Nitroso Dimethyl anthranilate

[sbasaleh]

Dear nitrosamine Team,

While I am reviewing the risk assessment sent by one of the excipients suppliers.
the supplier mentioned that (this product contains dimethyl anthranilate as a raw material. The formation of nitrosamines during our production process can be considered as highly unlikely. We have not analyzed this product on nitrosamines).

I searched in Google and found nitroso dimethyl anthranilate impurity.

Q1- is there a published acceptance limit for this impurity?
Q2- From your experience. what should I do in this case? knowing that this material is used as a colouring agent.

Thank you in advance.

[Naiffer_Host]

@sbasaleh

dimethyl anthranilate

While the presence of that impurity is a fair concern, the nitrosation reaction must occur. Consequently, Nitrosate and pH conditions must be present to be a genuine risk. Are there any other impurities in the excipient that could elevate the risk?

[sbasaleh]

Thank you Naiffer for your valuable response.
In addition to the coloring agent excipient( contains dimethyl anthranilate) , the product IS having other excipients with traces amount of nitrite and / or nitrate. water is used in the manufacturing process.

Do you think the risk is high ?
Is there any acceptance limit for this impurity?

[paliog]

In my opinion the risk is quite high.
According to the CPCA rules adopted by EMA, FDA and Canada HA, the following Acceptable Intake should be adopted.

Calculate Potency Score
Count of hydrogen atoms on each α-carbon [0, 3] and corresponding α-Hydrogen Score is 2
Score: 2
Potency Category 2 : AI = 100 ng/day

Moreover, consider that Dimethyl Anthralinate itself is phototoxic:
Dimethyl anthranilate (PubChem)
If the drug product is for cutaneous application, the best option may be the reformulation of the fragrance without dimethyl anthranilate.

[sbasaleh]

Thank you Paliog for the clarification

[GENERAPHARM]

COMMISSION REGULATION (EU) 2022/135
of 31 January 2022
amending Regulation (EC) No 1223/2009 of the European Parliament and of the Council as regards the use of Methyl-N-methylanthranilate in cosmetic products

[Naiffer_Host]

Please keep this recent publication in perspective when weighting the water as a source of Nitrites…

Nitrite in Pharmaceutical Manufacturing Water: Development of an Ultra-Sensitive Analytical Method, Typical Data, and Discussion of Potential Nitrosamine Formation in Drug Substance and Drug Product from Water

Dr. Kumar et al. published a paper on nitrite in a variety of different types of water. https://pubs.acs.org/doi/10.1021/acs.oprd.4c00037 Twenty-one out of twenty-two purified water samples analyzed had nitrite levels that were below the quantitation limit of the method, i.e. <0.1 ppb. All potable water samples analyzed had nitrite levels that were <3.5 ppb. The results are contextualized to illustrate the amounts of nitrosamine that could be formed from process water during API and DP manufac…

[Yosukemino]

Hi, @sbasaleh,

I think you can focus on the amount of dimethyl anthranilate. The amount of dimethyl anthranilate is not considered so high, because the amount of color agent used is not so high in general and dimethyl anthranilate is contained in an impurity level. It reduces the nitrosamine contamination risk.