I am not aware whether this topic has been raised previously, but let me share with you a concern of mine.
We are under evaluation of a new supplier. We observe that they use AC in the final synthetic step. In literature it is discussed that AC can catalyze nitrosamine formation (but the articles are more environment-oriented).
Although they have not reported high nitrosamine values in finished API, we observe high nitrosamine values in finished product.
Since we keep all rest factors same (manufacturing process, excipients, packaging etc), do you trust that we may notice high nitrosamine levels in FP especially considering that the yield of nitrosamine formation may be much higher with nitrite (trace nitrite levels found in excipients)?
If all the above is true, could you please recommend any alternative to AC?
Hi Eleni,
Based on the literature, Active Carbon is not a probable risk factor in generating Nitrosamines, when used in the purification steps of the APIs.
The nitrosamine formation in FP cannot be related to the use of active carbon in the API synthesis.
Hi Eleni,
usually AC is used for the purification of the organic compounds and from organic chemistry point of view is considered very difficult to be present as a residual or impurity in the ‘‘pure’’ compound.
May i ask you, the high levels of nitrosamine(s) you noticed in the final product are related to a NDSRIs or to nitrosamine(s) which are not related with the API?
kind regards
Hi Christos!
hope you are doing well! thank you for your response!
we are talking about an NDSRI found in API and in FP.
As for AC, since I am not so familiar with chemistry point of view, your feedback is appreciated. I am just wondering whether it could be potentially act in a way that enhances the yield of NDSRI in API and subsequently in API during storage.
Mostly, because rest reagents/ solvents are pretty much common among the two suppliers.
If the route of synthesis is not the same, or even if it is the same, the source of reagents/solvents can lead to different levels of nitrites, which consequentially can lead to different levels of NDSRI.
If AC is a possible concern, try testing both API, same batch, prior and after AC
Previous topic “Nitrosamines Risk in Pharmaceutical Waters” may be useful in the discussion. Maybe, the paper “N-Nitrosamines Formation from Secondary Amines by Nitrogen
Fixation on the Surface of Activated Carbon” can help too.
Hi
Coming back since the recently published EFPIA vs3.0 indicate that charcoal - among other solid materials used during DS synthesis - can contain low levels (ppm) of nitrogating agents (Guidance 1 - additional considerations for potential nitrosation risks).
There is indeed a distinction to be made to the intrinsic risk linked to activated carbon itself (in principle independent of origin, though pore size can vary) (“catalyst” for nitrosation as described in literature and cited discussions above (Padhye 2010 and Padhye 2011)) Nitrosamines Risk in Pharmaceutical Waters - Risk Assessment Strategy / Tools & Technology - Nitrosamines Exchange (usp.org)
and cross-contamination risks which can vary across suppliers as their processes for treating activated carbon can differ (questionnaires are needed, but are also useful to rule out this scenario - whereas the catalyst role is more intrinsic (though pH plays a role)). It is known that nitric acid washes to activated carbon can be done by some suppliers for washing away impurities and modulating physical properties of the activated carbon, though it is notstandard (and other acids can be considered as well). It will really dependent on why you need activated carbon in the process (what needs to be removed? if it is heavy metal removal: already more likely nitric acid pretreatment) and thus what type of AC you need, impacting how it is pretreated by the AC supplier if tailored AC selection was done.
When activated carbon treatment is late stage, vulnerable amines are present and targeted nitrosamines are well-soluble in the used solvent and unlikely to be fully retained on the activated carbon, then looking deeper into activated carbon impact on the risk is not a bad idea. Practical limitation could be the collaboration between AC, API and DP supplier this could require to maximize expertise and exchange.
API suppliers dealing with vulnerable amines and selecting new sources of AC (especially when needing to select nitric acid washed sources) should probably consider nitrosamine impact already in the design phase and conduct some stress testing with the vulnerable amine in relevant solvents and pH to check its compatibility with the AC from a nitrosamine formation perspective.
thank you very much for such a detailed response and for the shared documentation.
currently, we are trying to figure out the reason why they introduce AC in late synthesis step and investigate whether AC actually influences levels of the nitrosamine in final API.
let’s see
Once more, thank you all for taking some time assisting me on the present task Much appreciated! Wonderful community
