Bioequivalence and Bioavailability Forum

Dear All,

Hope somebody can give his/her oppinion about fulfillmet of proportional composition condition for a generic fixed combination in order to biowaive the lower strenght

                        Higher strength       Lower strength
Active substance A            20 mg             10 mg
Active substance B            20 mg             20 mg
Excipients                   400 mg            400 mg

We are planning to perform bioequivalence with the higher strenght and request for biowaiver for the lower but according to EMA guideline:

The conditions regarding proportional composition should be fulfilled for all active substances of fixed combinations
and
When considering the amount of each active substance in a fixed combination the other active substance(s) can be considered as excipients.

How should this be interpreted?

In this example when looking to substance A (substance B considered as an excipient), I clearly see that proportional composition condition is fulfilled (active substance is less than 5%). But what about looking substance B? Even being also under 5 % it could be interpreted that proportional composition condition is not fulfilled strictely speaking since one excipient (substance A) is not in same amount in both formulations. If they interprete in this way, biowaiver would be impossible if active substance are in different amounts like in this example.

Could anybody, as per your experience, let me know how EMA regulatory authorities interprete this?

Thanks in advance,