The 18 questions and answers on the topic of "risk assessment" deal with the expectations that will be placed on marketing authorisation holders and applicants in the future. They are intended to
- design their manufacturing processes and controls to prevent if possible or mitigate as much as possible the presence of N-nitrosamines in their API and FP(s);
- assess the risk of presence nitrosamine impurities in their API(s) and FP(s) and introduce any resultant changes to the dossier as needed (e.g. changes to their manufacturing processes);
- ensure that active substances and excipients used in their FPs are manufactured in compliance with good manufacturing practices in line with Article 46(f) of Directive 2001/83/EC.
While in September 2019 the "Call for Review" concentrated on impurities in chemically synthesized active pharmaceutical ingredients, biological APIs must now also be reviewed. In particular these are
- biologicals containing chemically synthesised fragments, where risk factors similar to chemically synthesised active substances are present;
- biologicals using processes where nitrosating reagents are deliberately added;
- biologicals packaged in certain primary packaging material, such as blister packs containing nitrocellulose.
The "Call for Review" is divided into three steps.:
- Step 1: Risk evaluation
- Step 2: If a risk exists, confirmatory tests must be performed and the results must be reported immediately.
- Step 3: If the presence of nitrosamines is confirmed, variations to reduce the risk should be submitted.
Important deadlines for marketing authorisation holders to submit the results from step 1:
- for products containing chemically synthesised APIs: until 31 March 2021
- for products containing biological APIs: until 1 July 2021
The Q&A also provides answers to questions on the following points:
- Currently known causes for the presence of nitrosamines
- Procedure after completion of steps 1 and 2 if new information becomes available
- Prioritization of certain factors in the risk assessment
- Performance of the risk assessment
- Conduction of the confirmatory tests
- Requirements for the analytical methods
- Limits for nitrosamines
- What-To-Do after detection of nitrosamine contamination
- Mitigation measures
- Changes required for marketing authorisations
- Procedure for new and existing marketing authorisation applications
- Information on the time of inclusion of a test for nitrosamines in the authorisation dossier
- Responsibilities of marketing authorisation holders for active substances with Certificates of Suitability (CEPs) and Active Substance Master Files (ASMFs)
EMA: Nitrosamine Website
EMA: 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