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Chiku ☆ India, 2012-01-11 09:10 (5266 d 21:36 ago) Posting: # 7896 Views: 11,842 |
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Dear all, Good morning! We are developing XR generic formulation (market US). Our formulation is bioequivalent as well as F2 value is matching in all the required dissolution mediums. The problem is we are failing in alcohol dose dumping study in 0.1 N HCl. what is the way out in this situation? wether regulatory (US FDA) will accept the dossier. Any justification can be provided? Further i read the following thread I get to understand EU's thinking but still confused about FDA's thinking. product developed is not opioid in this case. In our case F2 value is not matching few other statistical methods for dissolution calculation shows similarity. based on this can i give justification? or else reformulation is the only way out? We used eudragit and Innovator has used HPMC polymer. Thank you in anticipation! Regards Chiku:) Copypasted last two paragraphs from a follow-up post. You can edit your own posts for 24 hours; no need to post a new one. [Helmut] |
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Helmut ★★★   Vienna, Austria, 2012-01-11 16:44 (5266 d 14:02 ago) @ Chiku Posting: # 7902 Views: 10,666 |
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Dear Chiku! ❝ We are developing XR generic formulation (market US). Our formulation is bioequivalent as well as F2 value is matching in all the required dissolution mediums. ❝ The problem is we are failing in alcohol dose dumping study in 0.1 N HCl. what is the way out in this situation? wether regulatory (US FDA) will accept the dossier. Any justification can be provided? Did FDA publish a product-specific guidance? In vitro testing for alcohol induced dose dumping is not a general requirement – only in specific cases (like Oxycodone ER). ❝ I get to understand EU's thinking but still confused about FDA's thinking. product developed is not opioid in this case. See above. If there are no safety concerns I would not bother too much. ❝ In our case F2 value is not matching few other statistical methods for dissolution calculation shows similarity.  In the first sentence you said f2 ‘is matching in all the required dissolution mediums’. Do you mean: passing f2 in conventional media and failing in testing alcohol induced dose dumping?❝ […] based on this can i give justification? Alternative (multivariate) methods like Mahalanobis distance are acceptable for the FDA – if justified (don’t ask me what that means). If you look at the Oxycodone guidance you’ll find a funny statement: 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. ❝ or else reformulation is the only way out? We used eudragit and Innovator has used HPMC polymer. Only as a last resort (throwing away the successful BE study). Hypromellose is much less susceptible to alcohol than methacrylic acid / ethyl acrylate copolymer. — Dif-tor heh smusma 🖖🏼 Довге життя Україна! ![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png) Helmut Schütz ![[image]](https://static.bebac.at/img/CC by.png) The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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Chiku ☆ India, 2012-01-12 06:24 (5266 d 00:22 ago) @ Helmut Posting: # 7908 Views: 10,471 |
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Dear HS, ❝ Did FDA publish a product-specific guidance? In vitro testing for alcohol induced dose dumping is not a general requirement – only in specific cases (like Oxycodone ER). 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 . ❝ Exactly thats what i meant. ❝ 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). 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) DifferenceF2=33P.S. Hope to meet u soon @Mumbai. Regards Chiku:) |
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Helmut ★★★ Vienna, Austria, 2012-01-12 17:50 (5265 d 12:56 ago) @ Chiku Posting: # 7916 Views: 10,991 |
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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. ❝ ❝ 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 ❝ ❝ 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. — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
Ing. Helmut Schütz