@Ejtocce I believe you raised a fair point, We do know of excipient suppliers like your organization who are working closely with their customers to attend the nitrosamine challenges. I also agree that blanket nitrate content specification is a major analytical take and not always necessary. The way to define that is through risk assessment. I applaud your organization’s efforts and commitment to your customers.
A common goal of the community is to share best practices, so I will welcome learning more about the approaches you and your team have taken to support your customers. Moreover, What have been those lessons learned? Is there a challenge that this community could help overcome?
Assuming all this Nitrate-related information is shared and provided, I cannot help wondering are we ready to feed this information into the risk assessment strategy? Do we have a standardized approach to do so consistently?
As @GENERAPHARM pointed out, it’s a common observation in public forums that users received a statement letter or checklist from their supplier indicating ‘There is no nitrosamine in our products’. That just makes harder the risk assessment exercise.
From the chemistry point of view, It can not be denied either that a high level of Nitrate does not represent a high risk on its own until first, there is a conversation and solubilization of the acid species and second become in contact with the secondary amine at the right pH conditions. It’s only when becomes a true risk.
We also are aware of organizations like Lhasa working their Excipient database collecting Nitrate content information to help organizations with their risk assessment. Perhaps @David can help us coordinate a session to understand more the scope and reach of this work by Lhasa.
Hi @Naiffer_Host , we can reach out to the members of the nitrites in excipients consortium to see if such a presentation can be arranged; in the interim, there is information available here: Nitrites in Excipients , and it was indeed briefly mentioned not ten minutes ago as I type at the second session of the PhRMA nitrosamine workshop (slides will apparently be distributed to attendees at the end of the workshop).
We recently received a declaration of “neither nitrosamine impurities nor nitrite in the product under EMA/FDA guidances” from our excipient supplier. Though it looks to contain enough information for assessment, details are not clear. If secondary amine sources are included in API, we will ask the supplier for further information. As pointed out in this thread, it is impossible to obtain the measured value of nitrite in all excipients from suppliers. To solve this problem, communication is important. Depending on the risk of nitrosamine contamination, we can accept those declarations or ask suppliers for further information.
Even though in manufacturing process there is no potential for Nitrite in excipients but quality of water, environmental condition and cross contamination can be potential source. So unless we have trend data from supplier , difficult to believe just based on manufacturing process.
Also limit of Nitrite in particular excipient should be based on percentage contribution of that excipient in the formulation and acceptable daily intake of specified nitrosamine in drug product.
Many excipients supplier are now providing Nitrite and Nitrate data but do not want to include in excipient specification as control citing compliance to pharmacopeial monograph and same supply to most of companies. Excipient vendor provide no guarantee for consistence supply with respect to Nitrite level
Industry through an initiative overseen by Lhasa are compiling a database in relation to nitrite levels in excipients. Please see the following attached link for more information
@Yosukemino, thanks for your contribution.
Do you have any insights why do not consider the quantity of precursor amine present in the API for the nitrate calculation, instead of considering the NDMA quantity? With the information of which limit the precursor amine is being controlled in the final API, there is a possibility that this potential precursor amine is being controlled below the acceptable intake, therefore, the calculation of potential nitrosamine presence would be based on the quantity of amine present and not the nitrosamine under investigation.
Thank you for asking me, @letsfco. It’s a good question. I intended the case of API with the structure of the vulnerable amine. As pointed out in another thread, lots of APIs with the structure of the secondary amine are on the market. Besides, some excipients with the structure of the amine are considered the risk. The amount of nitrite in DP is very important in these cases.
And I agree with your thoughts. Considering the case of Metformin, an impurity with the structure of vulnerable amine will also be a risk. Then control of the amount of the amine is useful. The EFPIA points out in DP workflow that experimental data from model studies suggest that amine impurities at ICH Q3A and Q3B identification limits are not considered a risk for nitrosation with trace nitrite. If there are no possible amine sources, the risk of nitrosamine contamination is negligible.
In terms of excipients the problem is not nitrosamines but nitrite. Perhaps we should should label the problem as such. Nitrate is irrelevant to discussion as nitrates cannot nitrosate susceptible APIs and are not normally reducible to nitrites.
You cannot assign zero risk due to either natural origin or nitrogen content. MCC is natural origin and nominally nitrogen free. However it may contain traces of nitrite which may form nitroso derivatives of susceptible APIs.
@fernandaw@David Lot of interest on the topic of excipients. Do you think we could have a conversation to learn insights from the Excipient Database on Nitrites content, any trends to report?
I’m sure a first read out of trends can be quite useful to the community. Thx
