wien-ui
☆    

Oman,
2014-04-17 16:27
(3632 d 18:45 ago)

(edited by wien-ui on 2014-04-17 17:33)
Posting: # 12849
Views: 2,523
 

 Reference for Biowaiver [Regulatives / Guidelines]

Hi all,

suppose that we have a drug X (test drug) with three different strengths 250 mg,500 mg and 1000 mg. Applied for approval is only the BE study for the high strength 1000 mg against the originator Y 1000 mg as a reference drug, for the two other lower strengths 250 mg and 500 mg a biowaiver applications were submitted. my questions are:
- should we consider the originator Y 1000 mg as a reference drug for the biowaiver application for the 250,500 mg lower strengths?
- or should we consider the test drug X 1000 mg after his BE approval as a reference drug for the biowaiver application for the 250,500 mg lower strengths?
Can someone enlighten me? Please mention to evidences from guidelines.
Thanks in advance.
Dr_Dan
★★  

Germany,
2014-04-17 19:58
(3632 d 15:14 ago)

@ wien-ui
Posting: # 12852
Views: 2,193
 

 Reference for Biowaiver

Dear wien-ui
According to CPMP/EWP/QWP/1401/98 Rev. 1/ Corr ** the results of in vitro dissolution tests at three different buffers (normally pH 1.2, 4.5 and 6.8) and the media intended for drug product release (QC media), obtained with the batches of test and reference products that were used in the bioequivalence study should be reported. Appropriate in vitro dissolution should confirm the adequacy of waiving additional in vivo bioequivalence testing. Accordingly, dissolution should be investigated at different pH values as outlined in the previous section (normally pH 1.2, 4.5 and 6.8) unless otherwise justified. Similarity of in vitro dissolution should be demonstrated at all conditions within the applied product series, i.e. between additional strengths and the strength (i.e. batch) used for bioequivalence testing.
I hope this helps.
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
wien-ui
☆    

Oman,
2014-04-17 21:08
(3632 d 14:04 ago)

@ Dr_Dan
Posting: # 12854
Views: 2,194
 

 Reference for Biowaiver

Dear Dr_Dan, Thanks for reply.

I understand what you mean. The matter is that we have here an academic discussion ( Who should be the reference drug in the Biowaiver dissolution tests? is that the originator or the approved via BE Test drug?

'obtained with the batches of test and reference products that were used in the bioequivalence study should be reported'.

i.e the reference drug for the two lower strengths biowaiver in my example should be the originator Y 1000 mg, is that correct?
IMHO, the reference should be the originator as the whole BE Study based on a comparison with it, and statistically any variability and deviations in the BE will be greater when we consider the reference is the approved via BE Test drug. I could be wrong, but
Dr_Dan
★★  

Germany,
2014-04-18 13:32
(3631 d 21:40 ago)

@ wien-ui
Posting: # 12855
Views: 2,165
 

 Reference for Biowaiver

Dear wien-ui

❝ i.e the reference drug for the two lower strengths biowaiver in my example should be the originator Y 1000 mg, is that correct?


No. If bioequivalence between the test formulation "x 1000mg" and the reference "y 1000 mg" was demonstrated then dissolution profiles of the additional strengths "x 250mg" and "x 500mg" need to be similar to the test formulation strength "x 1000mg" used for the BE study. According to the guideline:"Similarity of in vitro dissolution should be demonstrated at all conditions within the applied product series, i.e. between additional strengths and the strength used for bioequivalence."
testing.

Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2014-04-18 14:16
(3631 d 20:56 ago)

@ Dr_Dan
Posting: # 12856
Views: 2,162
 

 linear PK!

Hi Dan & wien-ui,

I agree with Dan – if linear PK is proven. We once had a case where – although linear PK was claimed for the reference – the German BfArM wanted an in vivo dose proportionality study of the different strengths of the test.

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
wien-ui
☆    

Oman,
2014-04-18 15:17
(3631 d 19:55 ago)

@ Dr_Dan
Posting: # 12857
Views: 2,189
 

 Reference for Biowaiver

Hi Dan & Helmut,

But the variability could be very high, especially in the case of HVD&HVDP and especially when we widen the acceptance range (EMA) in the BE study. I'm with you that similarly in dissolution tests should be demonstrated for all strengths for the generic drug but most important is that the biowaivers strengths should to demonstrate similarity with the originator also.
Best regards,
Osama
UA Flag
Activity
 Admin contact
22,957 posts in 4,819 threads, 1,640 registered users;
81 visitors (0 registered, 81 guests [including 5 identified bots]).
Forum time: 10:12 CET (Europe/Vienna)

Nothing shows a lack of mathematical education more
than an overly precise calculation.    Carl Friedrich Gauß

The Bioequivalence and Bioavailability Forum is hosted by
BEBAC Ing. Helmut Schütz
HTML5