I have a combination product containing (Metformin HCl & Vildagliptin).
1st Question: In confirmatory testing for nitrosamines in the product, I will consider both N-nitroso vildagliptin & N-nitroso vildagliptin amide determination as being NDSRIs. Shall I need to determine NDMA only or all the small molecules nitrosamine (NDMA, NDEA, NMPA, NDBA … etc) should be determined.
2nd Question: In controlling nitrosamine impurities in excipient, I shall focus on the key excipient (filler), as microcrystalline cellulose. Should I request from supplier the nitrosamine risk assessment or a declaration for low nitrite levels will be sufficient ? & what is the maximum accepted nitrite level (any references)?
Here are some key considerations regarding your questions:
Confirmatory testing should be based on your Risk Assessment. Do not assume that your product will contain NDSRI (Nitrosamine Drug Substance Related Impurity) or small nitrosamines simply because they have been reported before. For instance, not all Metformin formulations will produce NDMA (N-Nitrosodimethylamine) or NDEA (N-Nitrosodiethylamine). Carefully study the risk of forming any nitrosamines based on your formulation, process, ingredients, and packaging. Do not rely solely on your suppliers’ “declaration letters” for assurance.
Generally, excipients (with a few exceptions) are not direct sources of nitrosamines; instead, they often contain precursors, such as nitrites or amines. The quantity of these precursors must be factored into your formulation risk assessment.
A fixed nitrite limit traditionally does not apply in this scenario. The risk associated with a particular excipient depends on the formulation and the level at which that excipient is used in the overall process. What may represent a high risk for one formulation might be considered a lower risk for another.
Please refer to this previous post for more context:
Our experience with Metformin combination drugs shows that it is very difficult to avoid the formation of the NDMA. Of course, the extension of the formation is different from product to product, depending on both the nature of the APIs and excipients, as Naiffer said.
Regarding the MCC, we have seen that the ‘‘low nitrite’’ grade, contains less than 100ppb of nitrites, which consider quite safe.
If it a single layer product, as Vildagliptin is a secondary amine, personally i believe that it would absorb all the available nitrites and no NDMA would be formed but since the two amines would have different kinetics in their nitrosation, i would propose to proceed with a confirmatory test for both NDMA and N-nitrosovildagliptin.
Finally, i do not consider as Vildagliptin amide as a risk, as it would be present in a very low quantity in the final product in comparison to Vildagliptin.
The risk is always there and if you are in the formulation stage you may consider using nitroso scavengers such as antioxidants or pH modifying agents.
I would like to add a question to the discussion.
To what depth should a risk analysis be performed regarding the evaluation of the excipients?
In terms of API it is clear that the molecule as well as the synthesis and used residual solvents should be considered, but what about the excipients?
If some excipient has a potential to form a nitrosamine impurity, for eg. diethylamine, then that is also a clear situation, but should the synthesis of the excipients and the used residual solvents be also taken into account?
Totally agree, but I would certainly not assume that NDMA would not be formed due to vildagliptin sequestering the nitrites without confirmatory testing data, especially in stability
