Question 5:
What should be done if new information (e.g. related to new potential risk factors or root causes) is identified after the submission of step 1and/or step 2 responses?

• In principle, it is expected that the risk assessment will be repeated routinely, even if information on step 1 and/or step 2 had already been submitted. Particular attention should hereby be given to questions 4 (on new risk factors) and 10 (on limit values for nitrosamines), which are regularly updated.
• Marketing authorisation holders should pay particular attention to the risk of nitrosamine contamination from active substances containing a sensitive amine. During formulation of the final product and/or storage, this, together with traces of nitrite, leads to a high risk (see Q&A 4, 8.)

Question 10:
Which limits apply for nitrosamines in medicinal products?

N-Nitrosdabigatran with 8 ng/day has been newly added to the table.

Question 14:
What is the approach for new and ongoing marketing authorisation applications (MAA)?

The link to a new risk assessment template to be used in authorisation applications has been added. You will find the template here.

Parallel to the Q&A, the CMDh has updated its practical guidance for MAHs on nitrosamine impurities. It gives detailed answers on

• Step 1, risk evaluation
• Step 2, confirmatory testing of the finished product for approved products
• Step 3, changes to the marketing authorisation

Sources:
EMA: Q&A for marketing authorization holders/applicants on nitrosamine impurities in human medicinal products

CMDh: Practical guidance for Marketing Authorisation Holders of nationally authorised products (incl. MRP/DCP) in relation to the Art. 5(3) Referral on Nitrosamines