Nitrosamine Impurities: Extension of the Deadline for the Submission of Variations

In September 2019, the EMA started a ‘call for review’ to all marketing authorisation holders of medicinal products containing chemically-synthesised and biological APIs to review their manufacturing processes with regard to contamination with nitrosamines. This ’ call for review’ consists of 3 steps:

Step 1: Marketing authorisation holders assess the potential risk of contamination with nitrosamines at the level of the API and/or the finished medicinal product by means of a risk analysis .
Step 2: If a risk is identified, a confirmatory test is carried out with the aim of confirming and quantifying the nitrosamine contamination or excluding it.
Step 3: Following confirmation of nitrosamine contamination by confirmatory testing, the marketing authorisation holder must take effective measures to reduce the risk , which need to be submitted using the appropriate variation(s) .

In the 11th revision of the document published on 29th July 2022, the deadline for submission of variations has been extended from 26th September 2022 to 1st October 2023. This gives pharmaceutical companies an extended timeframe of 12 months to take measures to reduce the risk of nitrosamine contamination and to submit the relevant variations to the competent authority.

The deadline for conducting the confirmatory review - 26th September 2022 for medicinal products with chemically-synthesised APIs and 1st July 2023 for those with biological APIs remains unchanged.


In USA, the deadline is Oct 2023 but many groups are planning to go and request an extension as with the NDSRI conundrum, this looks like an unattainable deadline.


Hi Aloka @ASrinivasan,
Thankyou for the update on the US timelines and the Industry approach on the proposed timelines.
Many of us from India work on products for US approvals and hence would be keen to follow up if any extension of timelines is a possibility in the future.
While every Corporation has dedicated team of experts working on Nitrosamines for exisiting products as part of PLCM, the activity in itself has technical & operational challenges that take time to implement at the shopfloor and hence a realistic approach on timelines will be the Industry expectation with high risk category of products being given the priority.

1 Like

Very well written Archana, what do you think would be a good time range to do this. Will 2025 or 2026 be more practical.

1 Like

@ASrinivasan by many groups are you referring to industry groups as PhRMA, AAM, CHPA, etc

Naiffer, I am not at liberty to specifically name clients, so I will be quite on specifics

1 Like

I understand! Thanks for sharing

HI Aloka @ASrinivasan
2026 seems to be a far more realistic and achievable timeline for high risk categories where risk mitigation involves modification to process, raw materials, excipients, potential risks associated wrt Stability and Packaging materials.
Considering PV and stability studies, these activities are time dependent and MAHs would perhaps not like to rush through at the cost of potential Recalls later.


And let us not forget that reformulation is not easy.

1 Like

Absolutely, reformulation is as good as doing a new one.