Agency scientists evaluated the risk of exposure to N-nitroso-varenicline at interim acceptable intake levels up to 185 ng per day (92.5 ppm) and determined that it presents minimal additional cancer risk when compared to a lifetime of exposure to N-nitroso-varenicline at the 37 ng per day (18.5 ppm) level.
Apotex is distributing Apo-Varenicline, a Canadian-approved drug product, under FDA’s temporary exercise of regulatory flexibility and discretion.
We have ongoing discussions here in the community related to this impurity
FDA’s acceptable intake limit is 37 ng/day and (and interim acceptable intake limit is 185 ng/day until the impurity can be eliminated or reduced to acceptable levels). ]
To calculate the Acceptable limit in ppm we need to have access to Maximum Daily Dose (MDD) of Varenicline tablet. Based on a search on literature it seems that the MDD is 1mg/day (correct me if this information is wrong). The expected acceptable limit (AL) for N-nitroso-varenicline impurity is AI/MDD (ppm) = 37/1= 37ppm
Based on FDA’s guidance for products with MDD < 880mg/day we should use methods with LOQ at or below 0.03ppm. This is a polemic discussion since based on the ICH M7 (and also EMA recommendations for nitrosamines) we could develop methods with LOQ at or below the Acceptable limit (37ppm for of Varenicline tablet) or LOQ at or below 10% of AL (methods being used to justify omission from specification)… 10% of AL would be 3,7 ppm far lower than the LOQ of 0.03ppm suggested by FDA.
An important question to answer is: What are the local recommendations for sensitivity established by your local regulatory body?
Thank you very much for your detailed reply. Currently, we don’t have any local recommendations, here we follow only US FDA recommendations. The MDD for varenicline is 2mg/day. So expected acceptable limit would be 18.5 ppm. I do understand your calculation now more clearly, but didn’t understand this statement “… 10% of AL would be 3.7 ppm (1.85 ppm) far lower than the LOQ of 0.03ppm suggested by FDA.” Could you please elaborate in detail? because to achieve the 0.03ppm limit w.r.t Varenicline in the formulation will be quite challenging?
Secondly, for the rest of the nitrosamines (such as NDMA, NDEA etc. ) what would be the criteria in Varenicline formulation ? Thank you very much in advance.
Based on ICH M7 ( and EMA recommendations), we could use method to justify omission from specification and for these methods we should work with methods with LOQ at or below 10% of the acceptable limit. In the Varenicline case, 10% of AL would be 3.7ppm.
If you need to follow FDA, the recommended LOQ would be LOQ at or below 0.03ppm (much more stringent than ICH M7 and EMA’s recommendation).
Thank you for your reply. Do you mean to say that ICH M7 (and EMA recommendations) acceptable limit for Varenicline case is 3.7 ppm (3700 ppb) and for FDA 0.03 ppm (30ppb)? How two different regulatory bodies would have 123 times difference in the LOQ requirements?? Please correct me if I am wrong.
No… Based on ICH M7 and EMA recommendations the SENSITIVITY requirement (LOQ) should be at or below the acceptable limit (37ppm considering 1mg/day as MDD). In case you use the method to justify omission from specifications, the ICH M7 and EMA suggest LOQ at or below 10% of acceptable limit (3.7ppm). Sent you a private message. Tks for the discussion!
The Boiling Point of Varenicline is about 400°C. In my search I did not find the boiling point of Varenicline N-Nitroso Impurity, but we can estimate it will be a little less than 400°C. Basically, the issue to use GC-MS methods is that you might not be able to volatilize the impurity, which would consequently not elute through the column and not be detected. We also know that some GC-MS systems can heat the injector up to 400°C, but the majority of GC columns are not stable at so high temperatures (there are some stable columns up to 400°C). Possible sensitivity issues might also be observed due to the extra column bleeding at high temperature. Thoughts?
Rightly said Amanda @AmandaGuiraldelli , GC MS would be more suitable for volatiles (low boilers), employing GC MS for compounds having boiling point of 400 °C and beyond could give rise to potential degradants/decomposition, artefacts, ghost peaks & column bleed issues.