Hi everyone, I am a newbie to your forum and badly in need of some sound advice. I am currently writting a submission for the approval of a drug/device combination. The problem I have run into is that after real time ageing the drug has shown slight degradation such that it no longer conforms to USP/EP monographs. This degradation in my opinion is not significant, the USP/EP allows 2.5 % impurities my results show 3.5 %. Is this likely to be a showstopper or can I rationalise my results. Help Please !

I'm no expert in combos, but I'll offer a couple of thoughts:

1. Does the drug similarly degrade in other environments? Or, is it interacting in some deleterious manner with the device-environment? If the latter, I'd think that would point toward a need for a more complete engineering understanding of the problem, and maybe a critical need for re-engineering of those product aspects that are responsible for the chemical interaction.

2. You're seeing 3.5% impurities at X time, with 2.5% as the limit. I don't actually know how the reg is structured, but I'm guessing that your amount of real time aging is related to the product life you want to declare. What about settling for a shorter product life, related to Y time at which age-deterioration-related impurities = 2.499%?

let me share my experience of handling similar scenarios [on filing drug products]

my thoughts
1. first things first, we must meet pharmacopoeia requirements.If its a generic product,then its even tougher, cause you have to file a comparison of profiles with innovator/RLD...etc., One option is available, but thats tedious, i.e., to justify through proper tox.studies and as well to identify how/what influences the impurity to be generated/increase...[in short characterize it.]

2. stability data usually "helps to support"/'related to" your composition of drug product and process, selection of packing, storage conditions and shelf life. Hope you have reviewed them comprehensively, but just thought of mentioning that, you have to view the impurity results which are getting in the context of the above areas indicated. Is the analytical method validated?

following are few references on approaches towards evaluations of impurities ...
ICH : WWW.ICH.ORG (http://WWW.ICH.ORG) [http://www.ich.org/cache/compo/276-254-1.html] (http://www.ich.org/cache/compo/276-254-1.html%5D)
Q3A(R2): Impurities in New Drug Substances (Revised Guideline)
Q3B(R2): Impurities in New Drug Products (Revised Guideline)

FDA : Question Based Review [refer to the impurities section of the document]
http://www.fda.gov/cder/ogd/QbR.htm

http://www.fda.gov/cder/ogd/QbR/QbR%20Frequently%20Asked%20Questions%20June2007.pdf


i think above references are relevant for device+drug combination as well.

hope this helps.
thanks