Susanh
☆    

Iceland,
2020-03-19 18:39
(188 d 21:25 ago)

Posting: # 21287
Views: 2,854
 

 Dissolution and bracketing - EMA [Regulatives / Guidelines]

Hi,

The dissolution at all pHs required for the biowaiver of strengths for submission of generic drugs in EU can be very difficult for drugs with low solubility. I know that the EU guideline allows for some variations were sink conditions are not achieved, e.g. the use same dose comparison (2 x 5 mg vs 10 mg) but this should be confirmed by comparison to the behaviour of the reference product.

I am repeatable running into problems showing similarity between strengths - also when comparing the same dose. And often the reference product does not behave as the test product.

The EU immediate release guideline (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **) allows for bracketing approach - see below.

Can bracketing be used for additional strengths were the dissolution is not similar? Could BE-studies been done on the highest and lowest strength and not on middle strengths in this case?

Bracketing approach
Where bioequivalence assessment at more than two strengths is needed, e.g. because of deviation fromproportional composition, a bracketing approach may be used. In this situation it can be acceptable toconduct two bioequivalence studies, if the strengths selected represent the extremes, e.g. the highestand the lowest strength or the two strengths differing most in composition, so that any differences incomposition in the remaining strengths is covered by the two conducted studies.

looking forward to your comments.
ping4santosh
★    

India,
2020-03-20 11:38
(188 d 04:26 ago)

@ Susanh
Posting: # 21290
Views: 1,703
 

 Dissolution and bracketing - EMA

Hi Susanh,

We do face difficulties with the BCS IV drugs with low solubility.

If the reference product doesn't behave as the test product in Disso profile, you need to reformulate. What are your F values? Do you have separate F values with different strengths? If yes, pl share.

IMO, even if you follow the bracketing approach, you will have to prove the disso data for each strength you plan to register.

Could BE-studies been done on the highest and lowest strength and not on middle strengths in this case?

Yes, In Vivo BE studies can be done on the highest and lowest strengths.

Cheers, SKM
wienui
★    

Germany, Oman,
2020-03-21 17:39
(186 d 22:25 ago)

(edited by wienui on 2020-03-21 18:36)
@ Susanh
Posting: # 21292
Views: 1,648
 

 Dissolution and bracketing

Hi Susanh,

» Can bracketing be used for additional strengths were the dissolution is not similar? Could BE-studies been done on the highest and lowest strength and not on middle strengths in this case?

Bracketing approach (when deviation from biowaiver criteria exist ) for additional strength Biowaivers is allowed according to both EMA and FDA but they differ in the principle for selecting the strengthes for which the 2 BE studies should be performed.

For EMA: Strengths selected must represent the extreme of deviation(s) from biowaiver conditions:-
Proportionality of strengths
Similarity of dissolution
Linearity of pharmacokinetics (under fasted and/or fed administration)

i.e in your case the two strength which differ in Similarity of dissolution and ( proportionality or PK linearity)

For FDA : The 2 BE-studies must be done on the highest and lowest strengthes.

Best regards,

Cheers,
Osama
Susanh
☆    

Iceland,
2020-04-03 11:56
(174 d 05:08 ago)

@ wienui
Posting: # 21314
Views: 964
 

 Dissolution and bracketing

Hi and thanks for your response.
Just to make sure I’m understanding correctly:
  • I have generic IR product for EU submission
  • There are 5 strengths that are dose proportional
  • All the General biowaiver criteria are fulfilled except the f2 similarity is not achieved between the highest strength (used in BE study) and the lower strengths

Do I need to do a BE study on all the strengths that are not showing similarity in dissolution
Or
Can I use bracketing approach and just add one study, either on the lowest strength or the strength differing most in dissolution?
Thanks for your help.
Susan
wienui
★    

Germany, Oman,
2020-04-04 08:42
(173 d 08:22 ago)

(edited by wienui on 2020-04-04 09:25)
@ Susanh
Posting: # 21315
Views: 942
 

 Dissolution and bracketing (EMA)

Hi Susan,

» All the General biowaiver criteria are fulfilled except the f2 similarity is not achieved between the highest strength (used in BE study) and the lower strengths

I see from your post above that you had tried to use same dose comparison (2 x 5 mg vs 10 mg), but it didn't help.

» Do I need to do a BE study on all the strengths that are not showing similarity in dissolution

No you don't need if you intended to use the bracketing approach.

What about the similarity in dissolution between the lower strengths for which BE were not conducted, are They similar or there were dissolution differences?

If there are similar between each others, then as you mentioned just perform one BE study for the strength differing most in dissolution with the highest strength (EMA).

In your place I will try to take EMA scientific advice, but you have to keep in mind that any scientific advice or protocol assistance given is not legally binding with regard to any future marketing authorisation application of the product concerned, either on the Agency/CHMP/COMP, or on the Applicant.

Cheers,
Osama
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