Hi All,
Lidocaine & Prilocaine cream USP,2.5% & 2.5% is having MDD 1500 mg/day for each (Lidocaine 1500 mg/day & Prilocaine 1500 mg/day)
Can anyone guide me MDD need to consider 1500 mg/day or 3000 mg/day to calculate the specification (Analytical limit). Thanks
Did you identify a true risk of formation of the “small nitrosamines” in your product? Are the corresponding precursor amines used or likely to be introduced in the manufacturing process? If yes, are these vulnerable amines introduced from on or both the constituents (Lidocaine & Prilocaine)?
If no vulnerable amines are involved in the synthesis, there is no need to analyze the small nitrosamines. If the risk of formation of a particular nitrosamine is from a single API (in the combination product) you need to consider 1500 mg/day MDD. If the risk is from both the APIs then you need to consider an MDD of 3000 mg/day.
Dear Muzaffar,
Thank you for the reply and giving the clarity. As I am working for the customer project, I will ask the same to get the clarity.
The customer asked to quantify 7 FDA listed nitrosamine to assess in the product.
Thanks
Vivek
The testing of the 7 FDA nitrosamines is something that I have seen companies doing - without the consideration of the product itself.
Both lidocaine and prilocaine have limits for nitrosamines set by various authorities, and these should be the primary concern of the risk assessment, followed by the potential for formation of small nitrosamines.
This should then guide the testing to be carried out - the 7 FDA nitrosamines should not just be the default testing option.
I’d like to point to the recent update of FDA guidance regarding determination of the Acceptance intake for multiple nitrosamines:
Here, AI(ppm)i = AI(ng/day)i/MDD(mg/day)i
In the formula above, MDD simplifies, as both Xi and AIi are reported to the same MDD. MDD can be 1500mg/day or 3000mg/day - for clarity we need to specify which API we consider or if the sum of the MDD of the APIs is considered.
Dear All,
Thank you for the guidance. The same I communicated to the product owner to assess the nitrosamines and their limits.
Thanks
Vivek
Hi Vivek, Please use the MDD of an API from which the nitrosamine impurity originated. For example: if the NDMA is due to dimethylamine in Lidocaine route of synthesis, the limit would be 96/1500 = 0.064 ppm.
This part of the guideline is used for calculating the limit of multiple nitrosamine impurities in single API. Your @Vivek case seems to be different, here you are concerned with use of appropriate value of MDD in combination product for calculation of limit for Nitrosamine impurities, it seems. In that case, What @krishmnt suggested using MDD of an API from which the nitrosamine impurity originated looks to be the correct way of calculation.
Yes, it is logic to report each nitrosamine to the related API, however, it does not matter how the level in ppm = AI, ng/day / MDD, mg/day is calculated, as long as it is specified. That is because eventually the amount of the nitrosamine in the maximum daily dose is what matters, which is ppm x MDD.
Dear Marks,
Thanks for the reply.
Thanks
Vivek