Dear Yuvraj,
In Europe and apparently Canada, the negative Ames test could be used to set a limit of 1500ng/day. In the USA, this is not the same and more information could be asked for this.
Please see below a relative text in the version 2 of the Control of Nitrosamine Impurities in Human Drugs, is written: ''A negative result in a valid enhanced Ames assay may be used to support a higher limit for a nitrosamine; however, manufacturers and applicants should note that FDA may request additional safety data beyond the enhanced Ames assay to support alternative AI limits. In addition to the enhanced Ames test, the Agency is currently requesting a second in vitro mammalian cell mutation assay and in vitro metabolism data (including human hepatocyte or microsome) to support an AI limit of 1500 ng/day. Negative results in the in vitro mutation tests along with metabolism data are considered supportiveā'.*
Also let us know whether FDA listed N-Nitroso Meglumine is related to Excipient OR API with Meglumine Salt ?? Since source motioned in FDA guidance for N-Nitroso Meglumine are all API with Meglumine salts.
Dear desaimayur78,
the acceptance intake of 100ng/day corresponds to the N-nitrosomeglumin independently on the usage of meglumin in the final product.
So, i believe that the spec. limit for this nitrosamine would be as
100ng/day / maximum daily dose (in mg) of the given product as reflected in the SmPC (either is a salt of meglumin or not).
best regards
Christos
There will be a vast difference in limits of N-Nitroso Meglumine w.r.t. excipient and salt. Salt is having higher amount of Meglumine while excipient is very low in final drug product.
Dear desaimayur,
i got your point but in the guidelines (at least in Europe), the limit is calculated only from the acceptance intake of nitrosamine and the max daily dose of the API.
thank you