Sure, I also think it is a great idea, but belonging to the primary packaging suppliers, I cannot speak for the excipient suppliers. If we have any excipient suppliers in this group, I hope they would be available for this exchange.
I completely agree with you about the difficulties of removing nitrites from excipients and I can assure you that as finished dosage experts we are looking into a number of ways of reducing risk, including nitrite scavenging and process parameters. However, we have recently found quite surprising levels of nitrite in some excipients - in excess of 4000 ppb.
What would be very helpful from excipient manufacturers would be to have some hard data. Is it too much to ask for nitrite content to be added to excipient specifications? After all you are already doing such things as elemental impurities.
So far we have found it almost impossible to obtain any nitrite/nitrate data from excipient manufacturers.
From my side too I can say that excipients that makes no sense to have nitrites have come possitive. Quite interesting actually.
I also have seen quite difficult to obtain information on nitrites from excipients and adding into the specification without knowing where the nitrite source comes from would result in a lot of OOS (what limit should be set then? Lot of questions there). Nevertheless, we have received that information in some cases.
Some manufacturers have hundreds of excipients into their portfolio, even if the cost of testing nitrite I have seen seems ok, for hundreds it could be a problem. However, that is where it could be of use from the excipients manufacturers to evaluate what excipients makes sense to be tested and have some raw data into it. Even if the responsability is into the MAH, how can we set up also how much nitrite scavengers, etc if at first we dont know have much nitrite we expect, etc etc.
There is quite a lot of things to analize that should be said as now as part of finding a common medium point between every stakeholder.
I am glad your company is addressing the issue. Unfortunately we are getting responses such as “we do not deliberately add nitrosamines to our product” from certain suppliers.
This issue will separate the good suppliers from the bad and is a real business opportunity in my opinion.
The main problem at this time is really the lack of available knowledge regarding nitrite content and without that we cannot really address their real risk contribution to nitrosamine content in finished dosage forms.
@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.
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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).
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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.
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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
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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
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@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.
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zero nitrosamine is not inconsistent with trace nitrite. Nitrate irrelevant
EFPIA workflow does not include risk from nitrite in excipients. You can answer No to nitrosamine but still have nitrite
Have you contacted IPEC?
@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
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Hi there! We’re trying to apply the highest level of nitrosamine which could form from a daily dose according to the calculation below:
Can someone explain why the calculation considers the ratio between the molecular weight of nitrosamine/molecular weight of nitrite?
I believe @Lance can guide us on understanding the approach showcased above in connection with EFPIA’s workflow. Thx
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