Can we bypass confirmatory testing of DP based on Theoretical Calc. of NDSRI's

Hi Guys,
I have just received Nitrosamine Impurities Risk Assessment report from the API (Diphenhydramine HCl). The manufacturer has identified the “Risk” and possible formation of NDMA (96.0 ng/day) and N-nitroso-desmethyl-diphenhydramine (26.5 ng/day) with API MDD of 200 mg/day. They performed the testing of these two NDSRI’s with the validated method on three consecutive commercial batches and reported results for both NDSRI’s “Not-detected” in the report and at the end of the report concluded the Risk as 'low".

Now my question is: As a drug product manufacturer using the API from them, do we need to perform the confirmatory testing on three commercial batches of our DP or we can rely on the manufacturer claim of low risk. Is there any theoretical calculation we can show of to omit any testing requirement of the DP. Please let me know.

@Raza The journey is just beginning… as we have dived and deepened into several of the discussions here in the community, the risk of nitrosamine formation is not unique to the API. It’s only one of many areas of risk.
As DP manufactured, now you need to demonstrate on ‘your own’ risk assessment, that those or any other Nitrosamines will form along the manufacturing of the DP. Think of that fish diagram bone from @lucas10mauriz post … Formulation, Unitary operations, excipients, water, packaging operation, materials, etc…



The risk assessment is a compilation off all possible sources and the corresponding evaluation. We know that. Because of that, what was the possible root cause on the API would not neccesarilly be the case in the finished product manufacturing process and over shelf life.

To be able to dimiss with theoretical calculations i.e., calculating the nitrite content, that no nitrosamine is above the pertinent acceptable intake, your risk evaluation should discard 1st that no other sources could contribute to the issue (e.g., it there is a drying process with air in a fluid bed dryer, the NOX in the air). If that is the case, then it is a measured risk for example to theoretically calculate NA formation and dismiss the risk based on to that.


One of the impurities of the drug substance, N-Desmethyl Diphenhydramine is a vulnerable secondary amine that needs to be accounted for. It may easily form the corresponding nitroso derivative within the drug product, during manufacturing and storage. As it has a low AI, it is not expected that its presence can be ruled out by worst-case calculation based on total nitrite conversion and confirmatory testing will be probably required.

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Totally agree with the responses so far. To be able to discard the risk in the DP you would need strong evidence, for example, that based on theoretical calculations (as conservative as possible), the maximum amount of nitrosamine potentially forming would be <10% AI. Even so, there is always the risk that you are requested to demonstrate those claims via testing


Agreed. Your ONLY path forward is confirmatory testing of aged (stability) samples using a validated method.

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what if the DP manufacturer tests these possible nitrosamines through confirmatory testing and finds nitrosamines below 10% of respective limits , in such case, Is there a need for drug substance manufactureremphasized text to go for confirmatory testing when the risk assessment doesn’t find such favorable conditions (other than sec. amine) for nitrosamine formation theoretically?