Dear community members, I have been asked to participate in a panel discussion where I wish to bring perspectives on the NDSRIs challenges. I want your input on 3 specific areas, and I intend to summarize and echo the voice of our community in that panel.
What are the most prominent risk factors from API, Excipients, and Ingredients in the formation of NDSRIs? Do we have the tools and clarity to address such risk factors?
When it comes to Safety, What is the single most significant challenges and consideration for assessing safety of NDSRIs? What’s the ideal scenario to mitigate that challenge?
We know that reformulation of the finished product is on the table to mitigate nitrosamines impurities; however, what would be the most significant impact of such a strategy? Are factoring bioavailability or bioequivalence implications?
I would appreciate your input, thoughts, and opinions. Remember you can always reply anonymously if you prefer
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What are the most prominent risk factors from API, Excipients, and Ingredients in the formation of NDSRIs? Do we have the tools and clarity to address such risk factors?
Having worked as a consultant for nitrosamines, it is generally observed that nitrosamines (NDSRIs ) are lower in APIs than in drug products. Also, it is relatively easier to control the level of NDSRIs in API. The primary concern is the nitrite/nitrate levels in excipients lead to observing higher levels of NDSRIs in drug products.
When it comes to Safety, What are the single most significant challenges and considerations for assessing the safety of NDSRIs? What’s the ideal scenario to mitigate that challenge?
An ideal scenario would experimentally determine the TD50 value of NDSRIs. At present, the single most challenging is the timeline because regulators are establishing acceptable intake values for NDSRIs arbitrarily based on conservative statistical data. As a result, MAHs (especially brands) are in a position to spend time defending a realistic AI limit rather than collaborating with experts to establish an AI limit for NDSRIs (experimentally/robust prediction tools).
We know that reformulation of the finished product is on the table to mitigate nitrosamines impurities; however, what would be the most significant impact of such a strategy? Are factoring bioavailability or bioequivalence implications?
I can’t think of anything other than a reformulation to mitigate the risk of NDSRIs, if API is a precursor.
1. What are the most prominent risk factors from API, Excipients, and Ingredients in the formation of NDSRIs? Do we have the tools and clarity to address such risk factors?
Levels of residual Nitrites/Nitrates in API, Excipients and in water (if used in process). Favorable conditions to form NSDRI such as formulation pH and antioxidant levels. How much nitrite/nitrate (in ppm) will contribute how much NSDRI (in ppm), in reality?
Tools required
Controlling nitrites/Nitrates at lowest possible level.
Suitable analytical method for the above.
When it comes to Safety, What is the single most significant challenges and consideration for assessing safety of NDSRIs? What’s the ideal scenario to mitigate that challenge?
Establishing AI values based on toxicity
We know that reformulation of the finished product is on the table to mitigate nitrosamines impurities; however, what would be the most significant impact of such a strategy? Are factoring bioavailability or bio equivalence implications?
YES Also, running the stability for entire shelf life.
@vsnu999 that’s fantastic. Let me ask you a follow-up question. When it comes to #2 ‘Safety’. What’s the ideal scenario? Having clearly defined limits by the regulatory agency, knowing that harmonization has been a challenge from day 1. Or, an accepted pathway to limits definition (Ex: ICH M7), with a clear derisk mechanism for any emerging NDSRI?
Thanks @krishmnt for sharing those insights. Let me asked about #3, How about the impact of all the rework to a new formulation (ex: dissolution methods, IVIVC, methods transfer, etc) specially for those already in the market products?
I would like to make a better revision of the documents to provide more specific comments. I consider that the main sources are drugs and excipients that, during their synthesis, used any of the more known nitrosating agents and conditions to favour them. The forms to control can widely vary depending on many factors, but maybe some can be identified to standardize them, but is necessary to revise all data.
What are the most prominent risk factors from API, Excipients, and Ingredients in the formation of NDSRIs? Do we have the tools and clarity to address such risk factors?
→ Would the API/Excipients/Ingredients manufacturer be willing to disclose the details of their manufacture to show whether their processes used secondary and tertiary amines, or nitrites and nitrates. At the same time, API/Excipients/Ingredients manufacturers also need to ask their suppliers whether the raw materials also use secondary and tertiary amines, or nitrite and nitrate in the manufacture of API/Excipients/Ingredients. In addition to the presence or absence of Nitrosamine Impurity, the final assessment report should also indicate the possible residual amines, nitrite and nitrate.
When it comes to Safety, What is the single most significant challenges and consideration for assessing safety of NDSRIs?
→ The acceptance intake of NDSRIs.
What’s the ideal scenario to mitigate that challenge?
→ Decide the priority of evaluating nitrosamine impurities in the drug product based on the amount of the drug product used, and establish the daily acceptable intake of unknown nitrosamine impurities according to the priority and require the pharmaceutical industry to provide the corresponding evaluation results and reports of nitrosamine impurities.
What are the most prominent risk factors from API, Excipients, and Ingredients in the formation of NDSRIs? Do we have the tools and clarity to address such risk factors?
~Based on my experience: the potential risk factor in API, Intermediate, KSM and Raw materials raises If a compound has secondary amine and exists as HCl , Mesylate, HBr, tartrate and succinate… etc. i.e acid salts.
~The above compounds doesn’t need impact of any external sources to convert to Nitroso compounds, even atmospheric air itself will make the compound convert to NDSRI.
Hello @siva.
Your comment about the salts potentially forming novel nitrosamines on their own just in the presence of air has caught my attention.
I don’t think I have seen anything elsewhere on this, though I have only been working on nitrosamines full time for about 2 months. Do you have any references for this at all?
Many thanks.
Hai Marks,
Yes, the examples are Fluoxetine hydrochloride and Duloxetine hydrochloride and research is going on and I expect many more examples in near future.
