I would be very pleased if you could share your evaluation and comments on the following subject.
We request nitrosamine risk assessment studies from our raw material suppliers within the scope of drug product nitrosamine risk assessment. Suppliers, especially excipient suppliers, share the results of nitrite and nitrate analysis in the raw materials they produce. What should we consider when evaluating nitrite and nitrate levels of raw materials? What should be the maximum nitrite and nitrate levels in raw materials? What is the importance of nitrate presence in terms of nitrosamine risk?
@Elif Thanks for your question. I suggest doing a search in the community using the tag âExcipientâ so you can see all the discussions that have been happening on the particularity of Excipients in Nitrosamines challenges.
Additionally, 2 posts that illustrate the use of these reported values of Nitrites in examples of risk assessments.
Hi,
Presence of nitrates and nitrites in excipients, may potential cause of formation of nitrosamine impurities in the drug product if there is secondary / tertiary amine present in any of other component. Same can be confirmed and ruled out after testing of product.
(Addition to this, there are other factors too like acidic environment, chosen mfg. process etc.)
We cannot go by thumb rule for specific level or limits in excipients, chemistry wise needs to confirm the possibility of reaction between available nitrites / nitrates and secondary amines present in other components of drug product.
Hope this may useful.
Thank you for the useful information. I would appreciate if you can provide your thoughts my understanding below.
(1) The limit of Nitrite in finished drug is dependent on amount of excipient used, presence of other Nitrating chemicals, and the processing of finished drug.
(2) Based on 2023 IPEC questionnaire, âPresently, nitrite testing of excipients is not harmonized, and results may vary depending on the method used by different manufacturers of the same excipient. Users are encouraged to test themselves when comparing suppliersâ.
(3) In absence of limit for Nitrite in relevant USP monograph, majority of the excipient manufactures use <1ppm as a conservative limit for Nitrite.
I want to add the importance of the vulnerable amine to (1). The AIs of nitrosamines differ depending on the structure of nitrosamines.
For (3), the average of measured nitrites amounts in excipients was about 0.8 or so. But we should focus on the variety of measured values. No one cannot assure that the amounts of nitrites in your excipients are less than 1 ppm without reliable data, I think.
Thank you very much Yosukemino for your feedback. I typically receive questions like; (1) what limit of nitrite and nitrate is established by FDA? and (2) when we need to comply with those limits? I typically respond with 3 points I indicate and also add that I am not aware of any such limit set by FDA.
We as excipient manufacturer receive 2023 IPEC questionnaire from several drug manufacturers for nitrosamine contamination. In this questionnaire they seek nitrite limit <1ppm. Hence, I came up with previously mentioned response for nitrite limits. Would appreciate your expert thoughts on it. Thank you very much.
Everybody needs to understand that any limit of nitrite has to be put into the context of every scenario or case. If there is no vulnerable amine present, so you can have all the nitrite you want. If you have a vulnerable amine but does not react (NDSRIs) so it doesnât matter the nitrite content.
A blank nitrite limit does NOT make sense until is evaluated in every formulation or case. There are no cookie-cutter specifications to apply blindly.
The following discussion may help you understand the importance of nitrites in excipients, @prealbhatt.
The former is the topic for performing risk assessment by calculating the amounts of nitrites.
We should consider risk factors such as the maximum daily dose of the drug (API), the molecular weight of nitrosamines, acceptable intake of nitrosamines, the amounts of excipients used, and nitrite amounts in other excipients. Itâs the calculation of the model case, but itâs the same at confirmatory testing.
The latter is the topic related to low nitrites excipient. Some companies sell excipients with low nitrites excipients with measured values. This information is helpful for pharmaceutical companies.
In conclusion, we cannot say less than one ppm of nitrites in excipients is always enough, but the information is helpful.
In the early phase of the call for review on nitrosamines, a 1 ppm nitrite level was a little bit an ALARP point: many analytical methods to quantify accurately and reliable (cf. also NOx absorption risks) nitrite below 1 ppm were not existing yet and at the same time excipient manufacturing process capability was not optimized often to go that low. Eventually the evolving of testing methods and the improvement of manufacturing processes (fed by the increased understanding on NOx risks as discussed on this forum) makes starting to think in ppb levels of nitrite possible, especially for investigative purposes post-nitrosamine detection rather than routine controls.
Indeed, it is a focus when you need it, not something that is considered standard and very easy to achieve and in step 1 risk assessment (even for a nitroso-API where theoretically the identified amount of nitrite is the limiting reagent) you can still work/calculate with the ppm levels of nitrite as reported to you. If you identify thatâs too high to derisk (because other elements contributing to nitrosamine formation risks are also there and the NDSRI is formable under stoichiometric conditions), the state of the art analytical methodologies now offer you the choice to first test the nitrite or first the nitrosamine (whereas before showing a medicine was overall < 1 ppm of nitrite didnât say too much on its own).
Linked to the quest for low LOD/LOQ reliable nitrite testing methods:
Thank you for the detailed explanation, @ccdw . Your advanced knowledge and detailed explanations always lead us in a bright direction. I could update the information on the analytical methods of nitrite in excipients to the latest version. Itâs amazing!!
When I calculated the possible nitrosamine amount on paper from 2 ppm of nitrites in excipients, it could go over the NDSRIsâ limits easily, even though MDD was not so high. Those highly sensitive technologies and low nitrite excipients are helpful for risk assessment.
in the community using the tag âExcipientâ so you can see all the discussions that have been happening on the particularity of Excipients in Nitrosamines challenges.
