How to deal with risk assessment and control strategies for Nitrosamine impurities of related substances of API.
As of NDSRI formation in API, many related substances/ impurities / intermediate stages of API do possess amine source likely to form corresponding nitrosamine impurity of compound under consideration.
This is a complex matter. See the discussion in the following topic:
Risk assessment not strong enough, specifically on related impurities containing secondary amine
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As @paliog mentioned, it’s a complicated matter… one needs to assess any potential formation of nitrosamines, not just the NDSRI. You need to ask yourself about the reactivity of the amine compound and the potential purging during the synthesis.
That’s why a one page declaration letter from the supplier is not enough assessment!
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Gentleman’s, thanks for your expertise views.
Certainly, through risk assessment for all possible potential nitrosamine is only suitable option to deal with the challenge!
Risk evaluation in consideration with source of vulnerable Amine in manufacturing, presence of nitrosoating species, fate for nitrosamine impurity formation, purge factor calculation and analytical evaluation is must.
Additional do any one have relevant literatures in relation to degradation pathwayss for Nitrosamine impurities?
This will help in purge calculations…
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As a starting point you can check these articles:
- Chemistry of Nitrosamine Formation, Inhibition and Destruction (Douglass, et al., J. Soc. Cosmet. Chem., 1973)
- An Organic Chemist’s Guide to Nitrosamines. Structure, Reactivity & Role as Contaminants (Beard & Swager, J. Org Chem., 2021)
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You cannot miss this one…
Developing structure-activity relationships for N-nitrosamine activity
https://www.sciencedirect.com/science/article/pii/S2468111321000347
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Formation of Nitrosamines takes place with three sources
- secondary amine
- acidic condition
- Nitrite source
You need to have control either of these to avoid nitrosamine formation.
if you possess secondary amines in your API or related structure, then you should find out and control of nitrite source in the solvent or reagent or intermediate to avoid the nitrosamine formation
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In addition to the above points factors like pH, and temperature, etc… to be considered during Nitrosamine Risk Assessment.
Also, comprehensive assessment is to be consider the following point as discussed in the guidance:
1- Secondary/Tertiary amine
2- Nitrite source
3- Reaction Condition (pH, Temperature, etc…)
4- Vendor assessment in terms of the possibility of any contamination.
5- Recovered material/ Recovered material
6- Nitrosamine/Reagents carrover from eairler product if any. (If manufacturing facility used for multipurpose)
7- Packaging material if any uses of Nitrate source.
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