Nitrosamine contamination: EMA requests risk evaluation for drug products containing chemically synthesised APIs

On 26 September 2019, the EMA published a statement titled EMA advises companies on steps to take to avoid nitrosamines in human medicines (EMA/511347/2019)”. This document addresses all marketing authorisations holders for drugs containing chemically synthesised active substances in the EU. It requests that all marketing authorisation holders, who are ultimately responsible for the quality, safety and efficacy of a medicinal product, conduct a risk evaluation regarding potential nitrosamine contamination.
Along with this statement, the following documents on the topic were published on the EMA’s News page:

  • Information on nitrosamines for marketing authorisation holders (EMA/189634/2019) and

  • Questions and answers on “Information on nitrosamines for marketing authorisation holders” (EMA/428592/2019).

The key points of these documents are summarised below.

EMA advises companies on steps to take to avoid nitrosamines in human medicines

  • Marketing authorisation holders for drug products containing chemically synthesised active substances must evaluate the risk of nitrosamine contamination within six months.

  • The risk evaluation is to be conducted in a prioritised manner, i. e. preparations with a higher probability of being contaminated with nitrosamine are to be evaluated first.

  • The evaluation is to take the recently published review of sartan preparations and the limits mentioned therein into account.

  • Authorities must be informed about the evaluation results.

  • High-risk preparations must be analytically tested for nitrosamine contamination.

  • If nitrosamine is detected, the authorities must be informed immediately.

  • Subsequent changes to marketing authorisations must be applied for.

  • All steps must be completed within three years in a prioritised manner.

The following documents put the statement’s demands in more concrete terms.

Information on nitrosamines for marketing authorisation holders


  • Sources for nitrosamine contamination are primarily Sartan APIs or such compounds which match Sartan’s molecular structure (with a tetrazole ring as structural characteristic). Other sources may be certain solvents, reagents or other starting materials. Contaminated or badly cleaned equipment may also cause contamination with nitrosamine.

Responsibility of the marketing authorisation holders

  • Marketing authorisation holders must make sure that they and the holder of the manufacturing authorisation have access to information from the API manufacturers concerning nitrosamine impurities and the potential for cross-contamination. This is supposed to be attained through quality agreements. This information is essential for conducting a risk evaluation. It should be noted that API manufacturers must manufacture active substances under the GMP regulation of ICH Q7 and ICH Q7 Q&A.

  • This responsibility remains with the marketing authorisation holder even if information from the ASMF or the CEP is not accessible due to reasons of confidentiality.

Possible sources of nitrosamine impurities

  • Formation of nitrosamine during synthesis, i. a. in the presence of raw materials, starting materials and intermediates and/or through incomplete depletion of nitrosamine in subsequent synthesis steps.

  • Use of sodium nitrite or other nitrites in the presence of secondary or tertiary amines in the course of the synthesis. Secondary amines may form in amide-bases solvents, e. g. N,N-dimethylformamide, N-methylpyrrolidone or N,N-dimethylacetamide. Tertiary amines may be present in other frequently used solvents.

  • Cross contamination with sodium nitrite despite intensive but inefficient cleaning of the manufacturing equipment; thereby, sodium nitrite enters into the reaction mixture, where secondary or tertiary amines are present.

  • Recycled solvents, especially when the recycling process was performed by a subcontractor instead of inhouse.

  • Raw materials, starting materials, excipients, reagents, etc. that do not come from appropriately qualified suppliers.

Request for review of manufacturing processes

  • Step 1: risk evaluation
    - In cooperation with the API manufacturer and the drug product manufacturer, the marketing authorisation holder must perform a risk evaluation as per ICH Q9 and ICH M7 specifications.
    - This risk evaluation must be concluded within six moths after the statement was published.
    - The risk evaluation’s documentation must not be submitted, though it is to be made available upon request.
    - If a risk of a potential contamination has been detected, the marketing authorisation holder should proceed to Step 2.

  • Step 2: confirmatory testing
    - Risky preparations must be tested for nitrosamine contamination via validated and appropriately sensitive analytical methods. High-risk drug products are to be tested as soon as possible (prioritised approach).
    - If nitrosamine is found, the competent authorities are to be informed immediately, irrespective of the amount detected.

  • Step 3: changes to the marketing authorisation
    - Changes to the marketing authorisation, e. g. changes in the manufacturing process or product specifications, are to be applied for in a timely manner.
    - If there is a risk to public health, competent authorities must be informed immediately and timelines shortened.

Questions and answers on "Information on nitrosamines for marketing authorisation holders"

  • All drug products containing chemically synthesised APIs including generics and OTC products are to be reviewed. A risk-based approach should be adopted to prioritise the evaluations and confirmatory testing.

  • To prioritise risk evaluation, factors such as the maximum daily dose, duration of treatment, therapeutic indication and number of patients treated should be taken into account. FMEA or FMECA as described in ICH Q9 may be used as risk evaluation methods.

  • Drug and API manufacturers must supply the marketing authorisation holder with all relevant information to perform a risk evaluation. The potential sources for nitrosamine contamination listed in  "Information on nitrosamines for marketing authorisations” should be considered. The number of batches and samples used for testing must be scientifically justified.

  • As analytical methods to determine NDMA and NDEA in sartans, the procedures published by EDQM may be used. To determine other nitrosamines in different preparations, suitable and appropriately sensitive testing methods must be developed and validated before use.

  • If the presence of nitrosamine has been confirmed, the marketing authorisation holder must, irrespective of the amount detected, inform the competent authorities immediately, evaluate the risk for patients and take appropriate measures in order to prevent or minimise the exposure of patients to nitrosamine.

  • Limits for long-term exposure to nitrosamine in non-Sartan preparations are not yet available. Meanwhile, the provisions of the ICH M7 guideline are to be applied for evaluation, and the basic principles on toxicology of NDMA and NDEA as described in the "Assessment reports for Sartans" (Referral under Article 31 of Directive 2001/83/EC) to be considered. Limits for other nitrosamines such as NMBA, DIPNA and EIPNA may be found in the EMA document titled “Temporary interim limits for NMBA, DIPNA and EIPNA impurities in sartan blood pressure medicines".

  • Categories for changes that might impact the marketing authorisation regarding control strategy and active substance specification are Type IB (possibly Type IA, if the CEP is updated), changes to the manufacturing process Type II.

The range of activities the EMA has initiated together with EDQM and the authorities of the EU Member States play an important part in reducing nitrosamine impurities, not just in Sartan preparations.

Representatives of the EMA and the EDQM addressed the problem of nitrosamine contaminations at the 22nd APIC/CEFIC Conference in Prague from 23 to 25 October.

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