Nitrosamine due to preservative in ophthalmic

In case of ophthalmic formulations, the amount of preservative is too low. Even the MDD of API is quite low. In such cases, wherein the preservative amount is lower than the specification limits, is it necessary to perform the nitrosamine testing related to the preservative and preservative degradant impurities?
For eg: Based on the API MDD of 0.2mg and AI value of 18ng/day for Nitrosamine impurity, the specification limit for nitrosamine impurity comes around 90ppm. Now, the preservative instilled in the eye based on the MDD of formulation is 10ppm per day. In such case, wherein the preservative amount instilled is lower than the specification limit of Nitrosamine impurity what will be the mitigation strategy?


Hello Chirag,

Considering conservative limit of 18 ng/day or specific AI could be an alternative strategy when nitrosamines limit is more than excipient concentration.

For confirmation testing, 90 ppm could be the limit of Nitrosamines based on MDD of 0.2 mg. Stick to it since given in guidelines. However, You should consider performing additional spiking at LoQ (at or below 18 ng/g). Prove that the Nitrosamines are less than LoQ. This way you don’t need to spike at 90 ppm which is not realistic.

I have submitted such risk assessment with confirmation data to EMA for one of such product. It was well accepted without any deficiency.

Thank you

If I understood correctly the issue is that the preservative itself is a potential source of nitrosamine (i.e. the drug substance and other excipients are not).
Next, the amount of preservative present is below the AI for the corresponding nitrosamine.

If that is the situation, then even in the preservative was actually pure nitrosamine you would still be below AI in the product.

Seems to me that all you need to do is present that case as your justification for no risk and no testing.

Interestingly you see a risk in preservatives - I have only found one (very rarely used) that could be a potential risk.

If I have misunderstood the case then just ignore me :grinning:

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you understood correctly. can you list the name of the preservative wherein you found the nitrosamine risk.