What is the probability of nitrosamine formation during DP production

I need your comments regarding my below question. Any comment appreciated :slight_smile:

What is the probability of nitrosamine formation under the production conditions of the products that produced by methods such as granulation, powder mixture, liquid mixture if one of the raw materials used in the production process of the pharmaceutical product contains an amine and the other contains a nitrosating agent in their route of synthesis?

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Hi Figen,

Regarding your question, that would depend on many variables.

What I could say is that if compound 1 has an amine, it is a secondary, tertiary one? Is the amine an impurity or the raw material itself has an amine?

For compound 2, I cant say for sure how much content of nitrite would be in the finished material (that is important to address the rate of formation), it depends on the manufacturing process. For example azo colorants/saccharin, etc. use a nitrosation reaction of a primary amine, however nitrite is depleted with for example sulfamic acid, thus not much nitrite at the end. And also how much quantity of the material is in the formulation. Colorants are used in very low quantities, a sweetener could be used in more quantities to obtain the desired effect, etc. I would address with the manufacturer the nitrite topic to see if they have data on how much nitrite is expected taking into account the Route of synthesis used.

Regarding the manufacturing process, based on recent investigations, wet granulations, compression, coating could be the most critical. In general, liquid phases. I highly suggest 2 papers that address this more into detail:

Potential for the Formation of N-Nitrosamines during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk Posed by Trace Nitrite in Water | Organic Process Research & Development (acs.org)


Avoiding N-Nitrosodimethylamine Formation in Metformin Pharmaceuticals by Limiting Dimethylamine and Nitrite - ScienceDirect

They are not like tailored for each case, but gives fundamentals on the impact of certain root causes for nitrosamine formation. Of course there are several other papers, that could help also.

In summary, there is a non negligible probability that needs to be further addressed I may say.


Thank you very much for your kind respond:) This is very valuable.

Dear Figen,

In addition to Diego’s comment, this Guidance Note for EFPIA DP Workflow may be useful since the order of risk considering the drug product formulation is proposed as below:


Thank you very much for this valuable information sharing :slight_smile:

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The chances depend on the amount of nitrite present in the formulation. However, some of the root cause analysis show some formation of nitrosamine during steps like wet granulation, curing etc.

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If you would like to explore a great case study and a systematic approach for investigating nitrosamine root cause; please review NEH Nasr et all. "Investigating the root cause of N-nitrosodimethylamine formation in metformin pharmaceutical products"

Conclusions: Water, heat, and excipients’ nitrite and nitrate levels are the key players, which should collectively exist, to cause NDMA formation during MET tablets manufacturing.