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Obinoscopy ★ USA, 2018-04-20 10:09 (2344 d 02:39 ago) Posting: # 18704 Views: 34,737 |
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Dear All, I have a question concerning the criterion for classification of a pharmaceutical product as Class III. Some text would say there are two criteria namely: High Solubility and Low Permeability. However some other text would add a third criterion: Very Rapid Dissolution. Which is correct? If the later is correct, then where do we classify a product with High Solubility, Low Permeability and Rapid Dissolution (ie 85% of the API does not go into solution within 15 minutes but will within 30 minutes or even beyond)? Similarly, for BCS class I, must all products under this class be Rapidly Dissolving? If so, then how do we classify a product that's Highly Soluble, Highly Permeable and Moderately Dissolving (85% of API dissolves beyond 30 minutes across all physiologic pH. Regards — Scopy |
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Helmut ★★★   Vienna, Austria, 2018-04-20 14:15 (2343 d 22:33 ago) @ Obinoscopy Posting: # 18707 Views: 33,685 |
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Hi Scopy, maybe you are mixing something up. BCS of the drug and applicability of BCS-based biowaivers of the drug product. Classes1 of the drug:
For details see the FDA’s Biowaiver Guidance and Appendix III of the EMA’s BE Guideline.
— 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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Obinoscopy ★ USA, 2018-04-20 18:06 (2343 d 18:42 ago) @ Helmut Posting: # 18710 Views: 33,500 |
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Dear Helmut, Thanks for this clarification. I was actually leaning towards your explanation. Wanted to validate my thoughts. — Scopy |
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The Outlaw Torn ★ Europe, 2018-06-21 11:48 (2282 d 01:00 ago) @ Helmut Posting: # 18937 Views: 32,922 |
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Hi there Helmut (and anyone else who wishes to help me out), Long time no talk. I hope all is well. Regarding the in vitro dissolution requirement for BCS-based biowaivers. Is this needed for aqueous solutions (i.e. syrups)? I can't seem to find any information on aqueous solutions and the BCS. I did a quick search of the forum for BCS, but couldn't find what I was looking for (some guidance on how to proceed with a BCS-based submission of a syrup). Does anyone know of a good source of information on all that needs to be addressed (proven, etc) in a BCS-based biowaiver justification? By "all" I mean in addition to what Helmut has outlined above and what the guidelines describe, because providing exactly what the guideline asks for is never enough, it seems. Or is there no BCS option for oral solutions (not a solid dosage form). I thank y'all in advance. |
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nobody nothing 2018-06-21 12:33 (2282 d 00:14 ago) @ The Outlaw Torn Posting: # 18938 Views: 32,937 |
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If both (T and R) are solutions (not suspensions) and exhibit no excipients influencing absorption, no need for BE (or BCS biowaiver), in my opinion. OT: How to get this cool little EU-flag in the "latest posts" overview on the forum? Do you have an EU-IP or how does this work? — Kindest regards, nobody |
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The Outlaw Torn ★ Europe, 2018-06-21 14:11 (2281 d 22:37 ago) @ nobody Posting: # 18939 Views: 33,038 |
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Thanks for the response. Agreed if the situation was as you described. Unfortunately, R (syrup) is discontinued. Tablets are available (API is BCS I), but we are exploring BCS-based biowavers for this product and we're also trying to get familiar with BCS-based biowaiver needs in case we want to go that route with other products too. Not sure about the flag thing (I can't see any flags); but I requested an "Europe" designation a few years ago to remain incognito in order to be more open on BEBAC. And, yes, I actually am in Europe. |
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Helmut ★★★ Vienna, Austria, 2018-06-21 14:21 (2281 d 22:27 ago) @ nobody Posting: # 18940 Views: 33,001 |
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Γειά σου κανείς & Outlaw Torn, ❝ If both (T and R) are solutions (not suspensions) and exhibit no excipients influencing absorption, no need for BE (or BCS biowaiver), in my opinion. I agree. Sometimes the API tastes terrible (e.g., bitter) and a lot of excipients are added to mask it. Mannitol is not unusual (as a sweetener and to increase viscosity). Then you would be out of the game ⇒ in vivo study. If not, dissolution testing is possible but technically demanding. ❝ OT: How to get this cool little EU-flag in the "latest posts" overview on the forum? Do you have an EU-IP or how does this work? The IP geolocation (under ![[image]](https://static.bebac.at/img/CC by-sa.png) ) used in the forum is only ~98% accurate. The commercial product (99.8% accurate) would cost more than my entire domain & webspace. No way.As of today 0.44% of posts are located in the ![[image]](https://static.bebac.at/pics/EU-S.png) . Might be false positives. Duno.❝ Not sure about the flag thing (I can't see any flags); There. — 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 |
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The Outlaw Torn ★ Europe, 2018-06-21 14:47 (2281 d 22:00 ago) @ Helmut Posting: # 18941 Views: 32,965 |
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Thank you, Helmut. ❝ If not, dissolution testing is possible but technically demanding. If you can elaborate, it would be great. If not, that's okay too.  I'm still trying to wrap my head around whether there is the need to do dissolution testing in syrups.Also, Appendix III seems to imply that only solid dosage forms are eligible for BCS-based biowaivers. Is that your understanding? Cheers for now. |
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Helmut ★★★ Vienna, Austria, 2018-06-21 15:33 (2281 d 21:15 ago) @ The Outlaw Torn Posting: # 18942 Views: 32,945 |
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Hi Outlaw Torn, ❝ ❝ […] dissolution testing is possible but technically demanding. ❝ If you can elaborate, it would be great. If not, that's okay too. Dissolution is not my cup of tea. Only a few examples dealing with suspensions, e.g., this one: A suspension sample equivalent to a typical dose (5 mL) was taken on a weight basis using a suitable syringe–cannula system, and quantitatively transferred to the dissolution vessel midway between the surface of the dissolution medium and the top of the rotating blade. To calculate the exact weight of suspension added to the vessel, syringe and cannula were weighed at three stages: empty, filled with the suspension, and after the sample was expelled into the dissolution vessel. But in Dissolution Technologies we find:Questions and Answers February 2017 ❝ I'm still trying to wrap my head around whether there is the need to do dissolution testing in syrups. ❝ Also, Appendix III seems to imply that only solid dosage forms are eligible for BCS-based biowaivers. Is that your understanding? After reading it again, yes. This leaves us with nobody’s [msg]answer[/msg] about solutions:
— 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 |
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The Outlaw Torn ★ Europe, 2018-06-21 15:39 (2281 d 21:09 ago) @ Helmut Posting: # 18943 Views: 32,840 |
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That response goes a long way. Things are starting to gel. Thank you, Helmut. |
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The Outlaw Torn ★ Europe, 2018-06-27 17:22 (2275 d 19:25 ago) @ Helmut Posting: # 18980 Views: 32,754 |
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Hello everyone. Hope the weather is better where you are than where I am. One more question if you will (with subquestions, potentially), before we retire this thread. I think its obvious I'm curious about oral solutions and BCS based biowaivers, so no need form me to be sly. So, if anyone has experience with this or wants to comment on my thinking, please do and I will be appreciative. 1. The EU BE guideline says: In those cases where the test product is an oral solution which is intended to be bioequivalent to another immediated release oral dosage form, bioequivalence studies are required. 2. Appendix III on BCS based biowaivers states: The concept is applicable to immediate release, solid pharmaceutical products for oral administration and systemic action having the same pharmaceutical form. Fair enough on point 1 (oral versus solid); standard BE requirement stated without taking into account the BCS classification of the products. Now point 2 seems to indicate exclusivity to solid dosage forms when compared to a product that has the same pharmaceutical form. But we also know from the BE guideline that various immediate-release oral pharmaceutical forms shall be considered to be one and the same pharmaceutical form (except for ODT unless you can rule out buccal absorption, etc). Am I correct in assuming that the guideline seems to imply that a solid dosage form (T) can obtain a BCS-based biowaiver versus an oral solution (R), but somehow an oral solution claiming a BCS-based biowaiver versus a tablet is not covered? Personally, I think I have room to justify trying to submit a BCS-based biowaiver for an oral solution when the only option is a tablet reference product, both from a regulatory viewpoint and a scientific one. Or should I just up my thorazine dose? Of course all this hypothesizing is moot if anyone of you already has experience with this situation. Thanks in advance. |
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Obinoscopy ★ USA, 2018-07-01 04:06 (2272 d 08:42 ago) @ The Outlaw Torn Posting: # 19003 Views: 32,916 |
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❝ Hello everyone. Hope the weather is better where you are than where I am. It's 26°C here with light rain showers. I guess mine is better  .❝ Am I correct in assuming that the guideline seems to imply that a solid dosage form (T) can obtain a BCS-based biowaiver versus an oral solution (R), but somehow an oral solution claiming a BCS-based biowaiver versus a tablet is not covered? Personally I think BCS-based biowaiver is ruled out the moment the dosage form of the test and reference products are different. So whether its a solid dosage form (T) versus an oral solution (R) or vice versa, BCS-based biowaiver is to be ruled out. ❝ Personally, I think I have room to justify trying to submit a BCS-based biowaiver for an oral solution when the only option is a tablet reference product, both from a regulatory viewpoint and a scientific one. From a scientific stand point, I think its better both the test and reference product are in the same dosage form before one can waive an invivo BE study and deduce bioequivalence from dissolution studies. This is because excipients play a very important role in BE. It's possible for a BCS class I tablet (R) that is rapidly dissolving to have a different AUC and Cmax in plasma when compared to an oral solution (T) of same API and vice versa. This is because the different excipients in the two formulations might affect the absorption of the API differently. Its safer to apply BCS-based biowaiver on a product with a same dosage form as the reference product since the absorption of that dosage form has already been "validated". This is my thinking. ❝ Of course all this hypothesizing is moot if anyone of you already has experience with this situation. Thanks in advance. I am also hypothesizing . Also waiting for those with relevant experience on this  .— Scopy |
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The Outlaw Torn ★ Europe, 2018-07-03 17:02 (2269 d 19:45 ago) @ Obinoscopy Posting: # 19011 Views: 32,623 |
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❝ From a scientific stand point, I think its better both the test and reference product are in the same dosage form before one can waive an invivo BE study and deduce bioequivalence from dissolution studies. This is because excipients play a very important role in BE. Thanks, Obinoscopy. I agree this is the optimal case, and makes it easier on everyone, but in our case this is not possible. The assumption I posit is that BCS I (and III) drug products are assume to behave like solutions (to a great extent); the high solubility and rapid dissolution producing a solution in the stomach in short notice...practically like it was a solution to begin with. I think this is why there is a requirement for solid dosage forms to undergo dissolution testing and that it be rapid. So, scientifically, I think I make sense, especially when I'm trying to convince myself. Science and regulations really are strange bedfellows. Maybe Helmet can bring this subject up at the BioBridges conference during the discussion on ICH M9 (hint, hint, nudge, nudge). Thanks again for your input. |
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Helmut ★★★ Vienna, Austria, 2018-07-03 17:33 (2269 d 19:14 ago) @ The Outlaw Torn Posting: # 19012 Views: 32,655 |
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Hi Outlaw Torn, I agree. The original ideas behind BCS-based biowaiver were:
Which conditions have to be applied for #2 depends on the BCS class, excipients, no NTID,  I see no scientific reason why the procedure should not be reversed (test = solution, reference = IR). ❝ Science and regulations really are strange bedfellows. Yep. ❝ Maybe Helmet can bring this subject up at the BioBridges conference during the discussion on ICH M9 (hint, hint, nudge, nudge). Helmut ≠ Helmet (watch ![[image]](https://static.bebac.at/img/youtube.png) this).Henrike Potthast worked on ICH M9. She is always open for discussions. Why don’t you go there and ask her yourself? At trip to Prague is way cheaper than an in vivo study. — 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 |
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The Outlaw Torn ★ Europe, 2018-07-04 13:50 (2268 d 22:58 ago) @ Helmut Posting: # 19018 Views: 32,571 |
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Thank you Lampshade! LMAO at the video...got to watch the movie!Very comforting that you see it this way too. And I found a precedent where the CHMP ruled on this very issue during an arbitration hearing, though the initial application was 10a and shouldn't have been eligible, or needed, to use the BCS biowaiver option. I'd love to go to Prague. Love it the first time I went. I'd noticed that Henrike Potthast would be there and worked on ICH M9, with Jan Welink from the EU side. Might be able to convince someone around here that it's worth attending! Thanks again, Helmut. |
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Helmut ★★★ Vienna, Austria, 2018-07-04 14:03 (2268 d 22:45 ago) @ The Outlaw Torn Posting: # 19019 Views: 32,585 |
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Hi Outlaw Torn. ❝ LMAO at the video...got to watch the movie! You have to! One of my favorites, esp. the Rome scene.❝ I'd love to go to Prague. […] I'd noticed that Henrike Potthast would be there and worked on ICH M9, with Jan Welink from the EU side. We will have another presentation from the industry perspective by Sebastian Härtter (Boehringer). He was one of the two delegates of PhRMA working on the GL. — 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