Nitrosamine impurities | European Medicines Agency (2024)

Nitrosamines are chemical compounds classified as probable human carcinogens on the basis of animal studies.

EU regulators first became aware of nitrosamines in medicines in mid-2018 when nitrosamine impurities, includingN-nitrosodimethylamine (NDMA), weredetected in blood pressure medicines known as 'sartans'.

There is a very low risk that nitrosamine impurities at the levels found in medicines could cause cancer in humans.

EMA finalised areview under Article 5(3) of Regulation (EC) No 726/2004in June 2020 to provide guidance tomarketing authorisation holderson how to avoidthe presence of nitrosamine impurities in human medicines.

The CHMP asked marketing authorisation holders to review all chemical and biological human medicines for the possible presence of nitrosamines and test products at risk by following the guidance on this page.

Companies are required to have appropriate control strategies to prevent or limit the presence of these impurities and, where necessary, to improve their manufacturing processes.

The CHMP's assessment report is available below.

An implementation plan agreed in February 2021sets out how the European medicines regulatory network, together with the European Directorate for the Quality of Medicines & HealthCare (EDQM),will be implementing the outcome of the CHMP's review.

This includes specific measures that the network will takeifnitrosamines are detected in a medicine.

EMA and national competent authorities will continue to monitor the presence of nitrosamine impurities in medicines, in co-operation with regulators from outside the European Union (EU), and will work with marketing authorisation holders to find rapid solutions to address any adverse findings.

The Nitrosamine Implementation Oversight Group (NIOG)oversees the harmonised implementation of the CHMP'sArticle 5(3)opinion on nitrosamines.

Itwas set up by the European medicines regulatory network under the February 2021 implementation plan, andreports on progress to EMA's Management Board and the Heads of Medicines Agencies (HMA).

The group contains representatives from the CHMP, CMDh, EMA working parties, EDQMand EMA staff. It also acts as the main interface for the pharmaceutical industry stakeholders to discuss regulatory and scientific developments on nitrosamineswith EMA and the European medicines regulatory network.

For details of meetings involving pharmaceutical industry stakeholders and supporting documents, see:

• Meetings of the Nitrosamine Implementation Oversight Group (NIOG)

More information on the group's mandate, activities and composition is available in the documentbelow:

Marketing authorisation holders should review their manufacturing processes for all products containingchemically synthesised or biological active substancesto identify and, if necessary, mitigate the risk of presence of nitrosamine impurities.

The call for review was extended to biological active substances in July 2020, as an outcome ofCHMP's Article 5(3) opinion. This complements the review of chemically synthetised active substances, which has been ongoing since September 2019. To allow marketing authorisation holders enough time to implement the Article 5(3) opinion, the European medicines regulatory network agreed new deadlines. Further details and guidance are available below.

The European medicines regulatory network encourages marketing authorisation holders to submit the outcome of step 1 before the deadlinesif they complete the risk evaluation or identify a risk in their products.

Marketing authorisation holdersshould inform the national competent authorities for nationally authorised products or EMA forcentrally authorised productsas soon as possible if tests confirm the presence of nitrosamine, irrespective of the amount detected.

They should also assess theimmediate risk to patients and take appropriate action to avoid or minimise the exposure of patients to nitrosamines.

At all steps, timelines should be shortened and marketing authorisation holders should immediately inform authorities if findings indicate an immediate risk to public health.

Step 1: Risk evaluation

Conduct a risk evaluation to identify active substances and finished products at risk of N-nitrosamine formation or (cross-)contamination and report the outcome by:

• 31 March 2021 forchemical medicines;
• 1 July 2021 forbiological medicines.

If arisk is identified for an activesubstance,marketing authorisation holders shouldsubmit the step 1 response template and proceed with step 2 confirmatory testing of thefinished product.

Ifno riskis identified for an active substance, marketing authorisation holders shouldconduct a risk evaluation of the finished product and submit the outcome of step 1 only when they reach a final conclusion on the active substance and finished product.

Marketing authorisation holderscan submit a single email notification grouping products with identical outcome of step 1. For more information, seeQuestions 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

Marketing authorisation holdersshould use the templates below in their responses:

Marketing authorisation holdersfor centrally authorised products should send the completed template(s) only to nitrosamines.review.cap@ema.europa.euusing the subject 'Risk evaluation outcome/Risk identified or No risk identified/Marketing authorisation holder's name/Product name', as appropriate.

Step 2: Confirmatory testing

Perform further confirmatory testing on the products identified to be at risk of N-nitrosamine formation or (cross-)contamination and report confirmed presence of nitrosamines as soon as possible.

For more information on the development of analytical methods, seeNitrosamines EMEA-H-A5(3)-1490 - 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.

Marketing authorisation holdersshould use the templates below in their responses.

Marketing authorisation holdersshould only use the ''Step 2- Nitrosamine detected above acceptable intake or new nitrosamine detected response template' if they have detected a nitrosamine in their product and it meets at least one of the following criteria:

• it exceeds the acceptable intake limit;
• it exceeds the lifetime excess cancer risk of 1:100,000;
• it is anewly identified nitrosaminethatisnot covered in CHMP article 5 (3) opinion, irrespective of the amount detected.

In these cases, they should submit thistemplate in addition to the ‘Step 2 - Nitrosamine detected response template’.

If they have detected a nitrosamine, but it does not meet any of the above criteria, they should only use the ‘Step 2 Nitrosamine detected response template’.

The deadline for completing confirmatory testing for chemical medicines is 26 September 2022.

Marketing authorisation holders for centrally authorised products should send the completed template(s) to nitrosamines.review.cap@ema.europa.euusing the subject 'Confirmatory testing outcome/Risk confirmed or Risk not confirmed/Marketing authorisation holder's name/Product name', as appropriate.

Step 3: Update marketing authorisations

Apply for any necessary changes to the manufacturing process resulting from this review, by requesting a variation to the marketing authorisation via standard regulatory procedures.

Marketing authorisation holders for nationally authorised products should refer to theinformation on nitrosamines for marketing authorisation holderspublished on the CMDh website.

Marketing authorisation holders should complete the confirmatory testing and submit theirvariation applications by:

• 1 October2023forchemical medicines;
• 1 July 2023 forbiological medicines.

The CHMP and CMDhextended the deadline for submitting variation applications for chemical medicines from 26 September 2022 to 1 October 2023in July 2022.

Theextension aims to enablecompanies to perform a thorough investigation and to establish any required risk mitigating actions in light of newscientific developments since 2020, in particularthose concerningactive substance-derived nitrosamines.

This extension does not affect the deadline for completing the step 2 confirmatory testing for chemical medicines, which remains 26 September 2022. Marketing authorisation holders should submit complete step 2 outcomes by this deadline.

The European medicines regulatory network encourages marketing authorisation holders tosubmit variation applications as soon as they conclude their investigations,and before the extendeddeadline.

Questions and answers

A question-and-answerdocument is available for marketing authorisation holders on implementing theArticle 5(3)CHMP opinion. It covers the following:

• Outcome of the Article 5(3) referral
• Instructions, scope and timelines of the product review process
• principles and methodology for confirmatory and release testing
• Changes to marketing authorisations and requirements for new applications
• Outcome of the Article 5(3)referral and its relation to the recently published report on lessons learnt exercise from presence of nitrosamines in sartans
• New approaches for setting nitrosamines limits based on robust scientific knowledge about carcinogenic potency, including the Appendix 1 on acceptable intakes established for N-nitrosamines, Appendix 2on the carcinogenic potency categorisation approach (CPCA), and Appendix 3on the enhanced AMES test (EAT) protocol".

• Updated less than lifetime approach (LTL) to include authorised products for chronic use and define applicability, and the removal of the temporary AI (t-AI) approach in alignment with the CPCA and EAT protocol
• Updatedcontent(question3) to provide information on the future of the call for review (new)

The requirementsthat marketing authorisation holders for sartan medicines need to follow to avoid the presence of nitrosamine impurities in their productsare the same as for all human medicines.

The CHMP updated therequirements for sartans in November 2020, bringing them in line with the outcome of itsArticle 5(3) opinion. It first issued recommendations for sartans in January 2019.

For more information see:

• Angiotensin-II-receptor antagonists (sartans) containing a tetrazole group

Lessons learned

In June 2020, the European medicines regulatory network published the outcome of a lessons learned exercise on the presence of nitrosamines in sartan medicines (also known as angiotensin II receptor antagonists).This includes recommendations to help reduce the risk of impurities in medicines and ensure that regulators are better prepared to manage cases of unexpected impurities:

• Lessons learnt from presence of N-nitrosamine impurities in sartan medicines

Therecommendations apply to all medicines. They include:

• developing additional guidance on:
  • the roles and responsibilities of companies involved in the manufacture of medicines;
  • controlling impurities;
  • good manufacturing practice (GMP);
  • sampling and testing.
• improving communication with patients and healthcare professionals;
• expanding cooperation with international partners;
• further developing information technology systems.

An Lessons learnt from presence of N-nitrosamine impurities in sartan medicines - Implementation planagreed in October 2020sets out how theEuropean medicines regulatory networkintends to address each recommendation. Itidentifies lead responsibilities and indicative timelines.

The recommendationswere relevant for the Article 5(3) procedure.

A stakeholder consultationprocess fed into the lessons learned exercise,including ameeting with stakeholdersin November 2019:

• Overview of comments received on recommendations in report on lessons learnt from presence of N-nitrosamine impurities in sartan medicines

Authorities in the EU are investigating the presence of a nitrosamine impurity, 1-nitroso-4-methyl piperazine, inrifampicin),> medicines.),>

The national competent authorities are working closely with companies and the official medicines control laboratories (OMCLs) in the ongoing investigation of EU medicines.

As of February 2021, national competent authorities are asking marketing authorisation holders for rifampicin-containing medicinesto test their medicines before releasing them onto the market.

Thisis a precautionary step to ensure patient safety while the investigation is ongoing. It is inline with the measures introduced by EMA'sArticle 5(3) reviewto limit the presence of nitrosaminesin human medicines.

The national competent authoritieswillcarefully monitorresponses to this requestand take action ifnecessary.

Rifampicin is a first-line treatment for tuberculosis. It is also used for management of other serious infections, including blood infections and leprosy.

The risk to patients from not taking their rifampicin medicines far outweighs any potential risk from MeNP. Healthcare professionals should therefore continue to prescribe rifampicin medicines as normal in accordance with the product information.

Authorities will provide updates as necessary.

For more information, see the press release of theCo-ordination group for Mutual recognition and Decentralised procedures – human (CMDh).

EMA'sreview of ranitidine medicines led it to recommend their suspensionafter tests showed that some of these products contained NDMA.For more information, see:

• Ranitidine-containing medicinal products

EMA and the national competent authorities are investigatingthe impact oftests which detectedNDMAin some EU batches ofmetformin-containing medicines, used for the treatment of diabetes. This follows confirmation of NDMA in some batches outside the EU inlate 2019.

EMA and the national competent authoritiesare working closely with companies and the official medicines control laboratories (OMCLs) in the ongoing investigation of EU medicines.

As of October 2020,EMA and the national competent authorities are asking marketing authorisation holders formetformin-containing medicinesto test their medicines before releasing them onto the market.

Thisis a precautionary step to ensure patient safety while the investigation is ongoing. It is inline with the measures introduced by EMA'sArticle 5(3) reviewto limit the presence of nitrosaminesin human medicines.

EMA and the national competent authoritieswillcarefully monitorresponses to this requestand take action ifnecessary.

EMA advisespatients in the EU tocontinue to take metformin medication as the risks from not treatingdiabetes far outweighany possible effects of the low levels of NDMA seen in tests.

As metformin is considered a critical medicine, EMA and national authorities are cooperating closely to avoid possible shortages so patients can continue to get the treatments they need.

For more information, see:

• Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 12-15 October 2020(under 'EU regulators request nitrosamine testing of metformin medicines')(16/10/2020)
• Update on nitrosamines in EU medicines(03/02/2020)
• EMA update on metformin diabetes medicines(06/12/2019)

EMA's CHMPhas carried out areview ofthe presence of a nitrosamine impurity, N nitroso-varenicline, inChampix (varenicline), a smoking cessation medicine.

TheCHMP concluded that the marketing authorisation holder should make changes toChampix's authorisationto ensure that it conforms toacceptable nitrosamine intake limits forEU medicines, calculatedin line with theICH M7guideline.

As a precaution, the marketing authorisation holderrecalled several batches and paused distribution of Champix, as of June 2021.

As a result, there are shortages of the medicine in the EU that areexpected to continue. As Champix is not a critical medicine, the CHMP did not consider its temporary absence from the EU market to be a public health concern.

EMA has issued advice for healthcare professionals, including not to start new patients on Champix.

Patients should not stop taking Champix without first consulting their healthcare professional and should talk to them if they have any questions or concerns.

More information:

• Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 13-16 September 2021(under 'CHMP concludes assessment of presence of a nitrosamine impurity in Champix') (17/09/2021)
• Champix

Authorities in the EU are aware that some active substances are at a higher risk of formation of active substance derived nitrosamine impurities.

Suchactive substances containvulnerable amine functional groups that can undergo a reaction called nitrosation (often a secondary amine). Nitrosaminesare thought toform whenthe nitrosatable amine group in the active substances and trace nitrite impurities in the inactive ingredients (excipients) react.

Active substances that contain secondary amines appear particularly vulnerable to this reaction, although some cases involving active substances with tertiary amines have also been observed.

More information on the root causes of nitrosamine impurities is available inNitrosamines EMEA-H-A5(3)-1490 - 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 (Question 4).

All marketing authorisation holders for EU medicines shouldconsider this risk factor in their risk evaluations as a matter of priority, if they have not already done so.

If a risk is confirmed, they should prioritise confirmatory testing. If testing confirms the presence of nitrosamines, companies should immediately report their findings to the relevant competent authority.

Guidance for marketing authorisation holderson confirmatory testing is available.

This is a precautionary stepto ensure early detection of any potential risk, and to enable prompt regulatory action if necessary.

There is no immediate risk to patients who are taking these medicines. Patients who have any questions about their treatment should speak to their doctor.

Authorities will provide updates as necessary.