Is it possible that the N-nitroso impurity can be controlled by modulating the pH of final formulation ?? Whether the solid or liquid formulation???
Resoundingly yes. You can determine the pH range by modifying the NAP test from the IARC MONOGRAPHS ON THE EVALUATION OF THE CARCINOGENIC RISK OF CHEMICALS TO HUMANS and then work on the formulation from there.
From a drug substance point of view, we had identified and quantified a nitrosamine derived from the product. We demonstrated the influence of the pH during the manufacturing process (via lab trials), in “standard” condition (acidic condition) versus “labs trials conditions”, we can see a significant difference in nitrosamine level. On industrial batch, we also checked this point so by slightly modifying the pH (from 3 to 5) we reduced the nitrosamine content (yield unchanged but “reaction time” slightly longer by a few minutes). In addition, we add an IPC (to control the Ph during critical chemical step of the drug substances and we have reduced the nitrosamines and improved the quality of the active ingredients.
So, so answer is YES we can change the pH to improve the quality but it is necessary to check all others parameters (because a major change of pH can have a major impact on other critical process parameters, products, other process impurities etc etc.)
Fantastic findings… thanks for sharing with the community!
Hello Mathieu, thank you for dharing such important findings.
I would like to ask you a question though. Can you share what technique you used to determine the pH of the formulation during the IPC? Was it a slurry mixture?
As per me it, if it’s a slurry you can measure it or else can make the slurry in water and measure the pH.