The effect of nitrite and nitrate presence in raw materials on nitrosamine risk

[Elif]

I would be very pleased if you could share your evaluation and comments on the following subject.

We request nitrosamine risk assessment studies from our raw material suppliers within the scope of drug product nitrosamine risk assessment. Suppliers, especially excipient suppliers, share the results of nitrite and nitrate analysis in the raw materials they produce. What should we consider when evaluating nitrite and nitrate levels of raw materials? What should be the maximum nitrite and nitrate levels in raw materials? What is the importance of nitrate presence in terms of nitrosamine risk?

Thanks in advance.

[Naiffer_Host]

@Elif Thanks for your question. I suggest doing a search in the community using the tag ‘Excipient’ so you can see all the discussions that have been happening on the particularity of Excipients in Nitrosamines challenges.

Additionally, 2 posts that illustrate the use of these reported values of Nitrites in examples of risk assessments.

NDMA analytics in metformin products: Comparison of methods and pitfalls

How to avoid NDMA in Metformin? (In press)

Back in October 2020, we saw an increased concern about the potential presence of NDMA in Metformin. @trust_user_a @trust_user_b @trust_user_c “As of October 2020, EMA and the national competent authorities are asking marketing authorization holders for metformin-containing medicines to test their medicines before releasing them onto the market,” said EMA’s Committee on Human Medicinal Products (CHMP) in an update to its post-authorization nitrosamine impurity testing procedures” As a Nitros…

Lactose, Nitrosamine Risk?

I share the good example of nitrite calculation contained in excipients and others demonstrated by Dr. Urquhart in nitrosamine workshop last week. [nitrite in excipient] According to him, contamination risk is evaluated with 100% conversion at first. Next a conversion factor, whose detail is not included here, is considered and the calculated value is compared with (adjusted) ADI. This example may concern with API with secondary or tertiary amine, however if the amount of these amines is at …

[Yosukemino]

Hi, @Elif. I think this post is also helpful for you to understand the amounts of nitrites in excipients and their contribution to the drug product.

A Nitrite Excipient Database - Risk Assessment

If you haven’t, I encourage you to read the recent publication " A Nitrite Excipient Database: A Useful Tool to Support N- Nitrosamine Risk Assessments for Drug Products" by Boetzel et al. A fantastic update on the data-sharing consortium, maintained by Lhasa Limited. The goal of the initiative is to provide a common framework to contextualize and estimate the risk posed by the presence of nitrites to contribute to the formation of nitrosamines in drug products. Key takes aways: Average nitr…

[Elif]

Thank you very much for your valuable support.

[Elif]

Thank you very much for your kind respond.

[Shirish]

Hi,
Presence of nitrates and nitrites in excipients, may potential cause of formation of nitrosamine impurities in the drug product if there is secondary / tertiary amine present in any of other component. Same can be confirmed and ruled out after testing of product.
(Addition to this, there are other factors too like acidic environment, chosen mfg. process etc.)
We cannot go by thumb rule for specific level or limits in excipients, chemistry wise needs to confirm the possibility of reaction between available nitrites / nitrates and secondary amines present in other components of drug product.
Hope this may useful.

[sms_buha]

Really very useful stoichiometric calculations for reaction mechanism between nitrite and Nitrosamine.

[Elif]

Thank you very much for your response.