Nitrosamines: Considerations for Marketing Authorisation Holders

Following a press release from the EMA on 26 Sep 2019, all marketing authorisation holders (MAHs) for human medicines containing chemically synthesised active substances must review their products for the possible presence of the carcinogenic class of compounds called nitrosamines. But where has the requirement for this precautionary risk assessment come from?

Nitrosamines in Sartan Blood Pressure Medicines

EU authorities were notified in June 2018 that a valsartan Active Pharmaceutical Ingredient (API) manufacturer based in China had detected the presence of a nitrosamine (N-nitrosodimethylamine (NDMA)) process impurity. NDMA is a genotoxic and carcinogenic agent in animals and it is classified as probably carcinogenic to humans (Class 2A carcinogen) by the International Agency for Research on Cancer (IARC, WHO).


Image by Freepik

The initial investigation report by the manufacturer indicated that NDMA is formed at the tetrazole ring-forming step in the valsartan API manufacturing process and the level of NDMA present may depend on the reaction conditions used. As such the scope of the potential impact could not be limited to this manufacturer.

On 5 July 2018 the European Commission (EC) triggered a referral under Article 31 of Directive 2001/83/EC and requested the Committee for Medicinal Products for Human Use (CHMP) to assess the benefit-risk balance of valsartan-containing medicinal products based on these concerns and to issue a recommendation on whether the relevant marketing authorisations should be maintained, varied, suspended or revoked.

After the referral procedure started, NDMA was also identified in valsartan from other API manufacturers. In addition, further N-nitroso impurities were identified in some valsartan batches and in batches of other sartans. The scope of the referral was therefore widened to include all sartans with a tetrazole moiety in their molecular structure.

As some nitrosamines (including NDMA) are among the most potent mutagenic carcinogens known, when the potentially widescale problem of nitrosamine-contamination was confirmed, immediate measures were taken by competent authorities across the EU, such as recalls of affected batches from pharmacies.

On 01 Feb 2019 a press release was announced by the EMA that any companies manufacturing sartans must review their manufacturing processes to ensure they are not producing nitrosamine intermediates.

Wider Implications

Since these initial findings, NDMA was discovered in some ranitidine stomach acid lowering medicines. On request of the EC, the EMA started a review of ranitidine medicines in September 2019. Since this review started, the MHRA has been recalling unexpired batches of many ranitidine medicines.

Following this discovery several possible sources of nitrosamine contamination have been identified; from the reaction conditions in API synthesis, contamination of starting materials or from the use of non-dedicated equipment, even formation during drug product manufacture.

The 26 Sep 2019 EMA announcement was subsequently released, this requested all MAHs for human medicines containing chemically synthesised active substances review their medicines for the possible presence of nitrosamines and test all products at risk.

Since this announcement, on 06 Dec 2019 the EMA were made aware of trace amounts of nitrosamines being found in a small number of metformin diabetes medicines outside the EU.

Review Process

MAHs should work with manufacturers of API and finished products in order to review manufacturing processes with respect to the arrangements for preventing nitrosamine formation as well as contamination or cross-contamination. Guidance has been provided in a notice and question and answers document.

This review process involves 3 steps.

Step 1 – Risk Evaluation (must be completed by 26 March 2020 01 October 2020)

The principles described in ICH M7 guideline in relation to toxicology assessment, control strategy and changes to the manufacturing processes for active substances should be applied. Consideration should be taken as to possible sources of contamination of the raw materials, intermediates and finished materials and their degradation pathways. The stage at which these impurities are introduced should also be considered, as the risk of carryover into the finished product is reduced at the earliest stages of manufacture. However, the use of fate and purge knowledge to omit the need for testing needs to be carefully considered and scientifically justified.

MAHs should prioritise products in order to establish the sequence in which their products are to be evaluated. The currently identified root causes for the presence of nitrosamines are as follows:

  1. Use of sodium nitrite (NaNO2), or other nitrosating agents, in the presence of secondary, tertiary amines or quaternary ammonium salts within the same or different process steps (if carry over can occur).
  2. Use of sodium nitrite (NaNO2), or other nitrosating agents, in combination with reagents, solvents and catalysts, which are susceptible to degradation to secondary or tertiary amines, within the same or different process steps (if carry over can occur).
  3. Use of contaminated raw materials in the API manufacturing process (e.g. solvents, reagents and catalysts).
  4. Use of recovered materials (e.g. solvents, reagents and catalysts), including recovery outsourced to third parties who are not aware of the content of the materials they are processing and routine recovery processes carried out in non-dedicated equipment.
  5. Use of contaminated starting materials and intermediates supplied by vendors that use processes or raw materials which may allow nitrosamine formation.
  6. Cross-contaminations due to different processes run on the same line and due to operator-related errors such as inadequate phase separations.
  7. Degradation processes of starting materials, intermediates and drug substances, including those induced by inherent reactivity in combination with carry-over of sodium nitrite (NaNO2), or other nitrosating agents. This could potentially occur also during finished product formulation or storage.
  8. Use of certain packaging materials. Nitrosamine contamination has been observed by one MAH in a finished product stored in blister. The MAH has hypothesised that the lidding foil containing nitrocellulose printing primer may react with amines in printing ink to generate nitrosamines, which would be transferred to the product under certain packaging process conditions.

If the MAH has products with the potential for generating nitrosamines by the identified root causes, these products should be treated as high priority and the risk evaluation performed immediately.

MAHs should inform the concerned Competent Authorities when the risk evaluation is concluded. The CMDh have published practical guidance for MAHs in how to inform the competent authorities on the outcome of the evaluation. The actual risk evaluation documents do not need to be submitted but should be made available upon request. If a risk of presence of nitrosamines is identified as a result of the evaluation, the MAH should proceed to Step 2 (see below).

UPDATE – The European medicines regulatory network has agreed to extend the deadline to complete step 1 to 01 October 2020. This follows reports of the challenges encountered in meeting the original deadline of 26 March 2020, and the impact of the severe restrictions in place to combat the COVID-19 pandemic.

Step 2 – Confirmatory Testing (must be completed by 26 September 2022)

In the event of a risk of presence of nitrosamines is identified, confirmatory testing should be carried out using appropriately validated and sensitive methods. Products identified as high priority should be tested as soon as possible.

Methods for determination of NDMA and NDEA in sartans have already been developed by the Official Medicines Control Laboratories. These may serve as a starting point for the development and validation of analytical methods appropriate for other APIs.

MAHs should inform the competent authorities immediately if tests confirm the presence of a nitrosamine impurity.

Step 3 – Marketing Authorisation Changes (submission must be completed by 26 September 2022)

MAHs should apply for a variation in a timely manner to introduce any required changes. The variation should contain information on amendments to the marketing authorisation – i.e. module 3 (3.2.S and 3.2.P), the active substance master files (ASMF) or certificates of suitability (CEP) – that are necessary to amend the method of manufacture or control of the active substance and/or finished product.

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

Here at JensonR+, we will be continuing to monitor the situation in 2020 and beyond, so follow us on LinkedIn to receive any updates. If you would like to discuss the potential impact of this change to your products, then please do not hesitate to contact us at

Ben Smith