Unfolding AAM's White paper on Nitrosamines (APIs)

After recent posts (links below) on the FDA-Industry group meeting to discuss Nitrosamine last May. I revisited the white paper that AAM published “Nitrosamines, An industry position paper based on risk” (here document)
I would like to unfold and ask for your comment on some of the proposed actions:

  • When any inorganic or organic nitrite is used in any step of the manufacturing process of an API, an extensive evaluation should be done for all possible nitrosamines based on the starting materials, reagents and solvents in all the subsequent steps of the manufacturing process

  • If the nitrite is used upstream in the manufacturing process, steps will be taken to ensure that it is efficiently “washed out” to prevent nitrosation reactions from occurring downstream.

  • When a drug has a secondary or tertiary amine or an N-alkyl amide, N-alkyl carbamate or N-alkylurea in its structure or any of the intermediates or impurities in the API have these structures, the formation of corresponding nitrosamines will be investigated during the manufacturing process development, even if there is no obvious source of nitrite

  • When solvents or reagents such as DMF, DMA, DEA, DIPEA, MOR, NMM, PYR, or PIP are used in the manufacturing of an API, the sponsor would look for the corresponding nitrosamines. The incoming lots of all such solvents should be tested for the commonly occurring nitrosamines.

  • When any reagent used in the manufacturing of the API has a secondary, tertiary amine, or quaternary ammonium structure or could have a secondary or tertiary amine impurity, sponsors will look for nitrosamines related to these amines

  • N-alkylated amides, carbamates, and urea can be nitrosated. So, for reagents— starting materials with these structures—there is a possibility of nitrosamines being formed based on reaction conditions

  • If a Regulatory Starting Material (RSM) is downstream in a manufacturing process and supplied by an external vendor, a risk analysis related to the presence of nitrosamines will be performed based on the structure of the RSM, manufacturing process, and reagents used. The vendor should be able to provide information regarding how they control the nitrosamines in their RSM

  • Manufacturing processes that have a theoretical risk of nitrosamine presence, the alternative approaches, such as purge factor analysis, may be used to determine if the magnitude of risk warrants
    direct analytical testing.

For our members not familiar with AAM. They are an association representing the manufacturers and distributors of finished generic pharmaceutical products; manufacturers and distributors of bulk active pharmaceutical chemicals; and suppliers of other goods and services to the generic pharmaceutical industry.


Very well compiled flow of action points Naiffer :+1: @Naiffer_Host . Will take some time to go through this and revert back