Hi everyone,
Hope you’re well.
We have a question here.
A manufacturer controls DMF in final API as 880 ppm.
The maximum daily dose from API is 500 mg/day and we have a risk of nitrosamines formation (pH 3,5, nitrite in excipients and liquid formulation)
How would you calculate the NDMA limit for the finished product?
Can I consider this 880 ppm from DMF, or do I need to consider the entire API (96/500 = 0,2 ppm) The risk is only from the DMF…
Thank you!
@mariana.braz, a common question… the final requirement for your drug product is <0.2 ppm, based on the exact calculation you just did.
Thank you!
I have another question,
As the example shared by @Yosukemino,
Are you all using a ‘worst case’ in highest level of nitrosamines from daily dose? Or do you use some ‘formulation conversion factor’?
For example, if the only secondary amine in tablet is from the API, could I do 2,33 mcg x 23,4 % / 100 % = 0,55 mcg nitrosamine?
Hi,
Maybe I can help here. The rate of formation is highly dependant on the matrix and a conversion factor for one case would not neccesarilly be the same for “your matrix”.
Nonetheless, it is a risk to take if for ex. you use a conversion factor from literature, assuming your “vulnerable amine” has higher pKa and in less concentrations that the reference paper, as well as your matrix less nitrite content. Then, it may work.
Finally, you could do some kinetics assuming a “liquid model” and determine how much nitrosamine could be formed. Althought in some cases, still it would not be enough if you do not have sub-ppm data or your vulnerable amine when the possible nitrosamine could come from an API impurity. When the API is a secondary amine, there for sure will be an excess of the reagent. The other variable you would need is pH.
Edit 1: Also kinetics consider nitrite, but what about NOx in fluid bed driers as part of air composition. I am starting to see quite some cases where that is a problem. If you have a results of 9% the AI, lets say, is too close considering other sources that may impact the topic.
Therefore a safety marging may be needed.
Diego, thank you!
Do you know a paper about formulation conversion factor in liquid formulation?
Do you consider 0.2 ppm of nitrite in water when you calculating the nitrosamine level?
Hi,
I would not suggest assuming a conversion factor from other publications for liquid models but instead having my own value based on 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)
For water, actually we did test our water (mostly por potable sources), For purified water you could also use 0.001 ppm as indicated in the previous paper.
Hello, good day community!
Carrying out the risk assessment of a certain product with two active ingredients, we found that an excipient (coating) could cause the possible formation of a nitrosamine, so we want to calculate its maximum concentration limit (specification). We know that for this we can use:
AI (ng/day) / DDM of the drug (mg/day) = maximum concentration limit of nitrosamines (ppm)
My question is, since it is a nitrosamine not coming from one of the two active ingredients of the product, which DDM should be used? Or in this case, how could the limit be established?
I think you can use the mg of excipient in the maximum daily dose and consider this amount as MDD.
Example: A formulation with IFA X, maximum daily dose of 100 mg (equivalent to 4 tablets) has 10 mg/tablet of the excipient. Thus, in MDD, there is 40 mg (10 mg x 4) of excipient.
Hi @Yosukemino I’m deeply thankfull for this example! However, could you explain me how to calculate the “Wt (mcg)”?
I think MDD should be taken from Leaflet only as individual excipients (2 coating excipients if used in the formulation) contribute different MDD depending on mg/tablet
Thank you for asking, @FerCif96. The example is a bit confusing. API (50mg + 20mg salt) is contained in a tablet. MDD is 300 mg of API, or 6 tablets.
The weight of a tablet is also 300 mg, but this 300 mg is not used for calculation.
