Mauricio Sampaio
★    

Brazil,
2015-09-08 22:38
(3124 d 10:55 ago)

Posting: # 15390
Views: 12,151
 

 Biowaiver for Capecitabine - FDA x EMA [Dissolution / BCS / IVIVC]

Why FDA indicates a possibility to request a Biowaiver for Capecitabine (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm083276.pdf) and EMA assumes that data on solubility does not allow the BCS classification of capecitabine (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/07/WC500189272.pdf) ?

If both agencies are based on BCS classification from Amidon, who is correct? :confused:
Dr_Dan
★★  

Germany,
2015-09-09 11:00
(3123 d 22:32 ago)

@ Mauricio Sampaio
Posting: # 15391
Views: 10,411
 

 Biowaiver for Capecitabine - FDA x EMA

Dear Mauricio
capecitabine is unstable in acidic medium and in the opinion of EMA this does not allow the BCS classification of capecitabine. IMHO this is nonsense or at least no argument against a biowaiver. Stability in acidic media is a substance specific property. The aim of a BE study is to show possible differences in formulation. If both formulation rapidly disintegrate and the API is dissolved within 15 min. what would be the advantage of a BE study? Once dissolved capecitabine from the test formulation would be affected with regard to stability in the same way as capecitabine from the reference formulation, right?
I had the same discussion with a different drug and finally the biowaiver was accepted, but it is a case by case decision. BTW I do not like the EMA product specific bioequivalence recommendations. I think These are not well elaborated.
I hope this helps.
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
Mauricio Sampaio
★    

Brazil,
2015-09-09 20:42
(3123 d 12:51 ago)

@ Dr_Dan
Posting: # 15392
Views: 10,178
 

 Biowaiver for Capecitabine - FDA x EMA

Dear Dan, thank you for your explanation.
I agree partially with your position and in addition, as we know, Capecitabine tablets are to be taken orally 30 min after food intake. I think that the increase of pH range after food intake does not allow the change the stability of capecitabine as described in EMA.

P.S. "Stability in acidic media is a substance specific property" ....as well as the solubility ( correct ?)!
Dr_Dan
★★  

Germany,
2015-09-10 10:52
(3122 d 22:40 ago)

@ Mauricio Sampaio
Posting: # 15393
Views: 10,155
 

 …as well as the solubility

Dear Mauricio
No, solubility depends on the physico-chemical properties of the API and These can be different between the test and the reference formulation.
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
Mauricio Sampaio
★    

Brazil,
2015-09-15 08:56
(3118 d 00:37 ago)

@ Dr_Dan
Posting: # 15396
Views: 9,443
 

 …as well as the solubility

Dear Dan, thank you for clarification! Now I understood your last position about intrinsic property of Capecitabine. You are totally correct!

By the way, if capecitabine is unstable in acidic medium and this unstability is gradative in accordance with the passage of time, I think that is possible to conclude what is the BCS classification from Capecitabine. For example, in 30 minutes almost 30% of capecitabine is degraded. On the other hand, 70% at this moment is not degraded. Therefore, is possible to determinate if the drug (70% of capecitabine is not degraded) has high or low solubility.

Do you have an opinion about my comment? Could you share about that with your experience?

Thank you in advance!
Dr_Dan
★★  

Germany,
2015-09-15 10:53
(3117 d 22:39 ago)

@ Mauricio Sampaio
Posting: # 15398
Views: 9,475
 

 regulatory authorities have a different view

Dear Mauricio
in contrast to stable drugs the curve of the dissolution profile of a capecetabine formulation will not asymptotically approximate the 100% but decline after reaching a maximum which can not be 100%. It is reasonable to assume that everything is all right as Long as you can show similarity of the disso profile of your test formulation with the reference formulation, however, you have no proof. IMHO this is the reason why regulatory authorities have a different view (see this recent post of Helmut). In disso testing you regard two processes, disintegration and dissolution. In case of capecitabine there is a third process, degradation. It could be assumed that this third processes superimposes the first two processes and that therefore differences in formulation can not be detected.
I hope this helps.
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
Mauricio Sampaio
★    

Brazil,
2015-09-17 08:44
(3116 d 00:48 ago)

@ Dr_Dan
Posting: # 15412
Views: 9,305
 

 regulatory authorities have a different view

Well..., According new Draft Guidance published by FDA is very difficult to prove the high solubility of Capecitabine during 24 hours in pH 1. Even though this condition is unreal during administration of this drug (Capecitabine tablets are to be taken orally 30 min after food intake).

Thank you so much for your responses Mr. Dan
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