosamines in drug products. This is aligned with the investigation presented by Nanda
where excipients (e.g., antioxidants and amino acids) were used to prevent the formation of
nitrosamines within tablet formulations.17 Additionally, certain amino acid and primary amine
excipients have been shown not to be carcinogenic and/or to have scavenging and other nitrosamine
inhibition formation properties.18-23
Responsibilities of Excipient Users
As communicated by regulatory agencies, the drug product manufacturer and/or MAH are responsible
for completing a comprehensive risk assessment for the final drug product and sharing that as directed
with the appropriate regulatory authorities. Care should be given when excipients are evaluated as an
input for the drug product nitrosamine risk assessment to ensure proper conclusions are made.
Considerations for the potential sources and processes that may contribute to the formation or
contamination of nitrosamines should be thoughtfully evaluated. While excipients are typically not
considered a major risk factor in terms of themselves being a direct source of nitrosamines, it is
important to understand residual levels, if any, of nitrites that may be present in an excipient and that
can potentially interact with other materials such as an API and/or API fragments. For these specific
cases, the reader should refer to nitrosamine drug substance-related impurities (NDSRI) guidance per
regulatory bodies like FDA, Health Canada and EMA. Collaborative discussions between the excipient
manufacturer and the drug product manufacturer, drug product distributor, and/or MAH should occur
when needed to ensure available excipient information is understood within its proper context. The
ultimate goal is to ensure safe and effective medications are available for the treatment of patient
ailments.
Responsibilities of Excipient Suppliers
As the previous sections highlight, nitrosating agents and vulnerable amines may be found in some
excipients, but the responsibility for overall risk assessment for the presence of nitrosamines in a drug
product lies with the MAH or the drug product manufacturer. So, how should excipient manufacturers
and/or suppliers support MAHs with global supply chains with their risk assessments? First, IPEC
recommends use of the IPEC questionnaire because it is in the interests of excipient manufacturers
to provide information that would facilitate the safe use of their excipients generally, and equally for
nitrosamines risk assessments; however, it should be made clear that excipient manufacturers are
under no specific regulatory requirement to provide excipient risk assessments on nitrosamines to
regulatory agencies.
Available Information on Nitrosamines
Until the recent reports from regulatory authorities that nitrosamines were found in drug products,
there was little cause for excipient manufacturers to contemplate the potential presence of
nitrosamines or nitrosating agents in excipients. Therefore, excipient manufacturers typically do not
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 IPEC Position Paper
The Role of Excipients in Determining
N-Nitrosamine Risks for Drug Products

have substantial databases of information on the nitrite content of their systems, and any products
which formed nitrosamines in use. Such information may not have been shared by the drug
manufacturer with the vendor. On the other hand, excipient manufacturers generally have a detailed
understanding of the manufacturing processes and the basic chemistry of the raw materials used. It
is often possible to rule out the potential presence of nitrites based on this understanding. So, in
summary, excipient manufacturers may be able to provide information that would potentially exclude
the presence of nitrosamines, nitrosating agents (nitrites), or vulnerable amines, but they generally
will not possess analytical testing data on these substances.
Format for Providing Information to Excipient Customers/Users
IPEC has developed a questionnaire template that guide an excipient manufacturer through a series
of questions to provide information about a given excipient and its manufacturing process to help
inform the drug product manufacturers risk assessments. Many excipient manufacturers have been
using this template or similar formats to inform drug product manufacturers. The template can be used
as a starting point for providing excipient information to customers. The template is publicly available
on the IPEC website (IPEC Federation Questionnaire).
Reasonable Expectations / Misperceptions
Most excipient manufacturers are willing to share insights into the manufacturing processes for their
products to potentially rule out the likelihood for nitrosamines. The IPEC questionnaire templates are
good resources for excipient manufacturers to provide information on this topic, and their use is
encouraged.
Excipient manufacturers have fielded many requests for information on nitrosamines over the past
couple of years and have seen a few misperceptions that should be addressed.
• Responsibility for drug product risk assessment – this lies solely with the MAH or the drug
product manufacturer though excipient manufacturers are generally providing information to
support such assessments. While the regulatory responsibility is with the MAH, the excipient
supplier should carefully evaluate the potential risks of its excipient. A risk assessment for an
excipient is not a regulatory requirement for excipient suppliers, but they may play a role in
evaluating the risk.
• Obligation to test – some drug product manufacturers have indicated that an excipient
manufacturer should test their excipients to confirm the absence of nitrosamines and nitrites
or provide typical levels. Excipient manufacturers are under no obligation to test excipients for
these substances. Excipient manufacturers could voluntarily provide such data in cases where
it is deemed to be warranted.
It is important to note that the presence of nitrites in current or historic material is not a failure of
“Quality,” as this parameter is generally not included in any quality requirement in Certificates of
Analysis or Pharmacopeia.

Path forward / Summary

IPEC continues to monitor regulatory developments related to nitrosamines and drug products and
any impact these may have on excipients or excipient manufacturers. The presence of nitrogen-
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 IPEC Position Paper
The Role of Excipients in Determining
N-Nitrosamine Risks for Drug Products

containing components in an excipient does not necessarily lead to the formation of nitrosamines in a
drug product. To assist drug product manufacturers to fulfil their regulatory obligations in conducting
risk assessments for their drug products, IPEC encourages excipient manufacturers to share relevant
information using tools such as the IPEC questionnaire. Only the drug product manufacturer, drug
product distributor, and/or MAH can determine the potential risk of nitrosamine formation in the context
of the other components in specific formulations and manufacturing, packaging, and storage
conditions.

References
1. M7(R2) Mutagenic Impurities. ICH, Ed. 2023.
2. EMA reviewing medicines containing valsartan from Zhejiang Huahai following detection of an
impurity: some valsartan medicines being recalled across the EU. Press Release, 05 July
2018.
3. Teasdale, A.; Popkin, M., Regulatory Highlights. Org.Process Res. Dev. 2019, 23 (7),
1292-1297.
4. Woodcock, J., Statement alerting patients and health care professionals of NDMA found in
samples of ranitidine. Press Release, 13 September 2019.
5. EMA advises companies on steps to take to avoid nitrosamines in human medicines. Press
Release, 26 September 2019.
6. EMA Nitrosamine impurities in human medicinal products: Procedure under Article 5(3) of
Regulation EC (No) 726/2004 – Assessment Report (EMA/369136’2020).
https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-
assessment-report_en.pdf
7. EMA/409815/2020, Rev. 14, 21 December 2022: Questions and answers for marketing
authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation
(EC) No 726/2004 referral on nitrosamine impurities in human medicinal products.
https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-
questions-answers-marketing-authorisation-holders/applicants-chmp-opinion-article-53-
regulation-ec-no-726/2004-referral-nitrosamine-impurities-human-medicinal-
products_en.pdf
8. FDA Guidance: Control of Nitrosamines Impurities in Human Drugs. Guidance for Industry.
February 2021 (Revision 1). https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/control-nitrosamine-impurities-human-drugs.
9. European Pharmacopeia. Trolamine Monograph. Edition 10.5. July 2021.
10. Ashworth, Dirat, Teasdale, and Whiting. (2020). Potential for the Formation of N‑Nitrosamines
during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk
Posed by Trace Nitrite in Water. Organic Process Research & Development; 24:1629-1646.
11. Sluggett, et. al. (2018) Artifactual Degradation of Secondary Amine-Containing Drugs During
Accelerated Stability Testing When Saturated Sodium Nitrite Solutions are Used for Humidity
Control. Journal of Pharmaceutical and Biomedical Analysis. 149, 206-213.
12. Lundberg et al. Nature Reviews Microbiology, 2004.
13. Cioc, R., Joyce, C., Mayr, M., Bream, R. (2023) Formation of N-Nitrosamine Drug Substance
Related Impurities in Medicines: A Regulatory Perspective on Risk Factors and Mitigation
Strategies. Organic Process Research & Development, 27 (10), 1736-1750.
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The International Pharmaceutical Excipients Council – Federation (IPEC Federation) asbl
Rue Marie de Bourgogne 52 – 1000, Brussels, Belgium
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 IPEC Position Paper
The Role of Excipients in Determining
N-Nitrosamine Risks for Drug Products

14. Boetzel, et al. (2022) A Nitrite Excipient Database: A Useful Tool to Support N-Nitrosamine
Risk Assessments for Drug Products. Journal of Pharmaceutical Sciences.
https://doi.org/10.1016/j.xphs.2022.04.016
15. Song et al. (2015) Dietary Nitrates, Nitrites, and Nitrosamines Intake and the Risk of Gastric
Cancer: A Meta-Analysis. Nutrients. 2015 Dec; 7(12): 9872–9895.
https://doi.org/10.3390%2Fnu7125505
16. Wu et al, Reactive Impurities in Excipients, PharmSciTech, 2011
17. Nanda, et.al. (2021) Inhibition of N-Nitrosamine Formation in Drug Products: A Model Study.
Journal of Pharmaceutical Sciences; 110(12), 3773-3775.
18. Ohshima, H., Mahon, G. A. T., Wahrendorf, J. and Bartsch, H. (1983) Kinetic Model for
Predicting Carcinogenic Effects Caused by Endogenous Nitrosation; Cancer Res.; 43, 5072-
5076.
19. Garcia, H. and Lijinsky, W. (1973) Studies of the tumorigenic effect in feeding of nitrosamino
acids and of low doses of amines and nitrite to rats. Zeitschrift fur Krebsforschung und
Klinische Onkologie; 79, 141-144.
20. Danno, G.-I., Kanazawa, K., Toda, M., Mizuno, M., Ashida, H. and Natake, M., (1993) A
Mutagen from Histidine Reacted with Nitrite. J. Agric. Food Chem.; 41, 1090-1093.
21. Bolli, R., Woodtli, K., Bartschi, M., Hofferer, L., Lerch, P. (2010) L-Proline reduces IgG dimer
content and enhances the stability of intravenous immunoglobulin (IVIG) solutions.
Comparative Study; 38, 150 – 157.
22. Endo, H., Takahashi, K. and H. Aoyagi (1974) Screening of compounds structurally and
functionally related to N-methyl-N’-nitro-N-nitrosoguanidine, a gastric carcinogen. GANN; 65,
45-54.
23. Kato, T. and Kikugawa, K. (1992) Proteins and amino acids as scavengers of nitrite: inhibitory
effect on the formation of nitrosodimethylamine and diazoquinone. Food and Chem Tox, 30(7),
617-626.
24. FDA Guidance: Updates on possible mitigation strategies to reduce the risk of nitrosamine
drug substance-related impurities in drug products. November 2021.
https://www.fda.gov/drugs/drug-safety-and-availability/updates-possible-mitigation-strategies-
reduce-risk-nitrosamine-drug-substance-related-impurities#1

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