AI Limit for Topical Formulations (Ointments and Gel)

Dear members

Can any one suggest , how to calculate the AI for topical formulation. Is it the same approach by considering the Maximum daily dose?. Also how is it applied when combination of drugs are used in topical formulation.

There are several threads on the forum about this topic. Although I don’t know if there is any update to the criteria. For example:

It is a topic that also interests me. Both for creams and shampoos… The theory as far as I know is that the authority is going to apply the same criteria as other formulations. You must justify any deviation from that criterion to them.

Thanks IreneNS for the thread,will go through.

Ideally what we need from the authorities is an update to the CPCA approach to include a risk (reduction) factor for different routes of administration. Maybe a factor to be applied for topical applications to unbroken skin could be applied to the AI limit for other routes of administration?
Still one step at a time, CPCA is a major step forwards.

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As of now, unless experimental data is available and I expect will need to be provided by the sponsors, there is no route of administration differences. For example a biodermal assay will be needed for the specific nitrosamine to maybe argue the rate of absorption, etc.

To put correction factors, similar to what we have for PDEs for other compounds, quite a bit of data will be needed I suppose.


This may be a tricky question and generally regulatory bodies (e.g FDA/USP, EMA, etc) may have differing opinions when it comes to route- or site-of-action specific exposure to compounds of interest (either e.g leachables, impurities, degradants, etc.) and there applicable limits.

Just to highlight this, here the just recently FDA published draft guidance: " Quality Considerations for Topical Ophthalmic Drug Products, Oct 2023" (Quality Considerations for Topical Ophthalmic Drug Products | FDA). See Chapter IV for the FDA´s rationale “systemic vs ocular” effect.

But this is of course an “older discussion stemming from Genotox Impurities” which would also tangent the nitrosamines.