Bioequivalence and Bioavailability Forum

Hi Dr_Dan

❝ How can I show similarity for a formulation of a BCS class IV substance if dissolution testing shows that at pH x and pH y only 5 to 10% is dissolved from a formulation within 45 min.?

Not only Class IV but same holds true for class II drugs as well (typical example is Phenytoin, insoluble between pH 2-8) and EMA wants f2 calculations (for lower strengths) at Ph 1.2, 4/5 and 6.8.

❝ The BE-Guideline does not describe this situation and f2 value calculation is not possible. Any idea?

Condition 1. If you are looking for Biowaiver of lower strengths:
for example: BE strength is 400 mg and lowest strength is 100, you can use multiple tablets of 100 mg (4) to show similarity (to show that differences are due to the solubility of the API not formulation related)

Condition 2: If BE strength is a single strength and you want to show the similarity in dissolution profile.
a) Present whatever release data is with you 5 to 10% is dissolved from a formulation within 45 min (We have tried this with couple of product and later in day 70 query on EMA asked as to use the minimum amount of surfactant to get >80% release and then show the similarity. We had all the data generated at our end and we submitted along with complete solubility studies (done using various surfactants at various concentrations) and with minor suggestions related to the Q point, Products got approved.

b) Use minimum amount of surfactant up front and provide a proper dissolution method selection report.

c) Even if the F2 is not matching, submit the data and justify the reason behind the same. Guidance clearly says that “In the event that the results of comparative in vitro dissolution of the biobatches do not reflect bioequivalence as demonstrated in vivo the latter prevails. However, possible reasons for the discrepancy should be addressed and justified.”


Dear Nobody

If higher variability is a constrain you can always use Weibull method or MSD. EMA accept that.