Chromatography Forum

Hi,

In a couple of months a new resolution (i.e. law) will be in force in Brazil (RDC no 58). It is dealing with requirements for forced degradation studies of drug products. What is different from other guidelines is that it requires forced degradation by metal ions. This I have not seen anywhere else.

I have tried to get some answers on how they think this should be studied. The only answer so far is that I should test metal ions that the product is exposed to during manufacturing. But things like concentrations and what oxidation number the ion should have is still unknown.

Just wondering if someone else is working on this?
(not much HPLC here, but I didn't know where to put it)

Interesting, thanks for the update on this. I don't follow the Brazilian legislature.

Anyway, I've not performed forced degradation studies using metal ions but the few times I've come across it in literature, it seems the references are to Fe3+, Ni2+ and Cu2+. If I come across the concentrations, I'll update this post. I would think the concentration of the ions is not important since the objective should still be the same as with peroxide and other forced degradation parameters: you want to see anywhere between 5-20% degradation. You'll probably need to do some pre-validation studies to determine the proper concentration and time in order to achieve this level of degradation.

Thank you for your reply!

This resolution is of course only relevant if you sell drug product in Brazil, which my company is doing. It is also only valid for small molecules, not peptides and proteins.

I think your suggestion for ions looks good. I have chromium on my list as well, not sure what salt that would be best to use? I agree that I need to do prestudies here. The molecule that I will test first is actually an antioxidant, so I expect the reaction to be very fast.

I found two different articles in my library that discussed oxidation with metal ions. One mentioned concentrations of 100 ppm. The other mentioned concentrations of 0.05 mM. Interestingly, one mentioned the three metals and their oxidation numbers I originally posted. The other mentioned Fe2+, though that could be a typo since earlier in the document they stated Fe3+. You also had Cr on your list.

This could quickly become a complicated and large forced degradation study when you also consider you still need acid, base, peroxide, heat, etc. Were I in your shoes I would find a regulatory person who knows the landscape in Brazil and inquire as to how many metals are considered critical (and perhaps which ones) are considered critical to examine. They may not have an answer if the legislation is new but perhaps the government has some guidance. If not, maybe you need a meeting with their FDA-equivalent to get some guidance.

Thanks again!

We have asked the authority but they seem to know just as much as we do... I guess this is a "tick-box" exercise for them (it has to be in the documentation, no matter how relevant).

The good thing is that we already have the forced degradation data in place for all other conditions, so I only need to do the metals. The bad thing is that this is a "must pass" type of study. I don't like running studies that has only one possible outcome.

Your suggestion for concentrations sounds like a good starting point. I will let you know how it goes

Hi Mattias

I found this reference: http://www.intechopen.com/download/pdf/23726. In the oxidation studies they put 10 mg/2 ml of the drug in wáter with 100 ppm of Fe+3; Ni +2 and Cu+2. Saturated with bubbling oxigen in amber flasks during 1 to 3 days.
I suppose at ambient temp. Its a start.

Saludos desde Argentina, colega.

Fernando