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EMA: Final assessment report on nitrosamines

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has published a final assessment report on nitrosamine impurities.

The report calls on the pharmaceutical manufacturers concerned to reduce the presence of nitrosamines in medicinal products as far as possible and to comply with the defined limits.

We prepared an overview for you that summarizes the recommendations of the comprehensive 90-page report of the EMA: 

  • The presence of N-nitrosamines in medicinal products for human use should be reduced as far as possible, based on the limits of the principles stated in ICH M7 (R1) and calculated considering a lifetime daily exposure. 
  • The risk of presence of nitrosamines should be evaluated by marketing authorisation holders respectively applicants. If there is a risk, further confirmatory tests should be performed. For new applications for authorisation, a risk assessment on the presence of nitrosamines must be submitted with the application.
  • The risk assessment should include manufacturing processes of active substances and finished products, taking into account the root-causes, and subsequent confirmatory tests on the finished product, if a risk exists.
  • For biological medicinal products the general risk of nitrosamine formation is very low, but the following cases should be considered: Biological medicinal products containing chemically synthesised fragments where risk factors similar to chemically synthesised active substances exist, biological medicinal products to which nitrosating reagents are deliberately added during the manufacturing process, biological medicinal products packaged in primary packaging such as blisters made of nitrocellulose
  • If more than one nitrosamine has been found in a finished product or the active substance, it must be ensured that the total risk of the sum does not exceed 1:100,000 at life-time risk. Alternatively, the sum of all N-nitrosamines found should not exceed the limit for the most potent nitrosamine.
  • If the limit value for a single nitrosamine cannot be met according to ICH M7 (R1), the marketing authorisation holder should immediately submit an investigation report including the potential/identified causes, preventive/corrective measures and a discussion of the impact on the risk-benefit balance. The authorities decide on a case-by-case basis.
  • Exceptions to the limit values apply to finished products for the treatment of advanced cancer stages (here ICH Q3 A(R2), ICH Q3B(R2) and Q&A to ICH S9 apply) or in cases where the active substance itself is genotoxic (here limits for non-mutagenic impurities according to ICH M7 (R1) can be used).
  • If there are sufficient data on carcinogenicity from animal studies for a reliable TD50 value, a substance-specific limit should be derived from this.
  • If N-nitrosamines are found for which no substance-specific data are available, the class-specific TTC of 18 ng/d from the Lhasa carcinogenic potency database should be used. 

Marketing authorisation holders are obliged to carry out risk assessments for APIs as well as for the finished product, to ensure that the medicinal products are manufactured in accordance with the latest scientific and technical standards in accordance with Article 23 and Annex I of Directive 2001/83/EC and Article 16 of Directive (EC) 726/2004 and, where necessary, to adapt the manufacturing processes accordingly. 

It must also be ensured that all active substances and excipients are manufactured in accordance with the principles of good manufacturing practice as laid down in Article 46(f) of Directive 2001/83/EC.

Further detailed information for pharmaceutical companies can be found on the Nitrosamine website of the EMA


EMA: CHMP assessment report