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Back to the forum  2018-07-21 02:32 CEST (UTC+2h)
Obinoscopy
Junior

Nigeria,
2018-04-20 08:09

Posting: # 18704
Views: 1,542
 

 BCS III Classification [Dissolution / BCS / IVIVC]

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
Helmut
Hero
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Vienna, Austria,
2018-04-20 12:15

@ Obinoscopy
Posting: # 18707
Views: 1,330
 

 BCS-based biowaivers for Class III

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:
  1. high permeability, high solubility
      well absorbed, absorption rate higher than excretion
      BCS-based biowaiver generally possible
  2. high permeability, low solubility
      BA limited by solvation rate; IVIVC possible
  3. low permeability, high solubility
      BA limited by permeation rate
      BCS-biowaiver under certain conditions
  4. low permeability, low solubility
      low and highly variable BA
Whereas Class I drug products which are rapidly dissolving (≥85% dissolved in 30 minutes) may qualify for a biowaiver2 Class III drug products have to be very rapidly dissolving (≥85% dissolved in 15 minutes).
For details see the FDA’s Biowaiver Guidance and Appendix III of the EMA’s BE Guideline.


  1. Amidon GL, Lennernäs H, Shah VP, Crison JR. A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability. Pharm Res. 1995; 12(3): 413–20. doi:10.1023/A:1016212804288, [image] free resource.
  2. Yu LX, Amidon GL, Polli JE, Zhao H, Mehta MU, Conner DP, Shah VP, Lesko LJ, Chen ML, Lee VH, Hussain AS. Biopharmaceutics Classification System: The Scientific Basis for Biowaiver Extensions. Pharm Res. 2002; 19(7): 921-5. doi:10.1023/A:1016473601633, [image] free resource.

Cheers,
Helmut Schütz
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Obinoscopy
Junior

Nigeria,
2018-04-20 16:06

@ Helmut
Posting: # 18710
Views: 1,215
 

 BCS-based biowaivers for Class III

Dear Helmut,

Thanks for this clarification. I was actually leaning towards your explanation. Wanted to validate my thoughts.

Scopy
The Outlaw Torn
Regular

Europe,
2018-06-21 09:48
(edited by The Outlaw Torn on 2018-06-21 10:13)

@ Helmut
Posting: # 18937
Views: 703
 

 BCS-based biowaivers for Class III

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.
nobody
Senior

2018-06-21 10:33

@ The Outlaw Torn
Posting: # 18938
Views: 688
 

 BCS-based biowaivers for Class III

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
The Outlaw Torn
Regular

Europe,
2018-06-21 12:11

@ nobody
Posting: # 18939
Views: 675
 

 BCS-based biowaivers for Class III

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.
Helmut
Hero
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Vienna, Austria,
2018-06-21 12:21

@ nobody
Posting: # 18940
Views: 674
 

 BCS-based biowaivers for Class III: Syrups

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]) 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]. Might be false positives. Duno.


» Not sure about the flag thing (I can't see any flags);

There.

Cheers,
Helmut Schütz
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The Outlaw Torn
Regular

Europe,
2018-06-21 12:47

@ Helmut
Posting: # 18941
Views: 666
 

 BCS-based biowaivers for Class III: Syrups

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. :-D 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.
Helmut
Hero
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Homepage
Vienna, Austria,
2018-06-21 13:33

@ The Outlaw Torn
Posting: # 18942
Views: 655
 

 BE of solutions

Hi Outlaw Torn,

» » […] dissolution testing is possible but technically demanding.
» If you can elaborate, it would be great. If not, that's okay too. :-D

Dissolution is not my pot 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
Q How is the sample prepared, and how it is it added to the dissolution equipment for dissolution testing of a dry syrup for oral suspension?
A […] If a product, powder or granule, when reconstituted as directed in the instructions to the patient, results in a solution, no dissolution test is required.

(my emphasis)

» 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 answer about solutions:
  • No critical excipients ⇒ in vivo study may (!) be waived (note the elastic clause).
  • Critical excipients ⇒ in vivo study, unless the differences in the amounts of these excipients can be adequately justified by reference to other data.
No idea what “other data” are. When it comes to similarity of excipients see the GL’s Appendix III, Section IV.2.

Cheers,
Helmut Schütz
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The Outlaw Torn
Regular

Europe,
2018-06-21 13:39

@ Helmut
Posting: # 18943
Views: 652
 

 BE of solutions

That response goes a long way. Things are starting to gel. Thank you, Helmut.
The Outlaw Torn
Regular

Europe,
2018-06-27 15:22

@ Helmut
Posting: # 18980
Views: 509
 

 BE of solutions

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.
Obinoscopy
Junior

Nigeria,
2018-07-01 02:06

@ The Outlaw Torn
Posting: # 19003
Views: 436
 

 Solutions (T) vs Tablets (R) or Vice Versa= Invivo BE Study

» 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 :-D. Also waiting for those with relevant experience on this :-).

Scopy
The Outlaw Torn
Regular

Europe,
2018-07-03 15:02

@ Obinoscopy
Posting: # 19011
Views: 363
 

 Solutions (T) vs Tablets (R) or Vice Versa= Invivo BE Study

» 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. :-D

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.
Helmut
Hero
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Homepage
Vienna, Austria,
2018-07-03 15:33

@ The Outlaw Torn
Posting: # 19012
Views: 360
 

 Reversed procedure?

Hi Outlaw Torn,

I agree. The original ideas behind BCS-based biowaiver were:
  1. BE-studies of solutions are not required.
  2. If an oral formulation behaves like a solution, BE-studies could be waived.
#1 was applied for ages. Only recently certain conditions about excipients were added.
Which conditions have to be applied for #2 depends on the BCS class, excipients, no NTID, :blahblah:

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 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. ;-)

Cheers,
Helmut Schütz
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The Outlaw Torn
Regular

Europe,
2018-07-04 11:50

@ Helmut
Posting: # 19018
Views: 345
 

 Reversed procedure?

Thank you Lampshade! :-D 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.
Helmut
Hero
avatar
Homepage
Vienna, Austria,
2018-07-04 12:03

@ The Outlaw Torn
Posting: # 19019
Views: 345
 

 BioBridges

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.

Cheers,
Helmut Schütz
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