Degradation Products calculation

[michaelcarolus]

Hi everyone

When calculating degradation products for unknowns in a formulation that has multi actives how do you calculate the unknowns?
1. Do you calculate the unknowns as Area % or
2. Do you calcluate the unkowns with respect to the active that has the smallest area.

Thankin you in advance

Mike

[JZeszotarski]

If it is not known to which active the peak can be attributed, one needs to assume the worst case scenario and calculate it based on the active that results in the unknown peak having the largest amount. So, yes, one would use the active with the lowest response to calculate the unknown.

[HW Mueller]

We seem to have been through this many times..... how can you calculate anything if you don´t know what you have? OK, you can state what you did and then write on the pill´s label: This has x% of an unknown, the % is based on the assumtion that the response is y. Take it at your own risk as we do not know whether in reality the relative molar concentration of this (possibly highly poisonous) unknown is 95+%.
(I am getting paranoic also, being a pill swallower)

[michaelcarolus]

Thanks for the suggestions
Mike

[Albany-12303]

Could you stress the actives individually to find out which unknown belongs to what?

It seems that using the worst case scenario be calculating against the lowest conc active may cause too many problems - if the ratio of active peaks are 10:1 then a 0.1% unknown may end up being calculated as 1%!! - in which case the product may never be considered 'stable' or 'pure'.

It would be much easier to do some forced deg on the indiv actives than identify 5 or 6 unknowns!

[Alex Buske]

Michael,

i would go with albany's proposal, try to identify at least the lower conc. API degradants. We have done that, had no problems. Another possibility would be to use specific detection (i.e. fluorescence or UV-wavelengths) for the different APIs.
Hans,
No need to get paranoic. Certain criteria have to be met to get a pharmaceutical registration. While some scientific approaches (validation, stress testing, mass balance analysis) are required at the end people are rather pragmatic: You will need a specification that states a certain number for something and further on you will have to stay within this specification.
If I had an Api with a (measured) impurity of 0.2% and if that API with the impurity had been tox qualified and if the production batches showed constantly less than maybe 0.25% and if the impurity stayed within the spec during stability testing, then I would consider the whole thing as save, regardless wether the measured 0.2% corresponds to 0.02% or 2% in reality.

Alex

[HW Mueller]

Most likely that´s correct for most cases, but I am beginning to wonder whether some of the disasters, like the one a few weeks ago (a London hospital tested a medication from a German company ~6 people almost died), is due to impurities rather than the Api.
On the other hand, in nuclear medicine, even co-reagents like Sn++, EDTA analogs, N-bromosuccinimide, etc. etc. , are co-injected routinely (worldwide) in patients. It´s usually a "once in a lifetime" thing, and the amounts are small, though in much higher concentration than the radioactive radiopharmaceutical. But medications for chronic illness???

[michaelcarolus]

Hi everyone

I've managed to do some force degradation studies on my API's and can now attribute some of the "unknowns" to the relevant API. The % specified unknowns will now be calculated w.r.t the relevant API. One thing that we've learnt from this exercise is that the more you know about your degradant/unknowns the easier it becomes to report.

Thanks again