8 July 2025

EMA/144509/2025
European Medicines Agency

Nitrosamine impurities in human medicines

The response of the European Medicines Regulatory Network

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© European Medicines Agency, 2025. Reproduction is authorised provided the source is acknowledged.
Table of Contents

Executive summary ..................................................................................... 3

1. Introduction ............................................................................................ 4
2. CHMP scientific assessments ................................................................... 5
2.1. Article 31 reviews for sartans and ranitidine ............................................................ 5
Sartans ..................................................................................................................... 5
Lessons learnt from presence of N-nitrosamine impurities in sartan medicines .................... 6
Ranitidine .................................................................................................................. 6
2.2. Article 5(3) review for all human medicines ............................................................. 6

3. Overview of developed approaches ......................................................... 7

3.1. Procedural ........................................................................................................... 7
3.1.1. EMRN governance for implementation of the Article 5(3) CHMP opinion .................... 7
3.1.2. Call for review to MAHs ...................................................................................... 8
3.1.3. Guidance for MAHs ............................................................................................ 9
3.1.4. Nitrosamine case assessment workflow ................................................................ 9
3.2. Safety ............................................................................................................... 11
3.3. Quality .............................................................................................................. 12
3.4. Market surveillance ............................................................................................. 15
3.5. Medicine shortages and availability issues ............................................................. 15

4. Engagement and communication with stakeholders and international

partners .................................................................................................... 15
4.1. Industry, health care professionals and patients ..................................................... 15
4.2. Collaboration with international partners ............................................................... 16

5. Areas for future development ................................................................ 16

6. Conclusions ........................................................................................... 17
7. References ............................................................................................ 18

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Executive summary
This report provides an overview of the response of the European Medicines Regulatory Network (EMRN)
to the presence of nitrosamine impurities in human medicines.

Following the discovery in 2018 of these potentially carcinogenic impurities in a group of medicines used
to treat cardiovascular diseases, known as 'sartans’, and later in other medicines, the EMRN initiated a
number of regulatory and scientific reviews. These include Article 31 reviews of sartans and ranitidine
and an Article 5(3) review for all human medicines as well as, a lessons learnt on the experience from
the sartans.

Through these procedures, the EMRN established acceptable intake (AI) limits in collaboration with
international regulatory partners to ensure that exposure to nitrosamine impurities remained at or below
safe levels.

The network issued a call for review (CFR) for all marketing authorisation holders (MAHs) for authorised
human medicines containing chemical active substances. The CFR required MAHs to institute a stepwise
evaluation process to identify, assess and mitigate any risks of nitrosamines potentially present in their
medicines. The CFR was later extended to medicines containing biological active substances. In addition,
for marketing authorisation applications (MAAs), a requirement for applicants to submit risk assessments
on the potential presence of nitrosamines was also introduced.

The EMRN also established the Nitrosamine Implementation Oversight Group (NIOG) to oversee the
implementation of recommendations from the Article 5(3) review. There were also regular interactions
with international partners as well as industry associations to discuss regulatory requirements and
scientific information concerning nitrosamines.

These elements of the EMRN response were crucial in developing a harmonised approach in the EU for
protecting patients while maintaining availability of medicines. The development of this harmonised
regulatory approach for nitrosamines, as described in this report, has also supported the management
and assessment of individual cases where nitrosamines have been detected in human medicines within
the EU.

In terms of future developments to the regulatory framework, the latest scientific knowledge on
toxicology, safety and quality aspects of nitrosamines will be reflected in an addendum to the ICH M7
guideline on the assessment and control of mutagenic impurities in order to harmonise guidance on
nitrosamines across ICH members, which was initiated in June 2024.

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1. Introduction
The report evaluates the effectiveness of the EMRN (which includes EMA, National Competent Authorities
and the European Commission) response to nitrosamine impurities in medicines and provides an
overview of the measures put in place to protect public health, while ensuring that medicines remain
available for patients who need them. It also describes the refinement over time of the regulatory tools
used to manage nitrosamine impurities based on evolving scientific knowledge.

Managing the potential presence of nitrosamines in medicines has been a priority for the EMRN since
2018 when EU regulators became aware of the presence of these chemical compounds in valsartan-
containing medicines.

Nitrosamines are a class of chemical compounds with a nitroso functional group attached to an amine
compound. These compounds can be naturally occurring or synthetic. They can be found in some foods,
beverages and other consumer products as impurities.

Nitrosamines are classified as probable human carcinogens on the basis of animal studies and their
detection in medicines led to a number of regulatory measures in the EU. They are also categorized as
a sub-class of the N-nitroso class of cohort-of-concern (CoC) compounds in the ICH M7 guideline due to
the high carcinogenic potency of some chemicals within this structural class. Despite these concerns,
there only is a very low risk that nitrosamines impurities at the levels found in medicines can cause
cancer in humans.

Following the initial detection of nitrosamine impurities in angiotensin-II-receptor antagonists (‘sartans’),

the EMRN took several regulatory actions. In July 2018, at the request of the European Commission, the
European Medicines Agency (EMA) initiated an Article 31 1 review, which resulted in additional
requirements for MAHs for sartans to mitigate nitrosamine impurities in their products.

Following the review of sartans, EMA’s Committee for Medicinal Products for Human Use (CHMP)
conducted a second review of nitrosamines for all medicines for human use authorised in the European
Union. This second review, under Article 5(3) concluded in June 2020 and provided recommendations
on how to manage, detect and minimize nitrosamine impurities. In addition, the EMRN conducted a
lessons learnt exercise drawing on the experience from the sartans2.

Before the conclusion of the Article 5(3) review, the CHMP carried out an Article 31 review in which it
recommended the suspension of the marketing authorisations for all ranitidine-containing medicines in
due to the presence of N-nitrosodimethylamine (NDMA).

In 2020, the EMRN developed a framework for implementing the recommendations of the Article 5(3)
review. A key aspect of the Article 5(3) framework was the Call For Review (CFR), which required
companies to investigate the risk of nitrosamine impurities being present in their products. Companies
were required to institute a stepwise evaluation of the risk of nitrosamine contamination for all approved
human medicines within the EU, confirmatory testing when a risk was identified, and mitigation and
control measures as appropriate.

To support the CFR, guidance for MAHs was made available on the websites of EMA and the CMDh (the
Co-ordination group for Mutual recognition and Decentralised procedures – human)3. The guidance was
updated regularly to reflect the latest scientific evidence.

The Nitrosamine Implementation Oversight Group (NIOG) was created to oversee the implementation of
Article 5 (3) recommendations, including the CFR exercise, and to discuss related policies. Biannual
meetings took place between the NIOG and Interested Parties (IPs), serving as the main interface for
interacting with Industry stakeholders.

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Furthermore, the EMRN was involved in international fora concerned with the management of
nitrosamine impurities, such as the Nitrosamines International Technical Working Group (NITWG) and
the Nitrosamines International Strategic Group (NISG).

2. CHMP scientific assessments

2.1. Article 31 reviews for sartans and ranitidine

Sartans

Regulators became aware of the presence of nitrosamines in EU medicines in June 2018 when a
manufacturer of a valsartan-containing medicine reported the presence of NDMA. As a result, the
European Commission triggered an EU review of all valsartan medicines in the form of a referral under
Article 31 of Directive 2001/83/EC, started on 5 July 20184

During the review, conducted by the CHMP, it became clear that the NDMA formation in valsartan resulted
from the use of sodium nitrite in the manufacturing process to quench unreacted azide reagents under
acidic and/or thermal conditions in the presence of (aqueous) N,N-dimethylformamide, which can
hydrolyse to dimethylamine.

The CHMP subsequently requested analytical data on four other angiotensin receptor blockers
(candesartan, irbesartan, losartan and olmesartan) with the same reaction principle in their
manufacturing process. The analysed testing data confirmed the presence of NDMA in some batches
containing these active substances and, in September 2018, the scope of the review widened to cover
these other active substances.

Other small nitrosamines such as e.g. N-nitrosodiethylamine (NDEA), N-nitroso-N-methyl-4-

aminobutyric acid (NMBA), N-nitroso-di-n-butylamine (NDBA), N-nitrosoethylisopropylamine (EIPNA),
N-nitrosodiisopropylamine (DIPNA) and N-nitroso-N-methylaniline (NMPA) 5were subsequently detected
and were shown to form under analogous reaction conditions with other amines. Meanwhile, the
European Directorate for the Quality of Medicines and Healthcare (EDQM) re-assessed and suspended
many CEPs (Certifications of Suitability to the European Pharmacopoeia) for valsartan, irbesartan and
losartan.

At the conclusion of the review in April 2019, MAHs were given two years to review their manufacturing
processes, test for nitrosamine impurities, implement limits based on acceptable intake (AI) for NDMA
and NDEA and make any necessary changes to minimise nitrosamine contamination as much as
possible4.

In November 2020, the CHMP updated its recommendations for this review to align them with
recommendations from the Article 5(3) review for all human medicines, which concluded in June 2020.
The main change concerned the limits for nitrosamines, which had previously applied to the active
substance but was considered appropriate for the finished products. These limits, based on
internationally agreed standards (ICH M7(R1)), should ensure that the excess risk of cancer from
(multiple) nitrosamines in any sartan medicines does not exceed 1 in 100,000 for a person taking the
medicine for lifelong treatment4. A threshold of toxicological concern (TTC) of 18 ng/day was introduced
as a default limit for nitrosamines impurities where substance-specific toxicological data were not
available6.

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The CHMP and CMDh published a detailed questions-and-answers (Q&A) document containing guidance
on how to implement the outcome of the Article 31 review in order to support MAHs and ensure a
harmonised approach among Member States when assessing relevant updates to dossiers6.

Lessons learnt from presence of N-nitrosamine impurities in sartan

medicines

In May 2019, after the conclusion of the sartans Article 31 review, the EMRN conducted a lessons learnt
exercise to identify areas for improvement to prevent unexpected impurities, such as N-nitrosamines,
from occurring in human medicines and to support the regulatory network’s preparedness for managing
similar cases of unexpected impurities arising in the future.

As part of this exercise, a meeting with stakeholders, including industry associations and other
international regulatory agencies, took place in November 2019. Drawing on the experience from the
sartans incident, the lessons learnt group made recommendations covering prevention, incident
management, market surveillance, communication and international cooperation. These
recommendations were captured in a report that was published in June 20203. A plan was later published
in October 2020 setting out how the EMRN intended to implement the recommendations, with
information on responsibilities and indicative timelines7.

Since 2020, the EMRN has been working to implement the recommendations from the lessons learned
exercise. As of April 2025, the majority of the recommendations have been addressed.

Ranitidine

In September 2019, at the request of the EC, the CHMP started a review of ranitidine-containing
medicines following reports of NDMA above the AI limit. It was postulated that ranitidine degrades over
time to form NDMA, and that more NDMA can also be formed following ingestion. This review ultimately
led to the suspension of marketing authorisations for all ranitidine-containing medicinal products in the
EU in 20208. CEPs for ranitidine, that were valid at the beginning of the referral, were suspended by the
EDQM or withdrawn by the holder.11

The CHMP recommended conditions for lifting the suspension of ranitidine medicines, including
requirements for companies to provide more data. Following a request for re-examination, the CHMP
maintained the conditions for lifting the suspension of the medicines, including requirements for
companies to provide more data on the possible formation of NDMA from ranitidine inside the body. As
the formation of NDMA in the body was expected to be very low following a single low dose of ranitidine
given by injection or infusion (drip), the CHMP amended the conditions for lifting the suspension for
those ranitidine medicines.

2.2. Article 5(3) review for all human medicines

In September 2019, EMA’s Executive Director asked CHMP to provide guidance in accordance with Article
5(3) of Regulation (EC) No 726/2004 regarding the detection, management and prevention of presence
of N-nitrosamines in medicinal products for human use.

In making the request, in accordance with Article 5(3) of Regulation (EC) No 726/2004, the Executive
Director noted that it was important to learn from the experience with sartans and take a proactive
approach for other classes of medicines.

On 19 September 2019, during the first phase of the Article 5(3) review, a call for review was launched
requesting MAHs for human medicines containing chemically synthesised active substances to review

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their medicines for the possible presence of nitrosamines, to test all products at risk and to introduce
necessary changes to the marketing authorisations within 3 years.

The Article 5(3) review concluded in June 2020. There are two outcomes from the CHMP scientific review.
First, general guidance on how to deal with the presence of nitrosamines in all human medicinal products
was set out. As a result, MAHs/applicants are requested to mitigate the risk of the presence of
nitrosamines as much as possible and to ensure the quality of their medicinal products. Secondly as a
result of the Article 5(3)6 referral, the scope of the call to review to MAHs was extended to include
medicines containing biological active substances.

The review set limits for (multiple) nitrosamines using internationally agreed standards (ICH M7(R1))
based on lifetime exposure. Patients should generally not be exposed to a lifetime risk of cancer
exceeding 1 in 100,000 from nitrosamines in their medicines.

Companies were required to establish appropriate control strategies for both active substances and
finished products. They were also required to conduct risk evaluations for the presence of nitrosamines
in their products and perform confirmatory testing if a risk is identified.

The recommendations from this review also covered:

• The need to set specification limits for (multiple) nitrosamines for a particular medicinal product, in
line with published AI limits.

• Flexibility in control strategies (regular testing, skip testing, omission of specification).

• Considerations for analytical method development and sensitivity requirements.

• Control options when more than one nitrosamine is present in the same product.

• Methodologies for setting AI limits for new nitrosamines where insufficient toxicity data were
available, including the establishment of a class-specific TTC limit of 18 ng/day.

• Exceptions for medicines indicated for treatment of advanced cancer or where the active substance
itself is genotoxic at therapeutic concentrations.

• The exceptional and temporary use of higher limits for products containing nitrosamine impurities
above the AI limit but which still have a positive benefit/risk ratio.

• The need for further epidemiological studies.

Information concerning the implementation of the outcome of the Article 5(3) review for all human
medicines is presented in more detail in the following sections.

3. Overview of developed approaches

3.1. Procedural

3.1.1. EMRN governance for implementation of the Article 5(3) CHMP

opinion

In 2021, the EMRN established the Nitrosamine Implementation Oversight Group (NIOG) with a mandate
to oversee the implementation of the recommendations from the Article 5(3) review. The NIOG was to
carry out the following tasks:

• Provide non-product specific oversight of the implementation of the CHMP’s Article 5(3) opinion;

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• Report progress to the EMRN regarding MAH’s compliance with the call for review timelines, progress
with the updating of guidance and other aspects related to the implementation of the
recommendations;

• Evaluate the need for updating current guidance/Q&As or for publishing new scientific and procedural
guidance;

• Provide support in the drafting of guidance and delivering training to assessors;

• Address any specific matters related to the call for review that require clarification;

• Provide a link with stakeholders, including by initiating and maintaining dialogue and interaction with
the pharmaceutical industry

To date, 13 NIOG meetings have taken place. In addition, 6 meetings with interested parties (industry
trade associations, NIOG-IPs) have taken place to discuss scientific developments in the field of
nitrosamines, as well as policy issues related to the CFR. Regulatory agencies outside the EU also
participated in these meetings as observers. Meeting highlights and presentations are available on EMA’s
website.

3.1.2. Call for review to MAHs

On 26 September 2019, EMA and the CMDh announced the launch of the CFR exercise, requesting MAHs
to review their manufacturing processes in order to identify and, if necessary, mitigate the risk of the
presence of nitrosamine impurities and report back to authorities.

MAHs were requested to evaluate the risk of nitrosamines in their authorised products based on the
available scientific information (step 1). If a risk was identified, confirmatory testing (step 2) should
follow and, lastly, if the presence of a nitrosamine was confirmed through testing, mitigation measures
should be implemented (step 3).

Response templates and information on reporting mechanisms were made available and deadlines for
each step were defined. Following the conclusion of the Article 5(3) opinion, the scope of the CFR was
widened to include human medicines containing biological active substances with revised deadlines for
each of the steps. As the challenges in developing and validating sufficiently sensitive analytical methods
to test all at-risk products became apparent, the CFR deadlines were extended for step 3 (to 1 July 2023
for medicines containing biological active substances and 1 October 2023 for medicines containing
chemically synthesized active substances).

EMA and National Competent Authorities recorded a high rate of compliance for step 1 reporting from
MAHs of centrally and nationally authorised products. A risk for small molecule nitrosamines (esp. NDMA,
NDEA) or nitrosamine drug substance-related impurities (NDSRIs) was identified for a proportion of
products containing chemical active substances, while for biological products the risk of nitrosamine
contamination proved to be low. For the products where a risk was identified, confirmatory testing was
performed and reported by companies and where nitrosamines were detected, additional regulatory
actions were taken as described in the sections below.

For small molecule nitrosamines and NDSRIs without carcinogenicity data, a carcinogenic potency
categorisation approach (CPCA) has been established based on structure-activity relationship with 5
potency categories and AI limits for each category (see Appendix 212 of the Q&A).

After the lapse of the deadlines for the CFR, MAHs and applicants are still expected to continue to comply
with the requirements to assess, identify, control, and report any potential nitrosamine impurities
throughout the product life cycle and notify relevant authorities using the established response
templates. As such, MAHs should revisit initial risk evaluation as and when new information becomes

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available, updating the submitted responses accordingly. Ultimately, MAHs have the legal responsibility
for ensuring the quality, safety and efficacy of their medicines.

3.1.3. Guidance for MAHs

In August 2020, the EMRN published a Q&A document providing MAHs with additional guidance on how
to implement the recommendations of the Article 5(3) opinion and on the CFR exercise4.

The document has been updated regularly in line with evolving scientific knowledge about nitrosamines
and to reflect procedural outcomes of the CFR exercise. The main updates were regarding the scope of
the products concerned (initially only applicable to chemical substances, and later also covering biological
products) ; acceptable nitrosamine levels (the extension of the less than lifetime (LTL) approach for
authorised products, initially only for critical products and later extended to all authorised products); the
revision of submission timelines for confirmatory testing (extension to CFR timelines); new information
on common risk factors and identified root causes; the implementation of the scientific framework (e.g.
in relation to removing the temporary universal limit or non-mutagenic impurity handling) and the
development of analytical test procedures (e.g. in relation to testing strategy and required sensitivity).

A major milestone was reached in July 2023, with the implementation of the carcinogenic potency
categorization approach (CPCA) and the enhanced Ames test (EAT) to determine compound-specific AI
limits (in ng/day), as well as the publication of the agreed AI limits for nitrosamine impurities with
periodic updates.

These updates were discussed with stakeholders, including international regulators, and conveyed to
industry stakeholders during regular NIOG-IP meetings.

In addition, the CMDh published a practical guidance document for MAHs of nationally authorised
products (NAPs) 9 . Close collaboration between EMA, CHMP and the CMDh ensured a harmonised
approach for CAPs and NAPs and early identification of areas to be further clarified.

For authorised medicines, MAHs are responsible for introducing changes to their active and/or finished
products if nitrosamines are identified. They should submit a variation, as necessary, to amend their
manufacturing processes, controls and specifications, product formulation, raw materials, and packaging
to mitigate the risk of nitrosamines formation.

The potential presence of nitrosamines is also evaluated as part of marketing authorisation applications
(MAAs). At the submission stage, applicants must submit the risk evaluation as an attachment to the
marketing authorisation dossier (step 1) and, if a nitrosamine is identified, include necessary information
on the mitigation strategy and confirmatory testing (step 2). If relevant information is not submitted as
part of the MAA, it is requested during the MAA review process. Outstanding issues related to nitrosamine
impurities have to be addressed before the final opinion, including confirmatory testing, as applicable,
to ensure the benefit-risk balance of the product is not impacted. For line extensions or variations, a risk
evaluation is generally not needed, because the product would have already been assessed as part of
the call for review. However, a risk evaluation may be requested during the line extension or variation
procedure if changes are introduced that can impact the risk of nitrosamines being present.

3.1.4. Nitrosamine case assessment workflow

The EMRN agreed a workflow10 to support the management of the reporting of nitrosamines associated
with the CFR. As products containing nitrosamines can be authorised centrally or nationally, mechanisms
for harmonising the management of cases were published as part of the EMRN approach for the
implementation of the CHMP’s Article 5(3) opinion. The workflow sets out 4 different scenarios when
confirmatory testing data are submitted during step 2:

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• Scenario a: a known nitrosamine is detected in a medicinal product and the nitrosamine level exceeds
the AI limit based on ICH M7 principles (1 in a 100,000 lifetime risk). The same scenario applies
where there is more than one known nitrosamine detected, and the total sum of the nitrosamines
exceeds the AI limit of the most potent nitrosamine, or the sum of all detected nitrosamines exceeds
the 1 in a 100,000 lifetime risk.

• Scenario b: a known nitrosamine is detected in a medicinal product and the nitrosamine level does
not exceed the AI limit based on ICH M7 principles (1 in a 100,000 lifetime risk), however the total
nitrosamine content is more than 10% of the AI limit. The same scenario applies where there is more
than one known nitrosamine detected, and the total sum of the nitrosamines does not exceed the AI
limit of the most potent nitrosamine, or the sum of all detected nitrosamines is below the 1 in a
100,000 lifetime risk.

• Scenario c: no nitrosamine is detected in a medicinal product, or the nitrosamine level of the known
nitrosamine is below or equal to 10% of the AI limit based on ICH M7 principles. The same scenario
applies if more than one known nitrosamine has been detected and the total nitrosamine content is
below or equal to 10% of the AI limit based on ICH M7 principles for the most potent nitrosamine or
the sum of all detected nitrosamines.

• Scenario d: one or more new nitrosamines, for which there is not yet a defined AI limit based on ICH
M7 principles, are detected in a medicinal product.

While for scenario c cases, no amendment to the marketing authorisation is expected, for scenarios a
and b, the marketing authorisation should be subject to changes (e.g. via a variation or referral).
Scenario d cases require, as a first step, the determination of the AI limits before recategorization as a
scenario a, b or c, depending on the nitrosamine content.

For each of the above scenarios, a process was developed to ensure the best use of existing platforms
(i.e. the Rapid Alert Network (RAN), the Incident Review Network (IRN)) and existing regulatory
pathways for quality defects, variations and referrals).

For the establishment of the AI limits, two main approaches are established. If nitrosamines are identified
with sufficient substance specific animal carcinogenicity data, the TD50 should be calculated and used to
derive a substance specific limit for lifetime exposure as recommended in ICH M7(R2) guideline. On the
other hand, if sufficient substance specific data to derive a substance specific limit for lifetime exposure
are not available, four options can be used:

• The CPCA

• Derivation by Structure-Activity Relationship (SAR) and read across

• GLP-compliant Enhanced Ames test (EAT)

• Relevant well-conducted in vivo mutagenicity study

Following the introduction of the CPCA in July 2023, the EMRN established a process flow to assess the
MAH proposals for AI limits for any new nitrosamine detected in their product. The proposed AI limit is
assessed and confirmed by the lead responsible competent authority (Lead Member State (LMS)/NCA
rapporteurs for nationally authorised products (NAPs) and CHMP rapporteurs for centrally authorised
products (CAPs)).

MAHs can propose AI limits different to those derived using CPCA based on in vitro or in vivo studies.
The product rapporteur (for CAPs) and LMS (for NAPs) are responsible for assessing the submitted data
in consultation with the Nitrosamine Safety Oversight Expert Group (NS-OEG) experts. Depending on
the outcome of the assessment, AI limits in Appendix 1 may be revised and amended.

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Scenario a cases are managed through quality defect procedures11 with the product rapporteur leading
the assessment of MAH data and proposed actions (i.e. CAPA) to determining the need for market
actions. If market action is needed as a potential response to identified scenario a cases, the EMRN is
responsible for issuing and circulating notifications of product recalls within the rapid alert network (RAN)
and informing international partners in accordance with the established recall procedure.

In case of potential shortages, the RAN is supported by Medicine Shortages Single Point of Contact
Working Party (SPOC WP) which advises on product criticality. Regulatory authorities may consider
implementing ad interim measures, such as the less-than-lifetime (LTL) approach during the corrective
and preventive action (CAPA) implementation period (3 years from AI limit establishment) applicable to
authorised human medicinal products. These measures are intended to ensure the continued availability
of safe and effective medicines, while further root cause investigations are carried out.

Additional considerations apply for critical medicinal products under exceptional circumstances and the
CHMP can request the Nitrosamines Multidisciplinary Expert Group (NMEG) to propose an ad interim AI
limit that would allow sufficient supply to patient while safeguarding patient health.

When potential public health threats arise, regulatory authorities need to work together effectively to
mitigate risks. The IRN was established by the EMA to coordinate actions across the EU. The IRN has so
far held 8 teleconferences in relation to nitrosamines to consider risk minimisation measures in human
medicines, regulatory procedure reviews (e.g. Article 31 reviews) and communication activities.

3.2. Safety

Nitrosamines are mutagenic carcinogens on the basis of animal studies and are classified as probable
human carcinogens. Nitrosamines need to be metabolically activated to express their mutagenic activity.
In the ICH M7 guideline on assessment and control of DNA reactive (mutagenic) impurities, they are
included in the class of high potency mutagenic carcinogens referred to as the cohort of concern, although
some nitrosamines with structural features hindering metabolic activation or DNA adduct formation may
be less potent mutagens or non-mutagenic.

The establishment of AI limits for nitrosamines in human medicinal products is performed by EU

toxicology experts. Initially, AI limits were established by the Safety Working Party (SWP) but due to the
increasing number of nitrosamines being reported, this task was delegated to the NS-OEG which was
formed in 2022, with oversight by the non-clinical working party (NcWP), the successor to the SWP
following the reorganisation of the EMA’s working parties. EU non-clinical guidance for nitrosamines is
published and updated in question 10 of the Q&A and associated appendices. The AI limits established
by the NS-OEG are published in Appendix 112 of the EMA Q&A.

The approaches to the safety assessment of nitrosamines in the EU/EEA have been developed in
collaboration with international regulatory partners through participation of EU experts in the
Nitrosamine International Technical Working Group (NITWG) with the objective of harmonising AI limits
and the approaches to nitrosamine safety assessment as far as is possible. Initially, most of the
nitrosamines reported were small nitrosamines. For many of these nitrosamines, sufficient substance
specific animal carcinogenicity data were available to support the establishment of the AI. However,
NDSRIs were increasingly reported and now make up the vast majority of nitrosamines reported.

As robust carcinogenicity data are not available for most NDSRIs, the lack of suitable surrogates for the
read-across approach posed challenges to the assigning of AI limits for these substances. Consequently,
in July 2023, the EMA and international regulators introduced the CPCA and the EAT as new approaches
for the AI limit assessment of new nitrosamines. The CPCA and EAT conditions have been published in
Appendix 2 and Appendix 3, respectively, of the EMA Q&A.

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The CPCA is a structure-activity relationship-based method that allows the rapid assignment of a
nitrosamine to 5 categories, each with a corresponding AI limit between 18 and 1500 ng/day, reflecting
predicted carcinogenic potency. Following implementation in July 2023, the CPCA approach has been
used to place nitrosamine impurities into one of five categories based on toxicological data and chemical
structure, with the aim of predicting the compound-related carcinogenic potential. For instance,
impurities classified as category 1 (AI limit of 18 ng/day) are predicted to have the highest potential of
causing cancer in humans (most potent), while those in category 2 (AI limit of 100 ng/day), category 3
(AI limit of 400 ng/day) and category 4 (AI limit of 1500 ng/day) are considered to have progressively
lower risks. Compounds falling under category 5 (AI limit of 1500 ng/day) are not predicted to have
mutagenic or carcinogenic potential.

The EAT defines the conditions which need to be satisfied for acceptance of negative tests to allow control
of nitrosamines at 1.5 µg/day. If a surrogate nitrosamine is available with sufficiently robust
carcinogenicity data, the TD50 from the surrogate substance can still serve as a point of departure for
derivation of AI limit on the basis of the structure activity relationship (SAR) and read across. A negative
result in a relevant well-conducted in vivo mutagenicity study can allow control of the nitrosamine as a
non-mutagenic impurity (NMI) according to ICH Q3A(R2) and ICH Q3B(R2) limits.

Figure 1. Process-flow for establishing AI limits

Currently, the LTL approach in ICH M7 cannot be applied routinely to nitrosamines. A limited and
temporary application of the LTL is permitted in certain circumstances, as described in the EMA Q&A
(question 22), to control the presence of nitrosamines exceeding the AI limit during CAPA implementation
(up to 3 years following AI limit establishment).

The paradigms for the safety testing and assessment of nitrosamines are continually evolving with the
generation of new data by industry, academia and regulators working individually and in collaboration.
These include data from EMA-funded studies conducted by the MUTAMIND consortium led by the
Fraunhofer Institute, and nitrosamines research activities carried out under the umbrella of the HESI
Genetic Toxicology Technical Committee (GTTC) Mechanism-based Genotoxicity Risk Assessment
(MGRA) working group in which EU toxicology experts are represented.

3.3. Quality

The various EMA referrals and reports published up to 2020 concerning nitrosamine impurities focussed
on known and theoretical root causes and recommendations for the development of analytical methods
for detecting and quantifying these impurities. Based on the experience and information available at that
time, the focus was mainly on small molecule nitrosamines, such as NDMA and NDEA.

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A comprehensive analysis of known root causes from previous referrals and theoretical root causes based
on literature data was carried out. The conclusions of these early analyses focussed mainly on reagents,
solvents and catalysts used within the API manufacturing process.

Several cases of small molecule nitrosamine formation in the finished product were also reported (e.g.
NDMA in ranitidine and in metformin). The origin and degradation pathways for these impurities in the
finished product formulations took some time to understand. In addition, certain risks associated with
blister pack sealing were highlighted. Furthermore, the potential presence of trace nitrite in excipients
was flagged as a potential root cause of nitrosamine formation taking place in finished product
formulations. As a result, the recommendation was made for any analytical testing to be carried out on
the finished product to ensure no risks were omitted from consideration. Finally, while the risk of
nitrosamine formation in biological products was considered to be low, it could not be ruled out based
on available science and therefore, risk assessments were also requested for biological products.

A review of published and pharmacopeial analytical methods used to detect and quantify these impurities
was also carried out. The majority of these methods were designed to detect and quantify small molecule
nitrosamines with established AI limits based on robust toxicology data. Recommendations were made
on the required analytical sensitivity, as well as ruling out false positive or negative results from
interference or sample contamination or instability. Recommendations were also made on the number
of batches to be tested to ensure representative sampling.

Since these initial reports and as a result of confirmatory testing and subsequent root cause
investigations recommended in the CFR, significant advances in the understanding of risk factors for
nitrosamine formation have been made. These have been summarized 13 in a review paper which has
been published by NITWG, a group of regulatory agencies. These scientific developments have been
discussed, along with other issues associated with confirmatory testing, during interactions with
stakeholders (industry, other regulators, and EU safety/toxicology experts) and guidance has been
updated regularly to highlight newly discovered risk factors or to account for changes in e.g.
safety/toxicology policy.

A summary of these developments and associated changes to published guidance since 2020 is given
below:

• A recognition that if a nitrosamine impurity could not be synthesised despite extensive efforts, then
it is unlikely to form. Confirmatory testing would not therefore be needed for theoretical nitrosamines
that do not form in practice.

• Allowances for testing only certain strengths based on the worst-case scenario when a product is
available in multiple strengths and extrapolation of the results is appropriate.

• Further guidance on testing and specification requirements in cases where more than one
nitrosamine is present in the same product to ensure the overall lifetime cancer risk does not exceed
1 in 100,000. This could be a fixed approach where a fixed limit is set for each nitrosamine present.
Alternatively, a flexible approach was developed whereby each nitrosamine is specified at its AI limit
in ppm/ppb and an additional limit for total nitrosamines is required.

• As risk factors associated with active substance and finished product processes were better
understood, an allowance was made to conduct confirmatory testing in the active substance, its
precursor intermediates or raw materials as surrogates of the finished product provided that no
further risk factors exist downstream of the tested materials. By analogy and based on an
understanding of risk factors, specification limits could be set in raw materials, intermediates, or the
active substance in lieu of the finished product.

• Scientific updates to guidance on risk factors and root causes as further data emerged.

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As reflected above, the main focus up to 2020 was on potent small molecule nitrosamines formed
primarily in the API manufacturing process. Since 2020, an increasing number of reports have been
received of nitrosamines related to the structure of the active substance itself (NDSRIs). It has been
estimated that around 40%14 of marketed products may be at risk of NDSRI formation based on the
structural features of the active substance. In general, 3 factors are required for formation of nitrosamine
impurities: a nitrosatable amine, a nitrosating agent, and conducive conditions (see Figure 2). In few
cases, oxidation of a hydrazine functional group can lead to NDSRI generation 13

Figure 2. Conditions for nitrosamine formation in active substance and finished product

There are potentially multiple effective approaches to avoiding nitrosamine formation by carefully
designing manufacturing processes for APIs. If unavoidable, they can also be removed by purification.
At this stage, it is considered that formation of nitrosamines in active substance manufacturing processes
is largely avoidable, provided that the risks are considered during manufacturing process development
and appropriately mitigated.

Mitigating the formation of NDSRIs in finished products is more challenging because the vulnerable amine
is an intrinsic (and critically important) part of the active substance and cannot be removed. Iit may not
be possible to remove or reduce the nitrosating agent to sufficiently low levels, the scope for amending
manufacturing process unit operations without impacting product CQAs is limited, and if NDSRIs are
formed, they cannot be removed by purifying the finished product.

In those cases where nitrosamines are detected above the AI limit, various remediation strategies could
be envisaged. These include reducing the nitrosating agent content to levels which sufficiently limit
NDSRI formation (e.g. removing/replacing an excipient or reducing its nitrite contents) and incorporation
of nitrite scavenging agents (antioxidant, amine) or pH modulator in the formulation.13 For situations
where nitrosamine levels increase during storage, more protective packaging, more restrictive storage
conditions and shorter shelf-lives could be all considered. Other approaches may also be viable
depending on the root cause. There have been multiple examples where the above strategies have been
successfully implemented in the last few years for products marketed in the EU to ensure nitrosamine
levels are kept below their acceptable intake limit.

However, the impact of changing the formulation on the finished product quality attributes (e.g. stability,
bioavailability) by incorporating a new excipient should be carefully considered and investigated as
appropriate.

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3.4. Market surveillance

Sampling and testing of human products, considered at risk of nitrosamine contamination, was put in
place following the first reports of contamination in sartan medicines. Sampling and testing were a key
part of the regulatory response to manage the sartans incident but also to explore why nitrosamines
came to be present in the first place. Thereafter, surveillance sampling and testing remained an
important tool used to control compliance with the requirements of the CFR by the competent authorities.
The Official Medicines Control Laboratories (OMCL) network, coordinated by EDQM, also developed
methods for testing specific nitrosamines.

During this period, ad hoc market surveillance testing was conducted by OMCLs across the EU Member
States in coordination with EMA and EDQM. Starting in 2023, EMA in collaboration with EDQM, put in
place a dedicated routine programme for the sampling and testing of human medicinal CAPs where there
is a risk of nitrosamine impurities. The aim of this initiative is to determine nitrosamines levels, compare
these with risk assessment and test data submitted by companies and to evaluate whether the analytical
methods are fit for purpose.

With respect to inspections, following the initial for-cause inspections of API manufacturing sites that
were conducted in response to the initial discovery of nitrosamines in sartans, risk-based inspections
were also used to verify elements of the CFR reporting. Verification during routine GMP inspections of
manufacturers will continue to be considered by EU inspectorates in the future.

3.5. Medicine shortages and availability issues

Following the detection of nitrosamines in sartans in 2018, associated recalls of sartan medicines had a
sizeable impact on market supply and caused critical shortages. There were concerns that dealing with
the presence of nitrosamines in medicines would cause widespread shortages on the market. However,
the EMRN was able to put in place measures to balance safety of patients with availability of much
needed medicines, and relatively few disruptions to supply were reported.

The Medicine Shortages Single Point of Contact Working Party (SPOC WP) was involved in cases of
nitrosamines and were consulted on the availability of alternatives and the criticality of products
identified with nitrosamines. The SPOC WP feedback on the potential risk of shortages was considered
as part of the assessment of the nitrosamine cases to inform the appropriate measures.

While the SPOC WP has discussed some cases for which supply disruptions occurred, critical shortages
occurred only exceptionally.

4. Engagement and communication with stakeholders and

international partners
4.1. Industry, health care professionals and patients

Since the initial identification of the risk of presence of nitrosamines impurities in sartan-containing
medicines, the EMRN has ensured that there was clear and timely communication with patients,
healthcare professionals and industry.

Engagement with these stakeholders was achieved, in the case of EMA, through established frameworks
of interaction,15, 16 and involved the dissemination of relevant information in accordance with Agency
processes and transparency rules.

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Both EMA and national competent authorities have updated patients and healthcare professionals about
the risks identified with medicines, ensuring that patients had a clear understanding of the risks
associated with the exposure to medicines containing nitrosamine impurities and what actions regulators
were taking. Some updates were provided on regulators websites. EMA and national competent
authorities also responded directly to individual members of the public who had queries or concerns.

EMA’s Patients and Consumers Working Party (PCWP) and the Healthcare Professional Working Party
(HCPWP) received regular updates on major policy developments and availability of medicines.

Regular interactions also took place between the EMRN and industry stakeholders through meetings of
the NIOG-IP. These meetings provided an opportunity for the NIOG to give updates on new guidance
and for the industry associations to provide updates on their progress, highlight challenges in complying
with the requested activities and present new scientific data generated by industry. It also served as a
forum to share updates on scientific progress concerning safety and quality aspects of nitrosamines in
advance of technical discussions within expert groups, such as the Nitrosamine Safety Oversight Expert
Group (NS-OEG) and the Quality Working Party (QWP).

4.2. Collaboration with international partners

Managing the presence of nitrosamine impurities in medicines is a challenge shared by regulators across
the globe. Beginning with the sartans case, information was shared between regulators, including
information on guidance, referrals and other regulatory actions such as market recalls.

In 2019, the Nitrosamine International Steering Group (NISG) was created. The mandate of this group
is to achieve consistency in regulatory activities between different international jurisdictions, including
information on market actions and product availability. Following the launch of the CFR in the EU, other
regulators launched similar activities with timelines and requirements aligned to the greatest extent,
taking into account local legal frameworks. As scientific data and understanding progressed, the NISG
evolved to include dedicated forums for detailed technical discussions, with the creation of the NITWG in
2020. The aim of this group is to discuss safety and quality topics related to nitrosamines and to seek
technical convergence among member jurisdictions, where possible. Scientific papers on root causes/
risk factors and on the CPCA approach have been published by NITWG quality and safety sub-groups.22,

EMA also established dedicated confidentiality agreements with other international regulators to share
information on nitrosamine topics. The engagement and agreement of major milestones at global level
with international authorities will remain one of the priorities of the Agency.

A dedicated communications group was also set up so regulators could share public communication (such
as press releases about nitrosamines) with each other in advance of publication.

5. Areas for future development

During the ICH plenary meeting of June 2024, the creation of an implementation working group to draft
an addendum to ICH M7 Guideline on assessment and control of mutagenic impurities was agreed. The
addendum will focus specifically on safety and toxicology aspects of nitrosamines. Quality topics may
also be included based on progress with scientific understanding. The document will provide harmonised
global guidance on nitrosamines based on the available scientific data. Subject matter experts from the
EMRN will participate in this work. At the start of the ICH revision process, the planned target date for
the revised ICH M7 is foreseen to be May 202817.

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In parallel, the EMRN will also continue to assess the scientific developments on the topic and to update
EU guidance as needed and in collaboration with relevant stakeholders.

6. Conclusions
The EMRN has established a framework and governance structures for controlling nitrosamine impurities
in medicines. The call for review launched in 2019 required MAHs to review their portfolios and conduct
confirmatory testing when risks were identified and to implement adequate preventive and corrective
actions if required. Reporting mechanisms were developed in order to facilitate submission of CFR
responses and compliance with the requests was generally good. The EMRN has had regular and
extensive interactions with industry stakeholders and international partners to discuss the latest
information on nitrosamine impurities.

The science around formation of nitrosamines has developed significantly in recent years, leading to
regular updates to guidance on risk factors and testing requirements. More recently, the recognition that
many products on the market were at risk of NDSRI formation led to a thorough review of the genotoxic
potential of these impurities and the development of the Carcinogenic Potency Categorization Approach
(CPCA) and the application of an enhanced Ames test, in collaboration with international regulatory
partners. At the time of this report, over 170 AI limits have been published on EMA’s website, many
derived from the latest scientific approaches.

The safety of patients has been carefully balanced with the need to ensure the availability of important
medicines. Relatively few products have been made unavailable and patients have not been unduly
exposed to nitrosamine impurities, demonstrating the success of this approach.

Authorities in the EU will continue to take all necessary measures to protect patients. EMA, together with
EU national competent authorities, remind MAHs of their responsibility to actively follow the latest science
and policy developments, re-visit nitrosamine risk assessments, conduct confirmatory testing as
appropriate, and ensure the quality, safety, and efficacy of their medicines for the safety and well-being
of patients.

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7. References
1. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on
the Community code relating to medicinal products for human use

2. Lessons learnt from presence of N-nitrosamine impurities in sartan medicines,

EMA/526934/2019

3. 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, EMA/409815/2020

4. Impact of the Article 5(3) scientific opinion on nitrosamines in human medicinal products on
the Opinion adopted pursuant to Article 31 of Directive 2001/83/EC for angiotensin-II-receptor
antagonists (sartans) containing a tetrazole group (candesartan, irbesartan, losartan,
olmesartan, valsartan)Angiotensin-II-receptor antagonists (sartans) containing a tetrazole
group – referral, EMA/47245/2021

5. Assessment report, Procedure under Article 5(3) of Regulation EC (No) 726/2004, Nitrosamine
impurities in human medicinal products, EMA/369136/2020

6. CMDh Questions & Answers on implementation of outcome of Art. 31 referral on angiotensin-

II-receptor antagonists (sartans) containing a tetrazole group, CMDh/400/2019

7. Lessons learnt from presence of N-nitrosamine impurities in sartan medicines, Implementation

Plan, EMA/503522/2020

8. EMA confirms recommendation to suspend all ranitidine medicines in the EU,

EMA/666097/2020

9. CMDh practical guidance for Marketing Authorisation Holders of nationally authorised products
(incl. MRP/DCP) in relation to the Art. 5(3) Referral on Nitrosamines, CMDh/412/2019

10. European Medicines Regulatory Network approach for the implementation of the CHMP Opinion
pursuant to Article 5(3) of Regulation (EC) No 726/2004 for nitrosamine impurities in human
medicines, EMA/425645/2020

11. Compilation of Union procedures on inspections and exchange of information

12. Acceptable intakes established for N-nitrosamines, EMA/165331/2025

13. Formation of N-Nitrosamine Drug Substance Related Impurities in Medicines: A Regulatory

Perspective on Risk Factors and Mitigation Strategies, Organic Process Research &
Development, Vol 27 Issue 10

14. The Nitrosamine “Saga”: Lessons Learned from Five Years of Scrutiny, Organic Process Research
& Development, Vol 27 Issue 10

15. Engagement Framework: EMA and patients, consumers and their organisations,
EMA/649909/2021

16. Revised framework for interaction between the European Medicines Agency and healthcare
professionals and their organisations, EMA/89918/2016

17. ICH M7(R2) Guideline on assessment and control of DNA reactive (mutagenic) impurities in
pharmaceuticals to limit potential carcinogenic risk - Step 5, EMA/CHMP/ICH/83812/2013

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