Hello Everyone,
I am seeking clarification on the conditions under which nitrosamine analysis can be omitted from product specifications. For instance, API suppliers state that since “nitrosamine analysis was performed post-production and results were below 10%, the test is being removed from the specification.” However, I do not believe this approach is acceptable.
The EMA guideline states: “Only if the amount of nitrosamine present is consistently below 10% of the acceptable limit based on AI in the API or in the finished product, then a test for the nitrosamine could be omitted from the specification.”
Regarding both general nitrosamines (NDMA, NDEA, etc.) and NDSRIs, under which specific circumstances can API suppliers and pharmaceutical companies omit nitrosamine testing from their specifications?
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When results are found to be below 10% at the initial post-production stage?
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When results remain below 10% at the end of the shelf life?
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When results remain below 10% following a 6-month stability analysis at 40°C / 75% RH?
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Other?
The above relates to the strategy that should be implemented after R&D pilot-scale production
based on our experience in finished product, NAs and NDSRIs should be below 10% till the end of shelf life to conclude omission. Similarly <30% to conclude period testing etc.
i am not sure what authorities accept during submission, whilst the possibility to have data till the end of shelflife is limited. perhaps this is a case by case decision based on assessors’ feedback. for instance, if results are <10% up to 6M you could claim omission from specs but at the same time you should monitor the impurity with an x frequency with a notification to authorities. In case results increase at >10% then you should revise specs.
i would also be interested in further feedback based on other colleagues’ experience.
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Dear Hasan,
Just complementing what Eleni said.
From experience, the exclusion of the test should be evaluated considering the nitrosamine formation. Seems obviously but…., if the nitrosamine will only be formed during synthesis so testing the nitrosamine on final API and proving the absence (<10% - with special attention on LOD) should be fine. Now if the nitrosamine is formed by amine impurity (process related or degradation) that might be on the API I usually request the manufacturer to test it on stability as well.
So…
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When results are found to be below 10% at the initial post-production stage?**
On API release, If the nitrosamine is an impurity with a possibility to be formed only during synthesis. Assessing that this nitrosamine is consistently removed from the process is enough to exclude it on specification. (now I would like to known from colleagues if this strategy has been reallly proved safe and been properly adressed by API manufacturers)…
When results remain below 10% at the end of the shelf life?
The best practice is, when nitrosamines is a degradation product, or and process related impurity present on API impurity profile, it should be evaluated till the end of the shelf life.
When results remain below 10% following a 6-month stability analysis at 40°C / 75% RH?
Accelerated stability is a good indicator, and it might be accepted in order to provide information while the long term stability is still running.
As far as I know, testing on API shelflife is optional and I haven’t seen agencies questioning it. Mainly because the responsibility will end up on drug product owner. You as Product owner, can maintain the nitrosamine on your API specification if you identify it as a critical attribute (and if you evaluate that it is a real risk). You should evaluate if the impurities of your API might lead to nitrosamine formation and the strategies of control…so one thing leads to another. From experience, what I have as practice is to ensure that API is free from the possibility of nitrosamine formation when it’s delivered to the Drug product production line, so if we identify the risk of nitrosamine formation during API stability the results on API stability are mandatory, (usually T0 and T final are enough).
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Keep in mind that with any answer, major changes, like ones that necessitate process validation, warrant reevaluation.
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