Oral Liquid Formulations

Hi,

Are there any approved oral liquid medications with nitrosamines / NDSRIs listed by agencies? Did anyone perform a risk assessment on oral liquids? Are there any specific guidance’s / items that need to be specifically focused for liquid oral formulations?

I appreciate your help.

Thank you.

The principles are the same for all dosage forms and the same guidance documents apply. Any potential sources of contamination with nitrosamines should be identified and, if a risk is determined, confirmatory test should be performed on fresh and stability samples. Based on the results, a control strategy may be required, including specifications, analytical procedures and acceptance criteria.
For solutions, the conversion rates of nitrite/vulnerable nitrogen containing structures are higher than for solid dosage forms. Water is a source of nitrite, and this should be controlled; lower pHs of the product increase the risk of nitrosation if vulnerable structures are present.
Additionally, contaminations through leaching from the primary container closure systems should also be assessed.

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Thank you for the information. Are there any approved liquid formulations with Nitrosamines limits listed?

The nitrosamine limit does not change with the dosage format - so a category 3 nitrosamine has a limit of 400ng/day whether it is in a tablet or a liquid (or any other dose format).

And this brings with it additional challenges for working with liquids. A tablet may weigh 500mg to deliver a dose. The same dose by liquid could be 20ml (around 22g). So any analytical method needs to potentially be 40 times more sensitive when working with liquids compared to tablets in theory. Sample preparation is everything.

You may also have many more potential sources of nitrite, as liquid formulations can be more complex than tablets, and also more potential interference in your analysis from all the additional excipients.

Add in, as mentioned in a previous response, that the rate of formation of nitrosamines is theoretically much faster in solution and liquid formulations quickly become quite “interesting”.

The overall process and daily limits are no different for liquids compared to any other dosage format though.

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Thank you Mark. Agreed, the additional challenges will be dose / sample prep and sensitivity.