I am having difficulty getting good information from an excipient supplier. They feel that nitrosamines apply only to APIs, and therefore they are out of scope of the process. Their nitrosamines statement only says that their product is free of nitrosamines.
I have followed up with a request specifically asking if their product contains any nitrosamine precursors, nitrites, or nitrosating agents, and if they have any multi-use equipment. In my response, I provided a direct link to the IPEC Position Paper and to the Health Canada guidance on nitrosamines impurities. The supplier response did not address any of my questions.
Are there any other resources that I can use to help an excipient supplier understand their responsibilities in this process? I wish to avoid having to do confirmatory testing due to incomplete information from an excipient supplier.
Having said that, if there are vulnerable amines that can be introduced from the active substance and a risk of nitrosamine impurity formation in the drug product has been identified, you can perform a quantitative risk assessment based on the cumulative nitrite content in the drug product. You can refer the following consortium article for the quantitative risk assessment. https://doi.org/10.1016/j.xphs.2022.04.016
Finally, you may have to perform the confirmatory testing based on the outcome of this assessment.
@KenM, we feel your pain !!! The good news is that not every excipient manufacturer is reacting that way to the apparent need to work closely with their customers. I have seen suppliers going above and beyond (that means not just the IPEC’s checklist) to help mitigate the presence of Nitrites and provide data to their customers.
Remember that the mitigation solution is not to replace every excipient for an ultralow nitrite or even nitrite-free (let’s have realistic expectations) but to understand the risk excipient. Use your formulation to calculate the risk of every excipient and assess the confirmed reactivity (if any) during the formulation. We have countless resources in the community on how to do each task.
The initiatives @Muzaffar mentioned are great ways to share data, but you will need data to contribute to the consortium.
@Yosukemino has reported this lack of information as a significant challenge to industry in Japan. Maybe he can provide some additional perspective.
Thank you for adding me to this interesting discussion, @Naiffer_Host.
IPEC position paper clearly explained MAH should take responsibility for risk assessment. Excipient manufacturers help with assessment but it is not an obligation for them. On the other hand, the IPEC and the Lhasa nitrite consortium held a collaborative meeting to solve this issue. I think now excipient manufacturers are more friendly than before.
Some excipient manufacturers such as IFF, DFE Pharma, and Asahi Kasei, provide low nitrite-grade excipients. To buy their products is another way.
And I want to add the recent discussion in the community. As far as I know, we do not have a magic bullet for this issue. Worst case estimation may be available but it is considered too conservative. MAH may test the amount of nitrite in their excipients by itself.
The excipient in question is propylene carbonate, and the API is difamilast. The drug product is an ointment, 1%w/w. The API has an amine group with an α-hydrogen, so I am concerned about residual nitrosating agents in the excipients.
