Bioequivalence and Bioavailability Forum

Dear Chiku!

❝ ❝ Did FDA publish a product-specific guidance?

❝ Yes they have published.. same sentence "Please conduct comparative dissolution testing on 12 dosage units each of all strengths of the test and reference products. Specifications will be determined upon review of the application" is also repeated.

OK, so I guess you have to wait and cross you fingers. No idea how FDA will deal with your situation. If they stated the alcohol testing in the guidance obviously they have some safety concerns.

❝ ❝ Only as a last resort (throwing away the successful BE study). Hypromellose is much less susceptible to alcohol than methacrylic acid / ethyl acrylate copolymer.

❝

❝ that would be difficult and painful after investing so much efforts (also the money).

Sure. That’s why I said ‘as a last resort’.

❝ I am pasting the data here if it helps.

❝ 0.1N HCl with 40% alcohol, USP-I with sinker, 100RPM, 900mL.

❝   TIME  AVG%  AVG%(Innovator)  Difference


❝  15 MIN  15      6                9
❝  30 MIN  23     11               13
❝  45 MIN  30     14               16
❝  60 MIN  36     18               18
❝  75 MIN  42     21               21
❝  90 MIN  48     23               25

❝ 105 MIN  53     26               27

❝ 120 MIN  58     28               30

❝

❝ F2=33

Well. The difference at the early time points is not that bad. In vivo alcohol would have left the stomach in the first hour or so and also triggers gastric secretion. On the other hand it slows gastric motility. It’s a mess. Maybe (!) FDA accepts the multivariate method showing similarity, but to be honest I have some doubts since the new product shows lower values at all time points. In the best case you have to put a black box warning on the label, in the worst case you don’t get the approval.

❝ P.S. Hope to meet u soon @Mumbai.

I’ll be there. I’m sure Jean-Michel can tell you more on in vitro stuff – I’m the in vivo guy.