N-nitroso Vonoprazan AI 96 ng/day- FDA

Limits of Nitrosamines
1

Dear Nitrosamines Exchange team,

I learnt that FDA has established a limit of 96 ng/day for N-nitroso vonoprazan based on below news. Can anyone help me to know how the limit has been derived, is it based on Read across or Toxicological data driven AI?

2

SMILES: O=S(C3=CN=CC=C3)=O

image
image480×616 13.2 KB

SMILES: O=S(C3=CN=CC=C3)=O

image
image620×696 18.5 KB

Another potential Nitroso impurity
SMILES: O=NN(CC1=CNC(C2=CC=CC=C2F)=C1)C
image

3

Can anybody in the regulatory aspects answer my query. How the FDA arrived N-nitroso Vonoprazan with a limit of 96 ng/day. Is it for the free base Vonoprazan or Vonoprazan Fumarate salt with a daily dose of 40 mg/day?

4

Dear @mnvsastry,

I surmise AI of 96 ng/day might be derived from NDMA.

However, please note this provisional relaxational given to only innovator Phathom Pharmaceuticals (VOQUEZNA) by FDA.

5

What limits to be considered for generic formulation?
Will it be 96ng/day or 18ng/day. NDSRI belongs to category 1

6

For generic formulation- I suggest it is better you either have in-silico or experimental justification that overrides CPCA category I - AI of 18/26.5 ng/day.

In case if you could not control within the limits derived from AI of 18/26.5 ng/day.